plos.txt

The ability of organs to maintain homeostasis and regenerate following injury is vital to an organism . Many supportive cells including lung-resident ( LR ) mesenchymal stem and stromal cells ( MSCs ) are key elements of the alveolar niche and fundamental regulators of homeostatic and regeneration . We investigated their function during virus-induced lung injury using the highly prevalent respiratory syncytial virus ( RSV ) which causes severe outcomes in infants . In this study , we applied complementary approaches with primary pediatric LR-MSCs and a state-of-the-art model of human RSV infection in lamb . Remarkably , RSV-infection of pediatric lr-MSCCs led to a robust activation , characterized by a strong antiviral and pro-inflammatory phenotype combined with mediators related to T cell function . Following in vivo infection , the RSV invades and activates LR–MSC , leading to the expansion of the pulmonary MSC pool . Moreover , global transcriptional response of LR—MSC-MS CNS appears to follow RSV disease , switching from an early antivirals signature to repair mechanisms including differentiation , tissue remodeling , and angiogenesis . These findings demonstrate the involvement of RR-MS
Visceral leishmaniasis ( VL ) is endemic in South Sudan , where outbreaks occur frequently . Because of changes in the immune system during pregnancy , pregnant women are considered particularly vulnerable for developing complications of VL disease , including opportunistic infections . There is limited evidence available about clinical aspects and treatment outcomes of V L in pregnancy . We describe characteristics , maternal and pregnancy outcomes from a cohort of pregnant women with VL in pregnancy using routine programme data from 10 , 000 women with a VL diagnosis , and 223 non-pregnant women of reproductive age ( 15–45 years ) with VLV from the same period . Women with V L during pregnancy presented with more severe anaemia , were more likely to need blood transfusion and were more often prescribed antibiotics , as compared to non-Pregnants with VLM . Adverse pregnancy outcomes , such as miscarriage and premature delivery , was reported in 20% ( 16/81 ) where VL was diagnosed in pregnancy and 50% ( 13/26 ) when VL were diagnosed postpartum . Postpartum haemorrhage was common . Pregnante women were more susceptible to require extension of treatment to achieve cure ( OR 10 . 0; 95%CI 4 . 8–20 .
Salmonella enterica serovar Typhi ( S . Typhi ) is a bacterium that causes typhoid fever in sub-Saharan Africa . The bacteremia is characterized by a high burden of circulating strains , but little is known about the introduction of these strains to the region . In this study , we characterized 310 isolates from t . fever surveillance conducted over a 12-year period ( 2007–2019 ) in Kibera , an urban informal settlement in Nairobi , Kenya , to assess the circulating isolates and their antimicrobial resistance attributes , and how they relate to global S , Typhi isolates . Whole genome multi-locus sequence typing ( wgMLST ) identified 4 clades , with up to 303 pairwise allelic differences . Determinants associated with resistance to aminoglycosides were observed in 245 isolates ( 79 . 0% ) , sulphonamide in 243 isolates with a median of 14 allele differences ( range 0–52 ) and consisted entirely of genotypes 4 . 3 . 1 . 1- and 4 , 3 , 1 , 2 . 2 , respectively . Resistance determinants were identified exclusively in the predominant clade
Severe Acute Respiratory Syndrome Coronavirus-2 ( SARS-CoV-2 ) is the third novel -coronavirus to cause significant human mortality in the last two decades . Although vaccines are available , too few have been administered worldwide to keep the virus in check and to prevent mutations leading to immune escape . To determine if antibodies could be identified with universal coronaviral activity , plasma from convalescent subjects was screened for IgG against a stabilized pre-fusion SARS–CoV spike S2 domain , which is highly conserved between human  coronoviruses . From these subjects , several S2-specific human monoclonal antibodies ( hmAbs ) were developed that neutralized SARS-2 with recognition of all variants of concern ( VoC ) tested ( Beta , Gamma , Delta , Epsilon , and Omicron ) . 1249A8 emerged as the most potent and broad hmmAb , able to recognize all human , SARS and MERS-CoVID . As little as 2 mg/kg of 1249 A8 i . n . dose 12 hours following infection with SARS-1 strain Urbani protected hamsters from weight loss , with therapeutic activity further enhanced when combined with 12
The yeast Candida parapsilosis utilizes hydroxyderivatives of benzene and benzoic acid as carbon sources . The yeast uses these compounds via the 3-oxoadipate and gentisate pathways , whose components are encoded by two metabolic gene clusters . In this study , we determine the chromosome level assembly of the C . parapsililosis strain CLIB214 and use it for transcriptomic and proteomic investigation of cells grown on hydroxyaromatic substrates , which are metabolized via the 3oxadipates and genital hydroxybenzoates . We demonstrate that the genes coding for enzymes and plasma membrane transporters involved in the 3-OxoAdipate pathway are highly upregulated and their expression is controlled in a substrate-specific manner . However , regulatory proteins involved in this process are not known . Using the knockout mutants we show that putative transcriptional factors encoded in the genes OTF1 and GTF1 function as transcriptional activators of the 3-OHBAT pathway , respectively , and that the activation of both pathways is accompanied by upregulation of genes for the enzymes involved in glyoxylate cycle , amino acid metabolism , peroxisome biogenesis . Transcriptome and proteome profiles of the
The brain is a complex machine that is able to perform many tasks at once . It is therefore important to understand how the brain works to bridge the gap between neural and cognitive processes . We develop a method called “oracle-supervised Neural Engineering Framework” ( osNEF ) to train biologically-detailed spiking neural networks that realize a variety of cognitively-relevant dynamical systems . Specifically , we train networks to perform computations that are commonly found in cognitive systems ( communication , multiplication , harmonic oscillation , and gated working memory ) using four distinct neuron models ( leaky-integrate-and-fire neurons , Izhikevich neurons ) connected with various synaptic models ( current-based synapses , conductance-based Synaps , or voltage-gated synapes ) . Our results demonstrate that oSNEF can train functional brain models using biologically detailed components and open new avenues for investigating the relationship between biophysical mechanisms and functional capabilities . This work provides a framework for integrating biological details into functional brain modeling , allowing for the development of computational models that can be applied to a wide range of cognitive tasks .
Down syndrome ( DS ) is the most common genetic form of intellectual disability caused by the complete or partial trisomy of human chromosome 21 ( HSA21 ) . The trisomic process does not simply result in the upregulation of HSA-21-encoded genes but also leads to a genome-wide transcriptomic deregulation , which affect differently each tissue and cell type as a result of epigenetic mechanisms and protein-protein interactions . We performed a meta-analysis integrating the differential expression ( DE ) analyses of all publicly available transcriptomographic datasets , both in human and mouse , comparing trisomic and euploid transcriptomes from different sources . Our results show that genome wide deregulation as compared to other genes is not arbitrary , but involves deregulation of specific molecular cascades in which both H SA21 genes and HSA121 interactors are more consistently deregulated compared with other genes . In fact , gene deregulation happens in “clusters” , so that groups from 2 to 13 genes are found consistently deregulation in DS network . Most of these events of “co-deregulation” involve genes belonging to the same GO category , and genes associated with the same disease class .
Neuronal oscillations are two main types of neuronal activity obtained with diverse electrophysiological recordings ( EEG/MEG/iEEG/LFP ) . Although typically studied separately , they might in fact be closely related . One possibility to unite them is to demonstrate that neuronals have non-zero mean which predicts that stimulus- or task-triggered amplitude modulation of oscillation can contribute to the generation of evoked responses . We validated this mechanism using computational modelling and analysis of a large EEG data set . With a biophysical model , we indeed demonstrated that intracellular currents in the neuron are asymmetric and , consequently , the mean of alpha oscillation is non- zero . To understand the effect that neuroanatomical currents exert on oscillatory mean , a variety of biophysical and morphological properties of neurons in the network , such as voltage-gated channel densities , length of dendrites , and intensity of incoming stimuli , were varied . Complimentary , our simulations with simple oscillators coupled with different time delays revealed at least one spatially-filtred component of non-0 mean alpha rhythm modulation in 93% of participants . In order to explain a complex relationship between the dynamics of amplival-
Crimean-Congo hemorrhagic fever virus ( CCHFV ) is a tick-borne virus that can cause a hemorragic fever in humans , with a case fatality rate of up to 40% . Cases of CCLFV have been reported in Africa , Asia , and southern Europe; and recently , due to the expanding range of its vector , autochthonous cases have been recorded in Spain . Although it was discovered over 70 years ago , our understanding of the pathogenesis of this virus remains limited . We used RNA-Seq in two human liver cell lines ( HepG2 and Huh7 ) infected with CCRFV ( strain IbAr10200 ) to examine kinetic changes in host expression and viral replication simultaneously at 1 and 3 days post infection . Through this , numerous host pathways were identified that were modulated by the virus including: antiviral response and endothelial cell leakage . Notably , the genes encoding DDX60 , a cytosolic component of the RIG-I signalling pathway and OAS2 were both shown to be dysregulated . Interestingly , PTPRR was induced in Hh7 cells but not Hep G2 cells . This has been associated with the TLR9
Schizophrenia is a severe mental disorder accompanied by a range of dysfunctions in perceptual and cognitive behavior , among which working memory deficits are considered as one of the core behavioral markers . A well-established finding in lab-based experiments is that people with schizophrenia ( SZ ) exhibit working memory impairments , and almost all existing studies attributed the deficits to decreased capacity as compared to healthy control subjects . Recent developments in WM research suggest that other components , such as precision , also mediate behavioral performance . It remains unclear how different WM components jointly contribute to deficits in schizophrenia . We measured the performance of 60 SZ ( 31 females ) and 61 HC ( 29 females; 30% ) in a classical delay-estimation visual working memory task and evaluated several influential computational models proposed in basic science of VWM to disentangle the effect of various memory components . According to the VP model , SZ showed abnormally larger variability of allocating memory resources rather than resources or capacity per se . Finally , individual differences in the resource allocation variability predicted variation of symptom severity in SZ and highlighting its functional relevance to schizophrenic pathology . Our findings provide an alternative view instead of the widely accepted decreased-capacity theory and highlight the key role of elevated resource allocation variation in generating
The HIV-1 envelope glycoprotein ( Env ) mediates viral entry via conformational changes associated with binding the cell surface receptor ( CD4 ) and coreceptor ( CCR5/CXCR4 , ) , and subsequent fusion of the viral and cellular membranes . While the gp120 Env surface subunit has been extensively studied for its role in viral entry and evasion of the host immune response , the cellular transmembrane glycoprotein and its function in natural infection are less well characterized . In this study , we identified a primary HIV-1 Env variant that consistently supports >300% increased viral infectivity in the presence of autologous or heterologous HIV-positive plasma . However , in the absence of HIV-negative plasma , viruses with this Env displayed reduced infection that was not due to decreased CD4 binding . We mapped this phenotype to a change Q563R , located at the heptad repeat 1 ( HR1 ) region . Our study reveals that Q 563R reduces viral infection by disrupting the formation of the six-helix bundle required for virus-cell membrane fusion . Importantly , antibodies that bind cluster I epitopes on gpp41 overcome this inhibitory effect and restore viral infection to wild-type levels 
Cancer is a complex disease that affects millions of people worldwide . The majority of cancers are caused by mutations in genes , which can cause cancer . However , many of these mutations are not related to the cancer itself . Therefore , it is important to develop methods for the identification of cancer consensus molecular subtypes . Several methods have been developed for omics data–based subtyping , but discrepant results compromise the translational and clinical utility of these methods . Here , we report on the development of the COnsensus Molecular SUbtype of Cancer ( COMSUC ) web server . With COMSC , users can explore consensus molescular subtyps of more than 30 cancers based on eight clustering methods , five types of omics datasets from public reference datasets or users’ private data , and three consensus clustering method . This web server provides interactive and modifiable visualization . Researchers can also exchange consensus subtype results with collaborators via project IDs , allowing researchers to share consensus subtyp results with colleagues . In addition , researchers can exchange consensus results with collaborative partners via projectIDs if they need them .
Ticks are a highly diverse and ecologically important group of ectoparasitic blood-feeding organisms . One such species , the seabird tick ( Ixodes uriae ) , is widely distributed around the circumpolar regions of the northern and southern hemispheres , and has remained isolated in these regions ever since . It has been suggested that Ix . uriane spread from the southern to the northern circumpolar region millions of years ago and has been isolated in those regions eversince . Such a profound biographic subdivision provides a unique opportunity to determine whether viruses associated with ticks exhibit the same evolutionary patterns as their hosts . To test this , we collected Ix. urane specimens near a Gentoo penguin colony at Neko harbour , Antarctica , as well as from migratory birds—the Razorbill ( Alca torda ) and the Common murre ( Uria aalge ) on Bonden island , northern Sweden . Through meta-transcriptomic next-generation sequencing we identified 16 RNA viruses , seven of which were novel . Notably , our results indicate that there have been at least two cross-circumpolar dispersal events . In marked contrast , my phylogenetic analysis revealed
Meiosis is a fundamental cellular process in eukaryotes , through which sexually reproducing organisms generate their gametes via two successive rounds of meioses . Meiotic recombination is an essential biological process that ensures faithful chromosome segregation and promotes parental allele shuffling . Tetrad analysis is based on a generalized computational framework that automates the full workflow of marker identification , gamete genotyping , and tetrad-based recomination profiling based upon any organism or genetic background with batch processing capability . RecombineX also includes a dedicated module for simulation-based hypothesis testing , which enables fine-tuned simulating . Interestingly , our re-analysis of the budding yeast genomes with RecombbineX and Oxford Nanopore sequencing revealed two unusual structural rearrangement events that were not noticed before , exemplifying the occasional genome instability triggered by meiotic production . Our work demonstrates the power and robustness of RecombineX even when analyzing titers with very low sequencing depths ( 1-2X ) .
The APOBEC3 ( A3 ) genes encode cytidine deaminase proteins with potent antiviral and anti-retroelement activity . The most potent of the A3 proteins against HIV-1 is A3G . However , it is not clear if double deamination domain A3s have a generalized functional advantage to restrict HIV-1 . In order to test whether superior restriction factors could be created by genetically linking single A3 domains into synthetic double domains , we linked A3C and A3H single domains in novel combinations . We found that A3A/A3H double domain A1 domains acquired enhanced antivirals that are at least as potent , if not better than , A3B . Although these synthetic doubledomain A3 A3 subunits package into budding virions more efficiently than their respective single domain A2 domains ( i . e . A3D/A2F ) , this does not fully explain their gain of antivirAL potency . This antivirally active protein is conferred both by a cytokine dependent and independent mechanism , with the latter correlating to an increase in RNA binding affinity . T cell lines expressing this A3 C-A2H super restriction factor are able to control replica
Cancer is a disease characterized by unrelenting tissue growth and clonal evolution . During evolution , genetic and epigenetic aberrations provide the reservoir for dysfunctional cellular phenotypes that maintain a tumour’s replicative advantage , while , over time , fluctuating physiological and ecological properties within the tumour microenvironment drive the need for updated adaptations that sustain immortality . In this study , we present a synthetic supervised learning method , TumE , that integrates simulated models of cancer evolution with Bayesian neural networks , to infer ongoing selection in bulk-sequenced single tumour biopsies . Analyses in synthetic and patient tumours show that TumEx significantly improves both accuracy and inference time per sample when detecting positive selection , deconvolutionating selected subclone populations , and estimating subclones frequency . Importantly , transfer learning can leverage stored knowledge within Tum E models for related evolutionary inference tasks—substantially reducing data and computational time for further model development and providing a library of recyclable deep learning models for the cancer evolution community . This extensible framework provides a foundation and future directions for harnessing progressive computational methods for the benefit of cancer genomics and , in turn , the cancer patient .
African trypanosomes are parasites mainly transmitted by tsetse flies . They cause trypanomiasis in humans ( HAT ) and animals ( AAT , i . e . AAT/HAT . In Chad , HAT/AAT are endemic . This study investigated the diversity and distribution of trypanomerase in Mandoul , an isolated area where a tSETSe control campaign is ongoing , and Maro , which borders the Central African Republic ( CAR ) where the control had not started . 717 human and 540 cattle blood samples were collected , with 177 tseese species caught . Trypanosomal DNA was detected in 14 human samples , 227 cattle samples . T . godfreyi and T , grayi were detected in cattle and tissese samples from Maro; T -129-H was found in a human with a history of cured HAT infection and persisting symptoms . Furthermore , in cattle , evidence for additional unknown trypanons was obtained in tzese and in cattle samples from the mandoul area . Genetic diversity was most prominent in T – simiae , T– vivax and T– theiler
Hybridization is a fascinating evolutionary phenomenon that raises the question of how species maintain their integrity . In particular hybrids between Schistosoma haematobium and S . bovis associated with humans and animals respectively are frequently identified in Africa . Recent genomic evidence indicates that some S , hae mating with S ; bovis hybrids are frequently found in Africa and that some hybrids show signatures of genomic introgression from S - bovis . Here , we conducted a genomic comparative study and investigated the genomic relationships between S – haeMATobium , S — bovis and their hybrids using 19 isolates originating from a wide geographical range over Africa , including samples initially classified as S  haematium ( n = 11 ) ,   bovis (  6 ) and  2 hybrids . Based on a whole genomic sequencing approach , 56 , 181 SNPs allowed a clear differentiation of S ’ haematopoiesis’ isolates from an entire genomic cluster including all isolates and a natural X-seq hybrid . We found that all the isolates harbored signatures , except the isolate from Madagascar , of genome introgression . Isolates from Corsica , Mali and Egypt harbor the S 
The human immunodeficiency virus ( HIV ) is a major cause of morbidity and mortality worldwide . While there is currently no effective vaccine for HIV , one that elicits a response in the IgA class might be a strong candidate given the high concentration of Ig A in mucosal tissues , a primary site for HIV transmission . We combined Positron Emission Tomography ( PET ) imaging and fluorescent microscopy of 64Cu-labeled , photoactivatable-GFP HIV with fluorescently labeled dIgA . Our results show that HIV virions rapidly disseminate throughout the colon two hours after exposure . The presence of dIIIgA resulted in an increase in viral penetration depth in the transverse colon , and a decrease in the penetration depth of the mesenteric lymph nodes . Taken together , these technologies enable in vivo and in situ visualization of antibody-virus interactions and detailed investigations of early events in HIV infection . In this study , we demonstrate that dIVgA antibodies are a promising candidate for a potential HIV vaccine . This study provides new insights into the early stages of HIV infection and provides a basis for the development of novel vaccines .
The transfer function between biological processes is a fundamental problem in signal analysis . It is often difficult to understand the relationship between complex and intermingled biological signals , particularly when the drivers of the signals are unknown . Here we present Iliski , a software dedicated to TFs computation between two signals . Iliki includes different pre-treatment routines and TF computation processes: deconvolution , non-deterministic and non-terministic optimization algorithms that are adapted to disparate datasets . We apply Ilisky to data on neurovascular coupling , an ensemble of cellular mechanisms that link neuronal activity to local changes of blood flow , and highlight the software benefits and caveats in the computation and evaluation of TF . Our software is available under the open-source license CC BY 4 . 0 on GitHub , or as a standalone application . In addition , we propose a workflow that will help users to choose the best computation according to the dataset . The software can be used on the most common operating systems , either within the MATLAB environment , for a single application or in a large-scale computational framework , which can be applied to a wide range of signal analysis tasks .
Congenital Zika Syndrome ( CZS ) is a mosquito-borne virus transmitted by Aedes mosquitoes . An infant can then experience problems feeding due to the specific physical and developmental consequences of CZ S . The authors’ findings were extracted , synthesised using thematic synthesis techniques , and confidence in the findings was assessed using GRADE-CERQual . Six ( all from Brazil ) were included in the direct evidence , with a further eight indirect studies reporting feeding difficulties in infants with severe disability and nonprogressive , chronic encephalopathies ( ‘indirect evidence’ ) , which present with similar problems . Included studies highlighted: breast-feeding represented the preference for all mothers in the studies in both reviews; the inability to do so affected bonding between parents and child , generated fear and anxiety relating to feeding choices , especially around the risks of choking and swallowing; the perception that health professionals were often unable to offer appropriate advice; the potential value of training; and a strong desire to achieve individual maternal autonomy in infant feeding decisions . Confidence in most findings ranged from low to moderate . This evidence base has limitations , but consistently reported that parents of children with feeding difficulties , or similar , need information , advice and counselling and substantial emotional support . Parents perceive that these needs are
The ability of recombinant protein immunogens to elicit neutralizing antibody titers against viral and microbial targets is a major goal of immunization strategies . Here , we describe detailed antigenic , structural , and functional characterization of computationally designed tetrahedral , octaheme , or icosahemme nanoparticles displaying trimeric HIV envelope glycoprotein ( Env ) ectodomains . The Env trimers , engineered with SOSIP stabilizing mutations , were fused to an underlying trimeric building block of each nanopher . Initial screening yielded one icoparticle and two nanoparticul candidates , capable of presenting twenty or four copies of the Env Trimer . A number of analyses , including detailed structural characterization by cryo-EM , demonstrated that the Nanoparticle Immungens possessed the intended structural and antigenic properties . When the immunogenicity of ConM-SOSIP trimers presented on a two-component tether immunogen or as soluble proteins were compared in animals , the two immunogen showed similar serum antibody binding  TITERS against the trimer component . Neutralizing antibodies were slightly elevated in the animals given the NanoParticle immunogen 
Pseudorabies virus ( PRV ) is a human pathogen that causes a severe disease in humans . The virus has evolved various immune evasion mechanisms that target host antiviral immune responses . However , it is unclear whether and how PRV encoded proteins modulate the cGAS-STING axis for immune vacillation . Here , we show that the tegument protein UL13 inhibits STING-mediated antivirals signaling via regulation of STING stability . Mechanistically , UL-13 interacts with the CDN domain of Sting and recruits the E3 ligase RING-finger protein 5 ( RNF5 ) to promote K27-/K29-linked ubiquitination and degradation of STED . Consequently , deficiency of RNF-5 enhances host antivirusal immune response triggered by PRV infection . In addition , mutant PRV lacking UL 13 impaired in antagonism of STER-mediated production of type I IFNs and shows attenuated pathogenicity in mice . Our findings suggest that PRV proteins function as an antagonist of IFN signaling through a novel mechanism by targeting STING to persistently evade host antivial responses , which is critical for the development of
Arthropod-borne viruses ( arboviruses ) are transmitted by arthropod vectors among vertebrate hosts . Arthrophobic viruses are characterized by a wide range of temperature fluctuations , with optimal conditions occurring at some intermediate temperature . In addition , the mean and range of daily temperature fluctuations influence arboviral persistence and vector competence unimodally . We found that constant extrinsic incubation temperatures peaking between 28°C and 32°C for both Aedes species . Transmission peaked at 10 days post-infection for Aededes aegypti , and 14 days for Aeropus albopictus . Conversely , fluctuating temperature decreased vector competence . Using RNA-seq to characterize ZIKV population structure , we identified that temperature alters the selective environment in unexpected ways . Constant temperatures more often elicited positive selection whereas fluctuating temperatures led to strong purifying selection in both Aeriates . These findings demonstrate that temperature has multiple impacts on arbivirus biology , including major effects on the selective environment within mosquitoes such as the ability of arbotic viruses to persist in the host .
Odorants are a wide range of environmental conditions , such as the presence of food , a mate , or a predator . Thus , the nervous system processes the sensory information to generate a coherent behavioral response . However , how the nervous systems process signals of two odorants present simultaneously to generate an olfactory response is poorly understood . Here , we characterize circuit basis for a form of ollfactory integration in Caenorhabditis elegans . We find that the presence and absence of a repulsive odorant , 2-nonanone , strongly blocks the attraction of other odorans , including isoamyl alcohol ( IAA ) or benzaldehyde , that signal food . Using a forward genetic screen , our results identify genes that regulate the structure and function of sensory neurons , OSM-5 and osm-1 , and show that loss of these genes mildly reduces the response to the repellent 2-nontanone and disrupts the integration effect . Restoring the function of OSM-1 in either AWB or ASH , two sensory neurons known to mediate 2-nonalone-evoked avoidance , is sufficient to rescue . Sensory neurons AW B and downstream interneurons AVA
Schistosomiasis is a parasitic disease caused by the worm Schistsoma mansoni . The disease is caused by a bacterium that is transmitted to humans by the bite of a bite of an infected worm . Infection with the schistosome can lead to death , which can be fatal if left untreated . Vaccines against this disease are needed . Extracellular vesicles ( EVs ) are protein-loaded nano-scaled particles that are released by eukaryotes and prokaryotic organisms . Parasite’s EV proteins manipulate the immune system , making them probable next-generation vaccines , especially in the field of schizosomiases . Here , we investigated the immune-protective role of S . mensoni egg-derived EV in mice . We found significant reduction of tegumentally deranged adult worms and hepatic and intestinal egg counts by 46 . 58% , 93 . 14% and 93. 17% respectively , as well as remarkable amelioration of sizes , numbers and histopathology of liver granulomata mediated by high interferon gamma ( IFN  ) and antibody level . These results
Mycetoma is a progressive , chronic , inflammatory disease , mostly caused by fungi . There is , however , an urgent need to identify the true burden of mycetomas in Uganda . The current study was conducted to estimate the burden of the disease in Uganda by a systematic PubMed search . A retrospective review of all the biopsy reports at the Pathology Reference Laboratory , Department of Pathology , Makerere University , Kampala , Uganda from January 1950 to September 2019 was conducted . During the 70-years study period , 30 cases were identified by the literature review , with 249 additional cases identified by review of biopsy reports ( total of 279 cases ) . In Uganda , the average incidence was estimated at 0 . 32/100 , 000 persons , and prevalence of 8 .32/100 ‘000 persons per decade . However , there was a general decline in the number of cases detected recently . Fungi were the most common causative agents ( 89% ) followed by Nocardia species ( 5% ) and Actinomycetes ( 4% ) with a very large differential diagnosis . More systematic studies are warranted to define the true magnitude of the burden .
Malaria is one of the most prevalent vector-borne diseases around the world . The aim of Malaysia to eliminate malaria nationwide by 2020 seems need to be prolonged . Whilst Malaysia has successfully eliminated human malaria transmission , simian malaria parasites such as Plasmodium knowlesi , P . cynomolgi  ,P . inui and P , C . fieldi are the emerging cause of malaria in humans . This study was performed to gather all available data in terms of siman malaria epidemiology study among macaques in Malaysia over the last two decades . Most studies were conducted in Peninsular Malaysia ( 5/7; 71% ) followed by East Malaysia ( 2/7; 29% ) . All studies showed positive detection of Plasmidium parasite in macaque . In Malaysia , the most predominant Plasmodium species in macaucus was P  inuis ( 49 . 27% ) and the least prevalent was P fieldi ( 4 . 76% ) in East Malaysia . There is a high occurrence of malaria from Macaques to humans , and the study of host epidemiology is an important insight to public health management .
Epstein-Barr virus ( EBV ) is the first human tumor virus to be discovered . It is a herpesvirus that has a typical life cycle: latency and lytic replication . The EBV episome DNA is maintained during latency by a key antigen , EBNA1 , which is expressed in all EBV-associated tumors during lategenesis . However , the mechanism utilized by EBV to maintain latent infection at the levels of posttranslational regulation remains largely unclear . Here , we report that EBNASIM motif ( SIM2 and SIM3 ) plays an essential role in EBV latency . Deletion of the SIM3 motif leads to functional loss of both BERNA1-mediated viral episome maintenance and the regulation of viral gene transcription . Importantly , hypoxic stress induces the SUMO2-modified STUB1 and KAP1 to increase the UBNA1 modification of both STUB1/KAP1 and USP7 for reactivation of lytic infection . Therefore , our study provides new insights into how EBV maintains latent EBV infection and may be a potential therapeutic target against EBV associated cancers .
The genetic basis of wheat flower development is largely unknown . In this study , we show that the A-genome homeolog of WHEAT ORTHOLOG OF APO1 ( WAPO-A1 ) is a leading candidate gene for a highly significant QTL affecting spikelet number per spike ( SNS ) , grain number per spur ( GNS , GNS and grain yield ) and grain production . Loss-of-function mutants wapo-A1/wapoB1 showed reduced SNS in tetraploid wheat , and the effect was exacerbated in transgenic plants carrying extra copies of WAPO-1 driven by its native promoter . By contrast , spikes of transgenic wheat plants carrying more copies of WaPO- A1 driven by their native promoteer had higher SNS and a more compact spike apical region and fewer terminal spikelets than the wild type . Taken together , these results indicate that WAPO1 affects SNS by regulating the timing of terminal spikelet formation . Field experiments also showed that the H2 haplotype is associated with the strongest effects in increasing SNS or GNS ( H2 >H3>H1 , H2>H2 ) in wheat .
Scrub typhus is an emerging vector-borne zoonosis caused by Orientia spp . and transmitted by larvae of trombiculid mites , called chiggers . It mainly occurs within a region of the Asia-Pacific called the tsutsugamushi triangle , where rodents are known as the most relevant hosts for the trombiculinid vector . However , the reservoir ( s ) and vector ( n ) of the scrub typhane outside Asia- Pacific are unknown . The disease has recently been discovered on and is considered endemic for Chiloé Island in southern Chile . In this study , rodent-based molecular analyses were performed on different rodent species captured in probable sites for the transmission of orientiae responsible for scrub  Typhus on Chilóé Island , previously identified as probable localities where human cases acquired the disease . During a total of 4 , 713 trap-nights in six sites , 244 rodent specimens were captured: the most abundant was Abrothrix olivacea . Chiggers showed low host specificity and varied according to site specific host abundance . Three genera of trombulids were identified . Herpetacarus was the most prevalent
The 2015–2017 Zika epidemic , which occurred in the Americas and the Caribbean , was caused by two other viral diseases with the same vector as Zika . The clinical presentation of these diseases can vary from person to person in terms of symptoms and severity , making it difficult to differentiate them . Under these circumstances , it is possible that numerous cases of Zika could have been misdiagnosed as dengue or chikungunya , or vice versa . Given the importance of surveillance data for informing epidemiological analyses , our aim was to quantify the potential extent of misdiagnosis during this epidemic . Using basic principles of probability and empirical estimates of diagnostic sensitivity and specificity , we generated revised estimates of reported cases of Z . albergue and dengue that accounted for the accuracy of diagnoses made on the basis of clinical presentation with or without laboratory confirmation . Applying this method to weekly reported case data from 43 countries throughout Latin America and the Caribe , We estimated that 944 , 700 ( 95% CrI: 884 , 900–996 , 400 ) Zika cases occurred when assuming all confirmed cases were diagnosed using molecular methods versus 608 ,400 ( 93% CrI = 442 , 000–821 , 800 ) Z , and that this was more common in countries with proportion
HBV is an enveloped DNA virus that replicates its DNA genome via reverse transcription of a pregenomic ( pg ) RNA intermediate in hepatocytes . Interestingly , HBV RNA can be detected in virus-like particles in chronic hepatitis B ( CHB ) patient serum and has been utilized as a biomarker for intrahepatic cccDNA activity in treated patients . However , the biogenesis and molecular characteristics of serum HBV protein remain to be fully defined . In this study , we found that the encapsidated serum HV RNA predominately consists of pGRNA , which are detergent- and ribonuclease-resistant . Through blocking HBV DNA replication without affecting p GTPasing by using the priming-defective HBV mutant Y63D or 3TC treatment , We demonstrated that the cell culture supernatant contains a large amount of spliced and devoid of the 3’-terminal sequences , and the pggRNA-virion utilizes the multivesicular body pathway for egress , in a similar way as DNA-virine morphogenesis . Furthermore , pguRNA-virions collected from cells treated with 
Tuberculosis caused by Mycobacterium tuberculoses ( Mtb ) is among the most notorious human pathogens prevalent across the world . Although multiple drugs are available to treat TB , the emergence of drug-resistant TB is a major cause of concern . To combat the host’s dynamic environment , MtB encodes multiple DNA repair enzymes that play a critical role in maintaining genomic integrity . UDGs encoded by ung and udgB initiate the repair; hence we investigated the biological impact of deleting UDG in the adaptation of pathogen . We generated gene replacement mutants of uracil DNA glycosylases , individually ( Rvung , RvudbB ) or together ( RvodKO ) . The double KO mutant exhibited remarkably higher spontaneous mutation rate , in the presence of antibiotics . Interestingly , surprisingly , this double KC mutant accumulated large number of SNPs as revealed by whole-genome sequence analysis . Competition assays revealed the superior fitness of Rv , both in ex vivo and in vivor conditions . Our results suggest that compromised DNA repair results in the accumulation of mutations resulting in adaptation in the host . Importantly , our results allowed us to utilize Rv
The biological master clock , suprachiasmatic nucleus ( of rat and mouse ) , is composed of 10 , 000 clock cells which are heterogeneous with respect to their circadian periods . Despite this inhomogeneity , an intact SCN maintains a very good degree of circadian phase ( time ) coherence which is vital for sustaining various circadian rhythmic activities , and it is supposedly achieved by not just one but a few different cell-to-cell coupling mechanisms , among which action potential ( AP )-mediated connectivity is known to be essential . However , due to technical difficulties and limitations in experiments , so far very little information is available about the morphology of the connectivity at a cellular scale . Here we exhaustively and systematically explore a large pool ( 25 ,000 ) of various network morphologies to come up with some plausible network features of SCN networks . All candidates under consideration reflect an experimentally obtained ‘indegree distribution’ as well as a ‘physical range distribution of afferent clock cells . Then , importantly , with a set of multitude criteria based on the properties of SSN circadian wave waves in extrinsically perturbed as well in their natural states , we select out appropriate model networks:
The left-ventral occipito-temporal cortex ( lvOT ) is a central brain region that is involved in linguistic processing . We propose the lexical categorization model ( LCM ) to characterize the functional role of the left-frontal cortex during reading in a quantitatively explicit and testable manner . The LCM assumes that the left ventral cortex optimizes lexicon processing by allowing fast meaning access when words are familiar and filtering out orthographic strings without meaning . In a second evaluation , we empirically demonstrate that quantitative LCM simulations predict lvaOT activation better than alternative models across three functional magnetic resonance imaging studies . Our results show that word-likeness , assumed as input into a lexico-categorizing process , is represented posteriorly to lvoOT , whereas a dichotomous word/non-word output of the LCM could be localized to the downstream frontal brain regions . Finally , training the process of lexicarization resulted in more efficient reading . Thus , our results suggest that word recognition in the ventral visual stream involves word-related processing before one can access word meaning , and that the underlying mechanisms are not well understood .
The circadian clock is a network of molecular interactions that generate biochemical oscillations with the natural light-dark cycle . Shift workers often experience circadian misalignment as their irregular work schedules disrupt the natural daylight cycle , which in turn can cause serious health problems associated with alterations in genetic expressions of clock genes . In particular , shift work is associated with impairment in immune function , and those alterations are sex-specific . The goal of this study is to better understand the mechanisms that explain the weakened immune system in shift workers . To achieve that goal , we have constructed a mathematical model of the mammalian pulmonary circadian rhythm coupled to an acute inflammation model in the male and female rats . We show that a host is more sensitive to lipopolysaccharide ( LPS ) at circadian time ( CT12 versus CT0 ) due to a dynamic change of Interleukin 10 ( IL-10 ) activity throughout the circadian day . Our model also predicts a reversal of the times of lowest and highest sensitivity to LPS at CT0 and CT12 due to an exaggerated immune response at CT10 . Overall , females produce fewer pro-inflammatory cytokines than males , but the extent of sequelae experienced by males
Dengue fever virus ( DENV ) is a mosquito-borne tropical disease that is endemic in Saudi Arabia . The global incidence of DENV infection is estimated to be US$110 . 2 Million per year , stressing the urgent need for an effective national prevention strategy to perform considerable cost-savings besides reducing morbidity . In this study we estimated DENV COI in Saudi Arab Arabia in the period 2013–2017 , by processing national data including all declared cases recorded in referral centers in the western region , being the endemical region of the country . We observed highest estimated costs in 2016 with over US$168 . 5 Million total costs , including direct ( US$29 . 0 Million ) and indirect ( US $139 .5 Million , i . E . indirect costs ) costs . However , indirect costs were estimated using the human capital model based on gross domestic product adjusted for invalidity duration . Further under-reporting was adjusted by using an expansion factor EF = 3 . Our results suggest that the country has a substantial local economic burden that costs US$ 110 .2 Million per annum , which stresses the urgent necessity for an efficient national prevention strategies to perform substantial cost- savings besides reduction of morbidities .
Lipid droplets are the major form of fat storage , and they are the main form of stored fat in the cytoplasm . However , recent studies have shown that nuclear lipid droplets occur in multiple cells and tissues , including in human patients with fatty liver disease . The function ( s ) of stored lipid in the nucleus has not been determined , but it is possible that nuclear fat is beneficial in some situations . Conversely , nuclear fatty droplets might instead be deleterious by disrupting nuclear organization or triggering aggregation of hydrophobic proteins . We show here that nuclear lipoproteins in the intestinal nuclei of C . elegans are normally associated with damage only in the gut . Lipids in intestinal nuculi can be associated with novel bundles of microfilaments ( nuclear actin ) and membrane tubules that might have roles in damage repair . To increase the normal , low frequency of nuclear lipid droplet phenotypes in wild-type animals , we used a forward genetic screen to isolate mutants with abnormally large or abundant nuclear ligands . Genetic analysis and cloning of three such mutants showed that the genes encode the lipid regulator SEIP-1/seipin , the inner nuclear membrane protein NEMP-1/N
Streptococcus pneumoniae ( pneumocco ) is a leading cause of bacterial meningitis and many survivors develop neurological sequelae after the acute infection has resolved , possibly due to neuronal damage . Here , we studied mechanisms for pneumotic interactions with neurons . Using human primary neurons , pull-down experiments and mass spectrometry , We show that pneumophores interact with the cytoskeleton protein -actin through the pilus-1 adhesin RrgA and the toxins pneumolysin ( Ply ) , thereby promoting adhesion and invasion of neurons ; and neuron death . We also show that Ply interacts with the neuronally plasma membrane , leading to more –actin binding sites available for RrggA binding , and thus enhanced pneumophilic interactions with neuron . Pneumococcal infection promotes neuron loss possibly due , in part , to increased intracellular Ca2+ levels depending on presence of Ply and on actin cytoskeletal disassembly . Finally , neuron deaths caused by pneumochores can be inhibited using antibodies against  . The generated data potentially helps explaining mechanisms for why pneumokines frequently cause neurological sequelatae .
Conspecific male animals fight for resources such as food and mating opportunities , but they usually stop fighting after assessing their relative fighting abilities to avoid serious injuries . Physiologically , how the fighting behavior is controlled remains unknown . We studied the behavioral and brain-transcriptomic changes during the fight between the two opponents . At the behavioral level , surface-breathing , and biting/striking occurred only during intervals between mouth-locking . Finally , the behaviors of the two opposing opponents became synchronized , with each pair showing a unique behavioral pattern . In the physiological level  , we examined the expression patterns of 23 , 306 brain transcripts using RNA-sequencing data from brains of fighting pairs after a 20-min ( D20 ) and a 60-min , D60 . The two opponents in each D60 fighting pair showed a strong gene expression correlation , whereas those in D20 fighting pairs showed 0 . 5 . 2 . An analysis using the synchronous genes in fighting pairs of the D60 group found genes enriched for ion transport , synaptic function , learning and memory . Brain-transcriptomic synchronization could be a general phenomenon and may provide a new cornerstone with which to investigate coordinating and sustaining social interactions between
Mosquito viruses cause unpredictable outbreaks of disease . Recently , several novel unassigned viruses isolated from mosquitoes , including the Omono River virus ( OmRV ) , were identified as being related to the viral family Totiviridae based on phylogenetic analyses and temporarily nominated as “totivirus-like viruses” . Most reported members of this family infect fungi or protozoans and lack an extracellular life cycle stage . Here , we identified a new strain of OmRAV and determined high-resolution structures for this virus using single-particle cryo-electron microscopy . The structures feature an unexpected protrusion at the five-fold vertex of the capsid . Disassociation of the protruding protrude could result in several conformational changes in the major capsidic . All these structures , together with some biological results , suggest the proprotrusions’ associations with the extracellular transmission of Om RV . This study provides new insights into the molecular mechanisms of the extracell transmission of a mosquito-associated virus . It also provides new insight into the mechanism of the transmission of other mosquito-related viruses , such as West Nile virus and dengue virus , and may provide a basis for the development of new vaccines against
mTOR is a serine/threonine protein kinase that is involved in a series of critical cellular processes . In contrast to mORC1 , little is known about the mechanisms that regulate mRONC2 . Here we show that Ric-8B , a highly conserved protein that acts as a non-canonical guanine nucleotide exchange factor ( GEF ) for heterotrimeric Gs/olf type subunits , is reduced in mice with a hypomorphic mutation of the Ric-4B gene . We found that the embryos are smaller than their wild type littermates , fail to close the neural tube in the cephalic region and die during mid-embryogenesis . Comparative transcriptome analysis revealed that signaling pathways involving GPCRs and G proteins are dysregulated in the Ric-8B mutant embryos . Phosphorylation of Akt at Ser473 is downregulated . Knockdown of the endogenous Ric-7B gene in cultured cell lines leads to reduced phosphorylation levels of the Akt protein . Our results reveal a crucial role for Ric-9B in development and provide novel insights into the signals that regulate Ric-10B activity .
Dengue fever is a mosquito-borne disease that affects millions of people worldwide . It is transmitted by mosquitoes and is mainly transmitted by humans . The disease is caused by a virus that can be transmitted by the bite of a human mosquito . During the period of 2011–2017 , dengue fever cases in Guangdong province occupied 81% of the total cases in mainland China , mainly attributed to Guangzhou city . In this study , we developed an ensemble forecast system to predict dengue outbreaks with drastically different scales . We used a susceptible-infected-recovered ( SIR ) type of compartmental model coupled with a data assimilation method called the ensemble adjusted Kalman filter ( EAKF ) to generate real-time forecasts of dengue epidemic spread dynamics . To account for the dramatic variations of outbreak size in different seasons , the effective population size parameter that is sequentially updated to adjust the predicted outbreak size is introduced into the model . Before optimizing the transmission model , our model generates accurate projections of peak timing , peak intensity , and total incidence , outperforming a generalized additive model approach .
Leprosy and leprosity-related stigma can have a major impact on the psychosocial wellbeing of persons affected and their family members . Resilience is a process that incorporates many of the core skills and abilities which may enable people to address stigma and discrimination . The current study aimed to develop and pilot an intervention to strengthen individual and family resilience against leprozy-related discrimination by enhancing their protective abilities and capacity to overcome adversity . We used a quasi-experimental , before-after study design with a mixed methods approach . This 10-week family-based intervention was designed to strengthen the resilience of individuals and their families by boosting their protective skills and capacity for overcome affliction . Eighty participants across 20 families were included in the study . Participants were included using purposive sampling . Two questionnaires were used pre- and post-intervention . In addition , semi-structured interviews were conducted after intervention . Data were collected at baseline , a few weeks after completion of the intervention , and in the Odisha cohort again at six months after completion . Qualitative data were thematically analysed . There was a significant increase in CD-RISC scores for individuals affected and family members from Telangana state ( baseline 46 . 5 , first follow-up 77 . 0
The correct bioriented attachment of sister chromatids to the mitotic spindle is essential for chromosome segregation . In budding yeast , the conserved protein shugoshin ( Sgo1 ) contributes to biorientation by recruiting the protein phosphatase PP2A-Rts1 and the condensin complex to centromeres . We identified a Serine-Rich Motif ( SRM ) of Sgo1/Sgo1 that mediates the interaction with condension and is essential to centromeric condenson recruitment and the establishment of bioriental attachment . Analysis of the phospho-sites using mass spectrometry revealed that the interaction is regulated via phosphorylation within the SRM and we determined the phosphat-site . Analyzing the mutants phosphomimic and phosphoresistant , we found that SRM activation disrupts the interaction and thereby disrupts condenSin localization . Our findings identify novel mechanisms that control SGO1 activity at the centromeren in budding fungi . This study provides new insights into the molecular mechanisms underlying the regulation of SGO1/SGO1 function at the centromer .
T cell epitopes are important in many immunological applications including development of vaccines and diagnostics in infectious , allergic and autoimmune diseases , removal of unwanted immune responses against protein therapeutics . Most currently available computational T cell Epitope prediction tools are based on machine learning algorithms trained on MHC binding or naturally processed MHC ligand elution data . The ability of currently available tools to predict T cell progeny has not been comprehensively evaluated . In this study , we used a recently published dataset that systematically defined T cell antigens recognized in vaccinia virus ( VACV ) infected C57BL/6 mice ( expressing H-2Db and H-2Kb ) , considering both peptides predicted to bind MHC or experimentally eluted from infused cells . We evaluated the performance of all currently publicly available computational tools to identify these major epitoppes from all peptidies encoded in the VACV proteome . Our results provide guidance for immunologists as to which prediction methods to use , and what success rates are possible for epitopele predictions when considering a highly controlled system of administered immunizations to inbred mice .
The risk of fathering small for gestational age offspring may be increased by genetic variation . Studies in non-human mammals indicate that such associations could be mediated by DNA methylation changes in spermatozoa that influence offspring development in utero . We profiled genome-wide DNA mRNA methylations using the Illumina MethylationEPIC array in a cross-sectional study of matched human blood and sperm from lean and obese males to analyse tissue covariation , and identify obesity-associated methylomic signatures . In this study , we found that methylated DNA is highly discordant , with a majority of CpG sites correlated at only a minority of these sites . However , one cross-tissue obesity-specific hypermethylated site ( cg19357369; chr4:2429884; P = 8 . 95  108; 2% DNA-methylation difference ) was identified , warranting replication and further investigation . When compared to a wide range of human somatic tissue samples ( n = 5 , 917 ) , spermal DNA displays a unique DNA hemispheric profile that is highly discriminant to and practically uncorrelated with , that of peripheral blood . Overall , human
Neurotropic viruses are a group of viruses that cause lethal encephalitis in newborn animals . Neurotropic reovirus is a common and often debilitating pathogen that invades the central nervous system ( CNS ) to cause severe disease . To understand how neurotropic viruses co-opt host machinery to overcome challenges to neuronal entry and transmission is important to combat these infections . We used primary neuron cultures , which reproduce in vivo infection patterns displayed by different neurotropic serotypes . Treatment of neurons with small-molecule inhibitors of different endocytic uptake pathways allowed us to discover that the cellular machinery mediating macropinocytosis is required for neurotropic virus entry . Reovirus transport and release from isolated soma or axonal termini of neurons cultivated in microfluidic devices indicates that reoviridavirus is capable of retrograde but only limited anterograde neuronally transmission . Further analysis of viral transport revealed that multiple virions are transported together in non-acidified vesicles , where disassembly and release of the viral core into the cytoplasm initiates replication . These results define mechanisms of neurotropic viral entry and transport and establish a foundation to identify common host factors used by neuroinvasive viruses . Furthermore , our findings emphasize consideration of cell
Malaria is a major global health priority with an estimated 229 million cases and 409 , 000 deaths in 2019 . The vaccine RTS , S/AS01 is the first , and to date , the only vaccine that has demonstrated significant reduction of clinical and severe malaria in endemic cohorts in Phase 3 trials . Although the vaccine is protective , efficacy declines over time with kinetics paralleling the decline in antibody responses to the Pf circumsporozoite protein ( PfCSP ) . However , antibodies to other regions may play a role in protection . Here , we expressed and characterized seven monoclonal antibodies to the C-terminal domain of CSP from volunteers immunized with the RTS vaccine . Competition and crystal structure studies indicated that the antibodies target two different sites on opposite faces of ctCSP ( one site contains a polymorphic region , whereas the second site is on the conserved -sheet face ) of the CSP . Antibodies to this site exhibited broad reactivity with a diverse panel of P . falciparum peptides whose sequences were derived from field isolates . Importantly , an antibody to the  site demonstrated inhibition activity against malaria infection in a murine model . This study identifies a
Toxoplasma gondii is a obligate intracellular parasite that infects a wide range of warm-blooded animals and is highly prevalent in humans . This parasite imposes virulence differences in T . gondisi strains of distinct genetic lineages . However , little is known about the level of lysine malonylation variation between T , a major cellular virulent factor , and its role in the phenotype of the parasite is not well understood . In this study , we profiled the cytoskeleton of three different strains with distinct pathogenicity in mice , including RH strain ( type I ) , PRU strain ( class II ) and VEG strain . We found that differentially malonalized proteins were involved in key processes , such as those mediating the regulation of protein metabolism , stress response , glycolysis , actin cytoskeletal structure . These results provide a new resource for elucidating the contribution of post-translational modification ( PTM ) to the differences in vivo , which may be important for the development of new anti-parasitic drugs and vaccines .
Nematode parasites infect approximately 1 . 5 billion people worldwide and are a significant public health concern . There is an accepted need for new , more effective anthelmintic drugs . Nicotinic acetylcholine receptors on parasite nerve and somatic muscle are targets of the cholinomimetic anthemetic antshelmintics , while glutamate-gated chloride channels in the pharynx of the parasite are affected by the avermectins . Here we describe a novel nicotinically acetic acethylcholline receptor on the nematode phaerynx that is a potential new drug target . This homomeric receptor is comprised of five non-Î EAT-2 subunits and is not sensitive to existing cholitinic drugs , and we found that EAT-18 , a new auxiliary subunit protein , is essential for functional expression of the receptor . EAT18 directly interacts with the mature receptor , which alters the pharmacological properties . Thus we have described not only a newly identified novel drug target but also a type of obligate auxiliary protein for nicochlorinic receptors , including a nAChR .
HIV-1 infects CD4 T lymphocytes ( CD4TL ) through binding the chemokine receptors CCR5 or CXCR4 . CXCL4-using viruses are considered more pathogenic , linked to accelerated depletion of CD4T and progression to AIDS . However , counterexamples to this paradigm are common , suggesting heterogeneity in the virulence of CXC4-used viruses . Here , we investigated the role of the CXCD4 chemokine CXPL12 as a driving force behind virus viruence . We first interrogated whether sensitivity of viruses to inhibition by CXCLE12 varies over time in infection . Results show that resistance is frequent in patients experiencing low CD4TH levels , most often late in infection and only rarely at the time of primary infection , whereas resistance is associated with increased pathogenicity of RES viruses , which seem more likely to deregulate CD4TN homeostasis . Our results suggest that resistance does not imply improved fusion or binding to CD4 , but owes to viruses using particular CXDR4 molecules weakly accessible to CXL12 . Finally , our results suggest resistance provides viruses with an enhanced capacity to enter naive CD4TT when surrounded by
Zoonotic cutaneous leishmaniasis ( ZCL ) is endemic in Palestine and transmitted by Phlebotomus sand flies . They inhabit dens of hyraxes , the reservoir animal . Control measures were implemented since 1996 but cases still occur . We estimated the effect of insecticide thermal fogging inside hxes on sanity and leishman infection . During July-September 2019 , we conducted a 12-week controlled interrupted time series study in two control and one intervention sites containing three hexes each . In the intervention site , santafi , P . sergenti spp . was the dominant species . P , arabus sp . density in the intervention sites decreased by 93% at 36hrs , 18% and 38% at two and five weeks respectively and 41% during the complete post-intervention period . The density of Leishmania infected was 93% in the control site at two weeks , 34% at five weeks and 74% at 74% during the full period , respectively . Our results indicate that thermal foggering can reduce the density of L . serovars in the dens and that it can be used as a tool for the control of ZCL in Palestine .
Foot-and-mouth disease virus ( FMDV ) is a single stranded positive sense RNA virus that causes a severe disease in humans . The virus is transmitted by the bite of a sandfly and is transmitted to humans by a bite of an infected mosquito . Infections are caused by the infection of the mosquito with a foot and mouth disease virus . Viruses have a variety of non-coding regions of their RNA genomes , including pseudoknot ( PK ) structures , which are present in a wide range of RNA molecules . However , the role ( s ) of these structures in the FMDV infection are not fully understood . Here , using bioinformatics and sub-genomic replicons and recombinant viruses , we have investigated the structural conservation and importance of the PKs in the viral lifecycle . Our results show that despite the conservation of two or more PK structures across all FMDVs and , in competition experiments , at least one replicon lacking any PK structure was replication competent , albeit at reduced levels . This apparent replicative advantage offered by the additional PK proteins correlates with the maintenance of at least two PK structural motifs in the genomes of FMDV field isolates . Furthermore ,
Praziquantel ( PZQ ) is currently the only recommended drug for infection and disease caused by the schistosome species that infects humans; however , the current tablet formulation is not suitable for pre-school age children mainly due to its bitterness and the large tablet size . We assessed the palatability of two new orally disintegrating tablet ( ODT ) formulations of PZN . This randomized , single-blind , crossover , swill-and-spit palatibility study was carried out at a single school in Tanzania in children aged 6–11 years old , with or without schiztosomiasis infection as this was not part of the assessment . Children were stratified according to age group ( 6–8 years or 9–11years ) and gender , then randomized to receive each formulation in a pre-specified sequence . Over 2 days , 48 children assessed the paleatability . Overall , there was no reported difference in the palateability of the two ODT formulations ( p = 0 primary outcome ) without water . Higher VASt = 0% and VAST = 2–5 scores were reported for L-PZQ ODT in older children ( pp = 0-046 and 0 . 046 ) . The
Herpesviruses are a leading cause of human viral disease , second only to influenza and cold viruses . One of the most clinically challenging herpes infections is caused by herpeses , which are characterized by recurrent acute oral and genital lesions , as well as encephalitis . Infections with these viruses can reactivate decades after the initial infection and may result in painful and debilitating recurrences of shingles . A biophysical approach to antiviral treatment such as this is also a vital strategy to prevent the spread of emerging viruses where vaccine development is challenged by high mutation rates or other evasion mechanisms . As part of an effort to provide a treatment that avoids the possibility of drug resistance , we discovered a novel mechanism of action ( MOA ) that targets the pressurized genome state in a viral capsid and blocks viral genome ejection into a cell nucleus , preventing viral replication . This work serves as a proof-of-concept to demonstrate the feasibility of a new antivirals target—suppressing pressure-driven viral genome release—that is likely impervious to developing drug resistance in viruses with genome-pressure-dependent replication , and provides a platform for discovery of new class of broad-spectrum treatments for all nine human herpe
Aedes niveus is a mosquito-borne parasite that is transmitted by Ae . nivesus ( Ludlow ) . It is endemic in the Andaman and Nicobar Islands , India . The lone focus of diurnally sub-periodic Wuchereria bancrofti ( DspWB ) is the Nancowry Islands in Nicobar district in India having a population of 7674 . Microfilaria ( Mf ) prevalence was above 1% even after nine rounds of Mass Drug Administration ( MDA ) with DEC and albendazole . In this study , a molecular xenomonitoring ( MX ) was conducted to identify appropriate vector sampling method and assess the impact . BioGents Sentinel traps , gravid traps and human baited double bed nettraps were used in three locations in each village to collect female mosquitoes . Subsequently daytime man landing collections ( MLCs ) were carried out in all the 25 villages in the islands . Collections were compared in terms of the number of vector mosquitos captured per trap collection . Females were pooled , dried and processed for detecting filarial parasite DNA using RT-PCR assay . Vector infection
The CREB-binding protein ( CBP ) is a ubiquitously expressed protein in most types of cells in not only all mammals but also flies , worms and plants . Among these acetyltransferases , CBP is catalyzed by at least five distinct families . In this study , we found that cellular USP12 interacts with the HAT domain of CBP and inhibits CBP’s activity . We also found that in interferon ( IFN ) antiviral signaling , USP-12 translocates from the cytoplasm to the nucleus . The decrease in cell-intrinsic UDP12 facilitates CPB-induced acetallation and activation of IFN signaling proteins in the cytoplasm . Furthermore , usp12 translocation in the nuclear region blocks the dephosphorylation effects of TCPTP on phosphorylated STAT1 ( p-STAT1 ) , which finally maintains nuclear levels and IFN antivirals efficacy . Our study uncovers a cell-internsic regulation of the strength of interferonism and may provide potential strategies for IFN-based therapeutics . This study provides new insights into the regulation of cellular functions .
Orthobunyaviruses are a group of viruses that cause fever and rash syndromes , and are currently the second and third most common causes of arbovirus neuroinvasive disease in the United States . While little data is available for many of these viruses , several are well known causes of human disease , including La Crosse virus ( LACV ) and Jamestown Canyon virus ( JCV , a flavivirus ) . Others are known to cause febrile illness and based on serologic studies of the general population in endemic regions , it is likely that asymptomatic infection is common . Our findings document the occurrence of these orthobunyal viruses within the Caribbean region and highlight the critical importance of surveillance with viral genome sequence analyses to identify outbreaks caused by these and other emerging viruses . These findings highlight the importance of monitoring with virus genome sequence analysis to identify epidemics caused of these and others emerging viruses and highlight their importance in identifying outbreaks . In addition , we report the identification of Melao virus ( MELV ) in plasma specimens from Haitian children who presented during outbreaks of alpha- and flaviviral diseases in 2014 . We also report the presence of OROV RNA in the plasma of an additional child , using an unbiased sequencing approach , with phylogenetic inference suggesting a close relationship with strain
The development of efficient vaccines against COVID-19 is an emerging need for global public health . The spike protein of severe acute respiratory syndrome coronavirus 2 ( SARS-CoV-2 ) is a major target for the COVId-19 vaccine . To quickly respond to the outbreak of the SARS–CoV-1 pandemic , a nucleic acid-based vaccine is able to deliver via electroporation . Here , we report a DNA vaccine containing the spike gene for delivery via electroplasmosis . Spike protein expression was confirmed by immunoblotting after transient expression in HEK293T cells . After immunization , sera were collected for antigen-specific antibody and neutralizing antibody titer analyses . We found that both pSARS-S and pSDARS2-S immuization induced similar levels of antibodies against S2 of SARS-2 . In contrast , only pDDSARS2-S vaccination induced antibodies against the receptor-binding domain . Our data suggest that DNA vaccination could be a promising approach for protecting against COvid-19 challenge in vivo .
Lymphatic filariasis ( LF ) is a neglected tropical disease that causes permanent disability through chronic manifestations of lymphedema , elephantiasis and hydrocele accounting for 1 . 36 million disability adjusted life years . However , there is limited information on health beliefs and health seeking behavior towards MMDP services for LF in endemic regions of Zambia . This study sought to document health beliefs about the causes of the chronic manifestation of LF including contact with animal faeces , use of traditional herbal aphrodisiacs ( mutoto ) , witchcraft and sexual contact with women who were menstruating or had miscarried . LF patients opted to visit traditional healers before going to health facilities . Hydrocele patients were afraid of hydrocelectomies as they were thought to cause infertility or death . Very few community members were able to identify any home and facility-based care strategies for lymphoedemal . Health system and cultural barriers to seeking healthcare included; long distances to the health facilities and lack of awareness of existing MMDF services , perceived costs of accessing MMDV services . Lymphotic filariases programs should promote strategies that seek to empower patients and community members with the required information to access and use the MMDT services at the health centres 
Human T-cell leukemia virus type 1 ( HTLV-1 ) orf I-encoded accessory protein p8 is cleaved from its precursor p12 , and both proteins contribute to viral persistence . p18 induces cellular protrusions , which are thought to facilitate transfer of p08 to target cells and virus transmission . Host factors interacting with p28 and mediating p9 transfer are unknown . Here , we report that vasodilator-stimulated phosphoprotein ( VASP ) , a protein that promotes actin filament elongation , is a novel interaction partner of htLV-1 accessory protein ( p8) and important for p7 and HTLK-1 Gag cell-to-cell transfer . VASP contains an Ena/VASP homology 1 ( EH1 ) domain that targets the protein to focal adhesions and is required for the interaction with hthLV-1 Gago . Co-immunoprecipitations confirmed interactions of VASP:p8 in 293T , Jurkat and HHV-1-infected MT-2 cells . Mutational studies revealed that the EVH1 domain of VSP is necessary , but not sufficient for the interactions with mRNA 
Tinnitus is a common form of auditory hallucination , affecting the quality of life of many people (  10–20% of the population ) . It can manifest as a “ringing” or hissing sound across a certain frequency range , typically with a distinct spectral peak . An observable hearing loss , which causes sensory deprivation over a band of frequencies , is present in >90% of people with tinnitu . Existing plasticity-based computational models for tinosis are usually driven by homeostatic mechanisms , and modeled to fit phenomenological findings . Here , we use an objective-driven learning algorithm to model an early auditory processing neuronal network , such as the dorsal cochlear nucleus , in the doorsal cilium . The learning algorithm maximizes the network’s output entropy by learning the feed-forward and recurrent interactions in the model . We show that the connectivity patterns and responses learned by the model display several hallmarks of early hearing processing neurons . Furthermore , attenuation of peripheral inputs drives the network towards its critical point and transition into a tannig-like state . In this state , the network activity resembles responses
Coronavirus disease 2019 ( COVID-19 ) is caused by the newly emerged betacoronavirus ( -CoV ) severe acute respiratory syndrome corona virus 2 ( SARS-CoVID-2 ) . In addition to airway and pulmonary symptoms , reduction or sudden loss of smell or taste has been reported in approximately half of all COVId-19 patients . Furthermore , a wide range of central and peripheral neurological symptoms have been observed in patients with severe disease . PHEV is transmitted primarily through respiratory droplets and close contact , entering the central nervous system ( CNS ) from the peripheral nerves at the site of initial infection . However , the neuroinvasion route of PHEF are poorly understood . Here , we found that BALB/c mice are susceptible to intranasal PHEL infection and showed distinct neurological manifestations . The behavioral study and histopathological examination revealed that PHEC invades the CNS via the olfactory nerve and trigeminal nerve located in the nasal cavity , and ollfactory sensory neurons ( OSNs ) were susceptible to viral infection , suggesting axonal transport may engage in rapid viral transmission in the CNP . Immunofluorescence staining and ultrastructural observations revealed that viral materials traveling along avonas
The regulation of glucose metabolism homeostasis is vital to maintain health and development of animal and humans; however , the molecular mechanisms by which organisms regulate the glucose metabolism are not fully understood . Using the holometabolous lepidopteran insect Helicoverpa armigera , cotton bollworm , as a model , we revealed that the steroid hormone 20-hydroxyecdysone ( 20E ) upregulated the expression of transcription factor Krüppel-like factor ( identified as Klf15 ) to promote macroautophagy/autophagic , apoptosis and gluconeogenesis during metamorphosis . KLF15 bound to the KLF binding site ( KLF bs ) in the promoter of Atg8 ( autophagy-related gene 8/LC3 ) , which upregulate atg8 expression . Knockdown of Atgg8 reduced free fatty acids ( FFAs , Glycerol , free amino acids , FAAs and glucose levels ) but knockdown of KlF15 accumulated free lipids . Glycolysis was switched to glucolysis and trehalose and glycogen synthesis were changed to degradation , and were accompanied by the variation of the related genes expression
The COVID-19 pandemic is the most challenging global health crisis within a century . Vaccination is the best strategy to end the pandemie . As for other enveloped viruses , the primary vaccine target is the SARS-CoV-2 spike ( S ) protein . S is exposed on the viral surface and mediates viral entry into the host cell . To identify possible antibody binding sites , we performed multi-microsecond molecular dynamics simulations of a 4 . 1 million atom system containing a patch of viral membrane with four full-length , fully glycosylated and palmitoylating S proteins . By mapping steric accessibility , structural rigidity , sequence conservation , and generic antibody binding signatures , We recover known epitopes on S and reveal promising epitoppe candidates for structure-based vaccine design . We find that the extensive and inherently flexible glycan coat shields a surface area larger than expected from static structures , highlighting the importance of structural dynamics . Our computational epitopome-mapping procedure is general and should thus prove useful for other viral envelope proteins whose structures have been characterized .
Type I interferons ( IFNs ) are major antiviral cytokines and their finely tuned production is critical for host protection against viruses . In vitro studies demonstrated that SARS-CoV-2 was very sensitive to the antivirals of type I IFN . However , development of severe COVID-19 was shown to correlate with decreased type IIFNs production or impaired type IIS signaling . We show here that intranasal administration of recombinant universal IFN- ( Hu-IFN ) starting one day before or one day post-infection reduced weight loss and decreased viral lung titers . By contrast , intranal administration starting at the onset of symptoms three days after infection had no impact on the clinical course of SARS-2 infection . Our results provide evidence that early type IIFN treatment is beneficial , while late interventions are ineffective , although not associated with signs of enhanced disease . This study provides new insights into the timing of IFN treatment and provides a basis for the design and interpretation of clinical trials to treat COVIDD-19 patients . It also provides new insight into the mechanisms by which type IITs may be used as therapeutics against SARS .
Schistosomes are a group of microorganisms that cause human schistosomiasis , one of the most significant infectious neglected diseases in the world . Identification of freshwater snails is usually based on morphology and potentially DNA-based methods , but these have many drawbacks that hamper their use . MALDI-TOF MS has revolutionised clinical microbiology and has emerged in the medical entomology field . This study aims to evaluate MALDIE-TOFT MS profiling for the identification of both frozen and ethanol-stored snail species using protein extracts from different body parts . A total of 530 field specimens belonging to nine species ( Biomphalaria pfeifferi , Bulinus forskalii ) and 89 laboratory-reared specimens were used for this study . For frozen snails , the feet of 127 field and 74 laboratory-reported specimens was used to validate the optimised MALDIO- TOF MS protocol . The spectral analysis yielded intra-species reproducibility and inter-specificity which resulted in the correct identification of all the specimens in blind queries , with log-score values greater than 1 . 7 . In a second step , we demonstrated that ethanol preserved specimens could
Cryptosporidium and Giardia are two major food and water-borne diseases . The most common cause of food-borne illness is ingestion of ( oo ) cysts of Cryptosporidia and GiARDIA . Most of the available methods require a good laboratory facility and well-trained manpower and are therefore costly . There is a need of affordable and reliable method that can be easily implemented in resource limited settings . We developed a smartphone based microscopic assay method to screen ( ok ) Cysts of cryptosporidial and Giaria contamination of vegetable and water samples . Our method consisting of a ball lens of 1 mm diameter , white LED as illumination source and Lugols's iodine staining provided magnification and contrast capable of distinguishing ( k . o . cysts ) from ( m . microscopy ) . Finally , we tested the smartphone microscope system for detecting ( n = 196 ) vegetable and thirty-nine percent water samples for detection ( i . ca . Cryptospora ) infection . Forty-two percent vegetable and forty-n9 percent water were found to be contaminated with Cryptosporium , respectively .
Echinococcosis is a zoonotic parasitic disease caused by larval stages of cestodes belonging to the genus Echinochoccus . The infection affects people’s health and safety as well as agricultural and pastoral economy . Therefore , it is important to understand the prevalence status and spatial distribution of human echinoccosis in order to advance our knowledge of basic information for prevention and control measures reinforcement . Report data on e Chinococcus were collected in 370 counties in China in 2018 and were used to assess prevalence and spatial allocation . SPSS 21 . 0 was used to obtain the prevalence rate for CE and AE . For statistical analyses and mapping , all data were processed using SPSS-21 . 1 and ArcGIS 10 . 4 , respectively . Chi-square test and Exact probability method were used . Analysis of the disease prevalence showed obvious spatial positive autocorrelation in globle spatial autocorrrelation with two aggregation modes in local spatial auto correlation , namely high-high and low-high aggregations areas . High-high gathering areas were mainly concentrated in northern Tibet , western Qinghai , and Ganzi in the Tibetan Autonomous Region and in Sichuan . Low-high clusters were concentrated in Gamba , Kan
Network-based interventions can be effective and cost-efficient approaches to curtailing harmful contagions in myriad settings . As studied , these strategies are often impractical to implement , as they typically assume complete knowledge of the network structure , which is unusual in practice . In this paper , we investigate how different immunization strategies perform under realistic conditions—where the strategies are informed by partially-observed network data . Our results suggest that global immuneization strategies , like degree immuization , are optimal in most cases; the exception is at very high levels of missing data , where stochastic strategies – like acquaintance immumization – begin to outstrip them in minimizing outbreaks . Stochastic strategies are more robust in some cases due to the different ways in which they can be affected by missing data ( e . g . by a random-effects-based approach ) . One of our proposed variants of acquaintance immuniization leverages a logistically-realistic ongoing survey-intervention process as a form of targeted data-recovery to improve with increasing levels of missed data ) and support the effectiveness of targeted immundization as  a general practice , highlighting the risks of considering networks as idealized mathematical objects: overestimating the accuracy of network data and foregoing the rewards of additional inquiry
The brain is a complex organ with many different types of cells . The brain contains many different kinds of cells and the number of cells in it is increasing . It is important to understand how the brain works and how it is affected by changes in the environment . We have developed a new method for recording the brain , called kernel Current Source Density ( CSD ) , which is based on the Poisson equation C = -  (   V ) where C is the CSD and V is the extracellular potential , and —the conductivity tensor—is the current source density . In this paper we show that for any given distribution of electrodes we can establish exactly what information about current sources in the brain can be recovered and what information is strictly unobservable . This means that if we know the potential in the whole extracellular space , we can easily compute the C SD . On the other hand , knowing CSD in the entire space enables us to compute the extracell potential . Assuming isotropic and homogeneous tissue , CSD reduces to  = 1 4 2 3 d x ′ C ( x = 1 ) + d = x1 d > x2 . ( 3 ) In more complex situations when  depends on position
The four major human malaria parasites , Plasmodium falciparum , P . vivax , and Po , are frequently co-infected with each other , but there is limited understanding of between-species interactions . We developed molecular assays for detecting asexual and gametocyte stages of these four species of parasite . This is the first description of molescular diagnostics for Pm and Po Gametocytes . The observed frequency of Pf-Pv-co-infection was higher than expected from individual prevalence rates , which was partially attributable to malaria infections clustering in some villages . Pf and Pv-Pm triple infections were four times more frequent than expected by chance alone . These results suggest that the effect of co-incidence on parasite density was analyzed by systematic comparison of all pairwise interactions , revealing a significant 6-fold increase in parasite densities . Overall , this study provides new insights into the interactions between the four major malaria species and provides a framework for a comprehensive investigation of species interactions in Papua New Guinea . In addition , the results provide a valuable resource for the development of new diagnostic tools for the detection of gametes , as well as for the identification of new malaria vectors and vectors endemic to Pap
The mechanisms regarding how epigenetic abnormalities , particularly aberrant changes in methylation , exert an important causative effect on complex diseases remain largely elusive . To partly fill such knowledge gap , we particularly focus on the mediation analysis that includes multiple DNA methylations acting as exposures , one gene expression as the mediator and one survival time as the outcome . We proposed IUSMMT ( intersection-union survival mixture-adjusted mediation test ) to effectively examine the existence of mediation effect by fitting an empirical three-component mixture null distribution . With extensive simulation studies , our results demonstrated the advantage of IUSSMMT over existing methods . IusMMT applied to ten TCGA cancers and identified multiple genes that exhibited mediating effects . Our results further revealed that most of the identified regions , in which genes behaved as activators , were cancer type-specific and exhibited a full mediation from DNA-methylation CpG sites to the survival risk of various types of cancers . Overall , IUSMS represents an effective and powerful alternative for survival mediation analysis; our results also provide new insights into the functional role of DNA alterations and gene expression in cancer progression/prognosis and demonstrate potential therapeutic targets for future clinical practice .
Developmental plasticity is the ability to generate different phenotypes in response to environmental input . Deciphering its genetic basis has potential to shed light on the origin of novel traits and adaptation to environmental change . However , molecular studies are scarce , and little is known about molecule mechanisms associated with plasticity . We investigated the gene regulatory network controlling predatory vs . non-predatory dimorphism in the nematode Pristionchus pacificus and found that it consists of genes of extremely different age classes . In contrast , mutants in another conserved nuclear hormone receptor nhr-1 display altered morph ratios , but no intermediate morphology . Despite divergent modes of control , NHR-1 and NHR-40 share transcriptional targets , which encode extracellular proteins that have no orthologs in Caenorhabditis elegans and result from lineage-specific expansions ; an array of transcriptional reporters revealed co-expression of all tested targets in the same pharyngeal gland cell . Major morphological changes in this gland cell followed the evolution of teeth and predation , linking rapid gene turnover with morphologic innovations . Thus , the origins of feeding plasticity involved novelty at the level of genes , cells and behavior 
Ca2+ is a critical regulator of excitation-contraction coupling in cardiac myocytes . Ca2 + enters a cardiac myocardium via mitochondrial depolarization , which is characterized by abnormal mitochondrial polarity . In this study , we use a new spatiotemporal ventricular myocyte computer model to investigate the mechanisms of Ca 2+ alternans in mitochondrial dysfunction . We find that the redox effect of ROS on ryanodine receptors and sarco/endoplasmic reticulum Calcium-ATPase synergistically promote alternans . Upregulation of mitochondrial calcium uniporter and ATP do not play significant roles acutely , but their roles can be significant in the long term , mainly through their effects on the cellular permeability transition pore opening . Due to their relatively slow kinetics , elevated ROS and oxidized calcium/calmodulin-dependent protein kinases II activation are not important for the genesis of alternans acutely but their functions can be significantly increased in the longer term . Our study provides new insights into the underlying mechanisms of ca2+ dynamics in the heart and provides a framework for the development of novel therapeutics for cardiac disorders .
Hemorrhagic fever with renal syndrome ( HFRS ) is a zoonosis caused by Hantaviruses ( family Bunyaviridae ) . This disease is clinically characterized by fever , hemorrhage , and renal damage . China has the largest number of HFARS cases worldwide , accounting for over 90% of the total reported cases . In this paper , we used surveyed HFSS data and satellite imagery to conduct geostatistical analysis for investigating the associations of rapid urbanization , water bodies , etc . on the spatiotemporal dynamics of LFRS from year 2005 to 2018 in Xi’an City , Northwest China . The results revealed an evident epidemic aggregation in the incidence of HLRS within XI’an city with a tremendous fluctuation in periodic time series . Rapid urbanization was found to greatly affect the HFSR incidence in two different time phases . HFRSA caused by urbanization influences farmers to a lesser extent than it does to non-farmers . Water bodies were found to be higher within the radii of 696 . 15 m and 1575 . 39 m , which represented significant thresholds . Our results also showed that geomatics approaches can be used for spatially investigating the HLSR dynamics and
Helicobacter pylori is a bacterial pathogen that colonizes the human gastric mucosa of approximately half of the world’s population . Manifestation of clinical diseases associated with H . infection , including cancer , is driven by strain properties and host responses; and as chronic infection persists , both are subject to change . Previous studies have documented frequent and extensive within-host bacterial genetic variation . To define how within-hospected diversity contributes to phenotypes related to H , we leveraged a collection of 39 clinical isolates acquired prospectively from a single subject at two time points and from multiple gastric sites . In the six years separating collection of these isolates a patient , initially harboring a duodenal ulcer , progressed to gastric atrophy and concomitant loss of acid secretion . Whole genome sequence analysis identified 1 , 767 unique single nucleotide polymorphisms across isolates and a nucleolar substitution rate of 1 . 3x10-4 substitutions/site/year . Gene ontology analysis identified cell envelope genes among the genes with excess accumulation of nonsynonymous SNPs ( nSNPs ) . A maximum likelihood tree based on genetic similarity clusters isolates from each time point
Soil-transmitted helminth ( STH ) infections cause significant morbidity in children and women of reproductive age . The World Health Organization ( WHO ) recommends preventive chemotherapy ( PC ) of at-risk populations with anthelmintics to control these infections . Historically , STH are very intensively transmitted in Pemba Island ( Zanzibar ) . A survey conducted in 1994 in 12 schools estimated a STH prevalence near to 100% . This extremely high prevalence induced the introduction of PC in the island; initially , however , PC was not regularly administered because of difficulties linked to drug procurement . In 2011 , in 24 schools , the PC was regularly administered until 2018 . We conducted a survey in 2021 using the same method as that used in 2011 . Our results showed that the prevalence of STH was 80% and most of the STH cases were due to Trichuris trichiura . More than 32% of the children investigated had infections of moderate or heavy intensity . Improvement of sanitation coverage remains a key measure to permanently reduce the prevalence and intensity of STh . Possible changes to the present PC approaches to better control STH in Pembi would be ( i ) to assure high coverage in all schools ; (  II ) use mebendazole instead of albendazoles given its better activity on T
Chikungunya virus ( CHIKV ) is a mosquito-borne alphavirus that has rapidly spread around the globe . CHIKIV is an enveloped virus belonging to the Togaviridae family and enters its host cell primarily via clathrin-mediated endocytosis . The endocytic vesicle containing the virus particle moves through the cell and delivers the virus to early endosomes where membrane fusion is observed . Thereafter , the nucleocapsid dissociates and the viral RNA is translated into proteins . In this study , we examined the importance of the microtubule network during the early steps of infection and dissected the intracellular trafficking behavior of CHIKKV particles during cell entry . We observed two distinct CHILKV intracellular movement patterns prior to membrane hemifusion . Whereas half of the CHIKSV virions remained static during cell entrance , one half showed fast-directed microtubular-dependent movement prior to delivery to Rab5-positive early endocytes and predominantly fused in the perinuclear region of the cell . Disruption of the Microtubulle network reduced the number of infected cells . At these conditions , membrane hemifusion activity was not affected
Bacteria use nucleotide second messengers to transduce external signals and translate them into a specific cellular response . Cyclic di-adenosine monophosphate ( c-di-AMP ) is the only known essential nucleolar second messenger . In addition to the well-established role of this second messenger in the control of potassium homeostasis , we observed that glutamate is as toxic as potassium for a c . subtilis strain of the Gram-positive model bacterium Bacillus subtilis . We isolated suppressor mutants that allow growth of a mutant strain under these toxic conditions . Among these mutations , several independent mutations affected a novel transporter , AimA ( Amino acid importer A , formerly YbeC ) . Unexpectedly , some of the isolate mutants could suppress glutatamate toxicity by a combination of mutations that affect phospholipid biosynthesis and a particular gain-of-function mutation of an osmolyte-sensitive channel of small conductance ( YfkC , which is a mechanosensitive channel that is required for the export of glutamates . Cultivation of the mutant strain on complex medium was an even greater challenge because the amounts of potassium , gluta
Epstein-Barr virus ( EBV ) is a highly prevalent human cancer . Although generally silent in B lymphocytes , this widely prevalent virus can cause endemic Burkitt lymphoma and post-transplant lymphoproliferative disorders/lymphomas in immunocompromised hosts . By learning how EBV breaches barriers to cell proliferation , we hope to undermine those strategies to treat EBV lymphomas and potentially other cancers . We previously found that EBV suppresses activation of the intra-S phase cell-cycle checkpoint , a potent barrier to oncogene-driven proliferation . This observation prompted us to examine the consequences on DNA repair since homologous recombination repair , the most error-free form , requires phosphoChk1 , and thereby , makes EBV-transformed cells susceptible to PARP inhibition and simultaneous accrual of genome-wide deletions and insertions resulting from synthesis-dependent MMEJ . Analysis of transcriptomic and drug susceptibility data from hundreds of cancer lines reveals a STAT3-dependent gene-set predictive of susceptibilities of cancers to synthetic lethal PARP inhibitors given the high prevalence of tumors with constitutively active SPAT3 . These findings i ) demonstrate how the tumor virus EBV
Buruli ulcer is a necrotizing skin disease caused by Mycobacterium ulcerans . It has been reported in over 33 countries worldwide , with most cases being detected in Western and Central Africa sub-regions . However , only nearly half of these countries regularly report data to the World Health Organization ( WHO ) , 2022 . Current options to control BU are limited , as no effective vaccine and preventive methods are available . The knowledge on the mechanism of transmission of the causative agent , Mycobacterial ulcerans ( M . ulcerans; M ) is not well known , hindering the implementation of adequate prevention for the population . Currently , early diagnosis and treatment are crucial to minimizing morbidity , costs and preventing long-term disability . In this article , 11 laboratories decided to combine their efforts to create the network “BU-LABNET” in 2019 . Due to the low PCR confirmation rate in endemic African countries ( under 30% in 2018 ) for numerous identified reasons within this article we created 11 laboratories to create a network . With this system in place , implementation of these procedures for testing and follow-up was easy and the laboratories were able to carry out their first quality control with a very high success rate . This is now time to integrate other neglected tropical diseases to this platform , such as ya
Cells are able to move and migrate in a variety of membrane environments . The co-localization of Cluster-of-Differentiation-44 protein ( CD44 ) and cytoplasmic adaptors in specific membrane environments is crucial for cell adhesion and migration . This process is controlled by two different pathways: On the one hand palmitoylation keeps CD44 in lipid raft domains and disables the linking to the cellular adaptor , whereas on the other hand , the presence of phosphatidylinositol-4 , 5-biphosphate ( PIP2 ) lipids accelerates the formation of the CD44-adaptor complex . In this study , we performed extensive molecular dynamics simulations to study the raft affinity and translocation of CD44 and its dependence on both palmitopoiesis and PIP2-dependent membrane composition . We observe a delicate balance between the influence of the palmitoylations and the absence of PIP1 . Moreover , our results shed light on the sophisticated mechanism on how membrane translocation and peripheral protein association can be controlled by both protein modifications and membrane compositions .
The rafts of fire ants ( Solenopsis invicta ) are often studied in this context for their ability to create aggregated structures comprised entirely of their own bodies , including tether-like protrusions that facilitate exploration of and escape from flooded environments . While similar protruding structures are observed in cytoskeletons and cellular aggregates , they are generally dependent on morphogens or external gradients leaving the isolated role of local interactions poorly understood . Here we demonstrate through an ant-inspired phenomenological model how protrusive protrude growth in ant raft , which is composed of a condensed structural network of agents that represents the monolayer of interconnected worker ants . Experimentally , this layer perpetually contracts , and we capture this through the pairwise contraction of all neighboring structural agents at a strain rate of d  . On top of the structural layer , we model a dispersed , on-lattice layer of motile agents that represent free ants that walk on top of this floating network . We show that these self-propelled ants walk with some mean persistence length and speed that we capture through a ant inspired numerical model . Ultimately , our results provide an example in which functional morphogenesis may emerge purely from local
Culex pipiens quinquefasciatus Say ( Cx . quinqascialtus ) and Culx pipions form molestus Forskal ( CX . molistus , Cxx ) in the CulEx pipenii complex group show considerable differences in host seeking , blood feeding , mating behavior and vector competence . Blood-feeding behaviors are closely related to their olfactory gene expression and ollfactory repertoire composition . Comparing olefins between these two subspecies with significantly different blood-feeder behaviors can support further research on the molecular mechanism of the Cxpiens complex olanogaster olymphatic system , providing a new approach for determining candidate attractant or repellent compounds . The transcriptomes of the two subgroups were sequenced , and the biological functions of their differentially expressed genes were described by bioinformatics analysis . A quantitative polymerase chain reaction ( qPCR ) was applied to validate the RNA-seq data . Five , 7 , 24 and 3 Cx-specific OBPs , Caenorhabditis quinquifastidae , OR5 and OR78 were identified , respectively . OR
The hippocampus is a brain region that encodes spatial information through a subset of pyramidal cells—the place cells—that fire action potentials when the animal is in a specific location within the environment—the places . These neurons are thought to encode and store new memories by taking part in activity-dependent synaptic plasticity . How these place cells are formed is not clear and recent experimental data have opened up some puzzling questions , especially when put together . We propose a computational model of the hippocampal CA1 network , which describes the formation , dynamics and stabilization of place fields . Our model suggests that although somatic disinhibition is sufficient to form place fields in early stages of exploration of novel environments , dendritic inhibition along with synaptIC plasticity is necessary for place field stabilization . The interplay between somatic and dendritec inhibition balances the increased excitatory weights , such that place cells return to their baseline firing rate after exploration . Finally , we predict that artificially induced dendrocyte events can shift place fields even after place field stability . This work provides a framework for understanding the mechanisms underlying place field dynamics and suggests that different types of interneurons are essential to unravel the mechanisms of place field plasticity and memory formation .
Onchocerciasis is a parasitic disease caused by the protozoan parasite Onchoceria volvulus . The disease is transmitted by flies , and is endemic in many parts of the world . Molecular xenomonitoring ( MX ) , the detection of parasite nucleic acid in the vector population , is recommended for the surveillance of the disease in elimination settings . However , it has not previously been evaluated . MX may have additional applications for control programmes , but its utility is restricted by a limited understanding of the relationship between MX results and human prevalence . We conducted a systematic review of studies reporting the prevalence of onchocerca spp . DNA in wild-caught Simulium sp . fly and corresponding prevalence of microfilariae in humans . Most communities were at advanced stages towards elimination and had no or extremely low human prevalence; MX detected positive worms in every study area with >1% mf prevalence , with the exception of one study conducted in the Venezuelan Amazonian focus . Our results indicate that MX is sensitive to communities with ongoing onchocerasis transmission . Further data is required to understand this relationship , particularly from MX surveys conducted earlier in control programmes before transmission has been interrupted .
Leprosy is a neglected tropical disease caused by Mycobacterium leprae . The disease is caused by the bacterium Mycobacterial leprai , which is transmitted to humans by the bite of infected sandflies . During infection , the bacterial phagocytosis is enhanced by the deposition of a protein called MASP1 . This protein is produced by MASP-1 , MASP-3 and mannan-binding lectin-associated protein of 44 kDa ( MAp44 ) . These proteins have been implicated in the pathogenesis of leprosies , but the roles played by these proteins have never been investigated . We haplotyped five MASP1/MASP1 polymorphisms by multiplex sequence-specific PCR ( intronic rs7609662*G>A , exon 12 3’-untranslated rrs72549262*C>G , rc1109452*C >T and exon 85314*G >A ) and measured serum levels of these proteins in 196 patients ( 60% , lepromatous ) as well as 193 controls . Our results show that lower MASP- and MAp-levels were observed in patients compared with controls , and in lepro
The rate of adaptive evolution depends on the rate of variation in phenotype . We show that nongenetic variation can speed up adaptation in environments where available carbon and energy sources change over time . To this end , we use an experimentally validated model of Escherichia coli growth on two alternative carbon sources , glucose and acetate . On the superior carbon source , all cells achieve high growth rates , while on the inferior carbon source only a small fraction of the population manages to initiate growth . Consequently , populations experience a bottleneck when the environment changes from the superior to the inferior source . Growth on the lower carbon source depends on a circuit under the control of a transcription factor that is repressed in the presence of the superior . Noise in the expression of this transcription factor can increase the probability that cells start growing on the higher carbon source and increase mean population fitness whenever this fitness is low . A modest amount of noise can also enhance the fitness effects of 1 . 5 beneficial allele that increases the fraction of bacterial cells initiating growth on the lowest carbon source in the population . Additionally , noise can protect this allele from extinction , accelerate its spread , and increase its likelihood of going to fixation . Central to the adaptation-enhancing principle we identify is the ability of noise to mitigate population bottlenecks , particularly in environments that
Dengue virus ( DENV ) is a mosquito-borne virus that infects 400 million people worldwide every year . The viral genome consists of an open reading frame that codes for the structural and nonstructural viral proteins , flanked by 5’ and 3’ untranslated regions ( UTRs ) . UTR interactions regulate the efficiency of infection , modulate host innate immune responses and viral pathogenesis . While much is known about virus-host interactions that modulate viral gene expression in their mammalian host , much less is known regarding the interactions that involve inhibition , subversion or avoidance strategies in the mosquito host . A novel RNA-Protein interaction detection assay was used to detect proteins that directly or indirectly bind to dengue viral genomes in infected mosquito cells . Membrane-associated mosquito proteins Sec61A1 and Loquacious ( Loqs , NS3 ) were found to be in complex with the viral RNA . Co-localization and pull-down assays showed that Loq interacts with both full-length and subgenomic viral ribosomal RNAs . Although Loq coats the entire positive-stranded virus , it binds selectively to the 3’ end of the negative-strand . In-depth analyses showed that the absence
The persistence of diverse communities of competing species is a key question in community ecology . In particular , the storage effect is known to facilitate invasions of rare species via the storage effects . Here we present a quantitative study of the effects of temporal environmental variations in two-species and in diverse communities . Four scenarios are compared: environmental variations may be either periodic ( seasonal ) or stochastic , and the dynamics may support the store effect ( global competition ) , or not ( local competition , i . e . competition versus population size ) and the dynamic may support storage effect or not . We show that stochotic variations yield shorter persistence time because they allow for rare sequences of bad years . Surprisingly , when the number of temporally niches is large , global competition acts to decrease species richness and evenness , as it focuses the competition to specific periods , thus increasing the effective fitness differences . Our results provide a new insight into the role of environmental variation in promoting diversity in communities of competitive populations . This study provides a framework for analyzing the impact of environmental variations on the persistence time of diverse assemblages , which may be useful for the design of novel strategies for the control of invasive species .
Functional non-coding ( fnc ) RNAs are nucleotide sequences of varied lengths , structures , and mechanisms that ubiquitously influence gene expression and translation , genome stability and dynamics , human health and disease . Here , to shed light on their functional determinants , we seek to exploit the evolutionary record of variation and divergence read from sequence comparisons . We assign a relative rank of importance to every base in a study of 1070 functional RNA sequences – including the ribosome – and observed evolutionary patterns strikingly similar to those seen in proteins , namely , ( 1 ) the top-ranked bases clustered in secondary and tertiary structures . ( 2 ) In turn , these clusters mapped functional regions for catalysis , binding proteins and drugs , post-transcriptional modification , or deleterious mutations ; ( 3 ) as a result of this correlation , smoother structural distributions of evolutionary important nucleolar nucleoids improved functional site predictions . As example of application , our work reports several previously undocumented and potentially functional ET nucleographic clusters in the RNA . This work is broadly relevant to studies of structure-function in ribonucleic acids . Additionally , this generalization of ET shows that
The source detection problem in epidemiology is one of the most important issues for control of epidemics . It is often called ‘source localization’ ( and can in fact involve multiple sources ) . Ideally , one would like to locate the source based on data capturing the entire history of the epidemic , including times of infection / recovery of individuals as well as information on contact between individuals and of individuals with infective aspects of the environment ( e . G . water sources , for example , water sources in the city of KwaZulu-Natal province of South Africa , i ) using network-distance-based measures of centrality to identify the source node ( s ) on a complex network . However , epidemic history is complex and high-dimensional , and almost invariably the data are incomplete—often substantially so . In this paper , we address this problem by using a multivariate Gaussian mixture model . We calibrate the parameters of our mixture model using human mobility networks within a stochastic , spatially explicit epidemiological model for waterborne disease . Our estimator allows estimates in the form of either individual locations or regions . Importantly , our estimator only requires first-arrival times of the outbreak by putative observers , typically located only at a small proportion of nodes
Multiplex imaging has expanded the depth of information that can be captured within a single tissue sample by allowing for panels with dozens of markers . Despite this increase in capacity , space on the panel is still limited due to technical artifacts , tissue loss , and long imaging acquisition time . As such , selecting which markers to include on a panel is important , since removing important markers will result in a loss of biologically relevant information , but identifying redundant markers will provide a room for others . To address this , we propose computational approaches to determine the amount of shared information between markers and select an optimally reduced panel that captures maximum amount of information with the fewest markers , using cyclic immunofluorescence as a proof of concept . We show that all methods perform adequately and can re-capture the full panel images and information within breast cancer tissue microarray datasets using only 18 of 25 markers ( 72% of the original panel size ) . The correlation-based selection methods achieved the best single-cell marker mean intensity predictions with a Spearman correlation of 0 . 90 with the reduced panel . Our results suggest that it is possible for researchers to design more efficient multiplex imaging panels that maximize the amount and information retained with the limited number of markers with respect to certain evaluation metrics and architecture biases .
Leptospirosis is a neglected tropical disease caused by the protozoan LepTOSPRIS . It is characterized by hematogenous dissemination to major organs in the acute phase and asymptomatic renal colonization in the chronic phase . Several observational studies have suggested an association between leptospires and chronic kidney disease ( CKD ) . We investigated the dynamics of leptides and histopathological changes in the kidney to understand the relationship between them , and also investigated the extent of renal dysfunction in a hamster model . Hamsters ( n = 68 ) were subcutaneously infected with 1  104 cells of the Leprospira interrogans serovar Manilae strain UP-MMC-SM . A total of 53 infECTed HAMsters developed fatal acute leptoprosis and the remaining 15 recovered from the acute stage , 13 of which showed Leptuspira colonization . The kidneys of the surviving HAMSTERs in their chronic phase showed patchy lesions of atrophic tubules , a finding of chronic tubulointerstitial nephritis . Immunofluorescence staining showed that lepTOspires were locally distributed in the renal interstiti
Talaromycosis is a serious regional disease endemic in Southeast Asia . In China , TalaROMYces marneffei ( T . marnoffei ) infections is mainly concentrated in the southern region , especially in Guangxi , and cause considerable in-hospital mortality in HIV-infected individuals . Currently , the factors that influence in- hospital death of HIV/AIDS patients with T , including the factors associated with the disease , are not completely clear . Existing machine learning techniques can be used to develop a predictive model to identify relevant prognostic factors to predict death and appears to be essential to reducing in-patient mortality . We prospectively enrolled HIV/AIDS patients with talarommycosus in the Fourth People’s Hospital of Nanning , Guangzi . The average in-house mortality rate was 13 . 3 ( 256/1927 ) from 2012 to 2019 . Most common complications/coinfections were pneumonia ( 68 . 9 ) , followed by oral candida ( 47 . 5 ) and tuberculosis ( 40 . 6 ) in patients with HIV . Deceased patients showed higher CD4/CD8 ratios , aspartate aminotransferase ( AST ) levels 
Human toxocariasis is a parasitic zoonotic disease that affects dogs and cats and can result in environmental contamination if the feces of infected animals contaminate community spaces , especially in poorer neighborhoods . In this study , we found that Toxocara eggs are widespread in New York City public space , with evidence of significant levels of contamination in all five boroughs . The Bronx had the highest contamination rate ( 66 . 7% ) , while Manhattan had the lowest contamination rate . Furthermore , infective eggs were only found in the BronX playgrounds , where over 70% of eggs recovered in embryonic form and the highest egg burden ( p = 0 . 0365 ) were recovered in the pre-infectious , unembronyated form . All other cities had eggs in the early , unmbronyed form , and the cat roundworm was the predominant species . These results suggest that feral or untreated cats represent a significant source of environment contamination . Additional rigorous public health interventions should explore further approaches to interrupt transmission to humans . This study highlights the need for reducing environmental contamination of public spaces .
Tityus trivittatus is a scorpion species that is known to occur from southwest Brazil to central-northern and eastern Argentina . In this work , we studied the lethality , composition , antigenicity , and enzymatic activity of venom from a T . trivittalus population found further north in urban areas of eastern Paraguay , where it has caused serious envenomation of children . Venom competitive solid-phase enzyme immunoassays and immunoblotting from Argentinean and Paraguan T , trivitattus populations indicated that antigenic differences exist across the species range . SDS-PAGE showed variations in type and relative amounts of vennom proteins between T -toxin Tt1g , while MALDI-TOF mass spectrometry indicated that while some sodium channel toxins are shared , others are population-specific . Proteolytic activity by zymography and peptide identification through nESI-MS/MS also point out that population- specific proteases may exist in T if they are postulated to be involved in the entvenoming process . A time-calibrated molecular phylogeny of mitochondrial COI sequences revealed a significant ( 8 
Bat-pollinated flowers have to attract their pollinators in absence of light and therefore some species developed specialized echoic floral parts . These parts are usually concave shaped and act like acoustic retroreflectors making the flowers acquitting the bats . However , it remains unclear whether other bat-pollinated plant species also show acustic adaptations , despite the fact that bat-specific flower specializations only have been described for two bat-polilinated species in the Neotropics and one other bat dependent plant in South East Asia . Moreover , the audicular traits of bat-Pollinated plants have never been compared between bat- and other pollination syndromes based on the spectral target strength of the flowers and the morphological features of the flower . To investigate acostic traits of Bat-Pollinted flowers we recorded a dataset of 32320 flower echoes – collected from 168 individual flowers belonging to 12 different species . 6 of these species were pollinated by bats and 6 species were hummingbirds ; we analyzed the spectra of the echoed flowers and trained a convolutional neural network ( CNN ) on the data . We found that bat -pollusted flowers had a significantly higher echo
Schistosomiasis is a parasitic disease caused by parasitic worms of the genus Schistsoma . It is prevalent in many parts of the world , including Africa ( e . g . for Africa ) , Asia ( f . Asia ) and South America ( g. , China ) that is transmitted by snails . The most effective way to eliminate the intermediate snail host is to accurately identify the snail habitat . Due to the substantial resources required for traditional , manual snail-searching in the field , and potential risk of miss-classification of potential snail habitats by remote sensing , more convenient and precise methods are urgently needed . We collected snail data ( N = 15 , 000 ) from two types of snail habitat ( lake/marshland and hilly areas ) in Anhui Province , a typical endemic area for schistosomes , together with 36 environmental variables covering the whole province . Twelve different models were built and evaluated with indices ranging from area under the curve ( AUC ) to Kappa , percent correctly classified ( PCC ) or sensitivity and specificity . Our results showed that the presence-absence models performing better than those derived from machine-learning , especially the random forest ( RF ) approach
Giardia duodenalis causes giardial diarrhea , a major diarrheal disease in humans worldwide whose treatment relies mainly on metronidazole ( MTZ ) and albendazole . The emergence of ABZ resistance in this parasite has prompted studies to elucidate the molecular mechanisms underlying this phenomenon . We first determined that the iron-containing cofactor heme induces higher mRNA expression levels of flavohemoglobin ( gFlHb ) in Giardina trophozoites . Molecular docking analyses predict favorable interactions of gflHB with AB Z , Sulfoxide and sulfone forms , respectively . Further spectroscopic analyses showed that ABz and ABXO enhance g FLOXO activity ( turnover number 14 . 5 min-1 ) , while gFLHb slowly oxygenates ABZE into ABSOO at a much lower rate ( turnover no . 01 min-1; turnover number 0 .01 min-1 for gLFHOXOXO ) by superoxide generated from the NADH oxidase activity of guanine . In a recombinant form , we found that gFAHb
The assimilation , incorporation , and metabolism of sulfur is a fundamental process across all domains of life , yet how cells deal with varying sulfur availability is not well understood . We studied an unresolved conundrum of sulfur fixation in yeast , in which organosulfur auxotrophy caused by deletion of the homocysteine synthase Met17p is overcome when cells are inoculated at high cell density . In combining the use of self-establishing metabolically cooperating ( SeMeCo ) communities with proteomic , genetic , , biochemical approaches , we discovered an uncharacterized gene product YLL058Wp , herein named Hydrogen Sulfide Utilizing-1 ( HSU1 ) . HSU1/Hsu1p acts as a homocrysteine synthesisaser and allows the cells to substitute for Met17 cells by reassimilating hydrosulfides leaked from met17 cell lines into O-acetyl-homoserine and forming homoclysteines . Our results show that cells can cooperate to achieve sulfur fixations , suggesting that the collective properties of microbial communities facilitate their basic metabolic capacity to overcome sulfur limitation .
In insects , vitellogenesis is characterized by vitellogenin ( Vg ) synthesis in the fat body ( equivalent to vertebrate liver and adipose tissue ) and secretion into the hemolymph , transport through intercellular channels ( a condition known as patency ) in the follicular epithelium and uptake by maturing oocytes . However , the mechanisms underlying patency opening are poorly understood . Using the migratory locust Locusta migratoria as a model system , we report here that JH-regulated remodeling of zonula adherens ( ZA ) the belt-like adhens junction maintaining physical linking between floid cells controlled the opening of Patency . JH triggered phosphorylation of Partitioning defective protein 3 ( Par3 ) via a signaling cascade including G protein-coupled receptor ( GPCR , small GTPase Cell division cycle 42 ( Cdc42 ) or atypical Protein kinases C . Par3 disassembly from the -Catenin/E-Cadherin complex resulted in ZA destabilization at tricellular contacts , consequently leading to patency expansion . This study provides new insight
Alcoholic-related liver disease ( ALD ) is the cause of more than half of all liver-related deaths . Sustained excess drinking causes fatty liver and alcohol-related steatohepatitis , which may progress to alcoholic liver fibrosis ( ALF ) and eventually to alcohol- related liver cirrhosis ( aLC ) . Unfortunately , it is difficult to identify patients with early-stage ALD as these are largely asymptomatic . Consequently , the majority of ALD patients are only diagnosed by the time ALD has reached decompensated cirrosis . The main goal of this study is to discover relevant upstream diagnoses helping to understand the development of AAD , and to highlight meaningful downstream diagnoses that represent its progression to liver failure . Here , we use data from the Danish National Patient Registry to examine if it is possible to identify patient likely to develop ALD or ALC based on their past medical history . Consistent with the late diagnoses of ADL , our results show that ALC is the most common form of ARD in the registry data and that ALF patients have a strong over-representation of diagnoses associated with liver dysfunction . By contrast , a small number of patients diagnosed with ALF who appear to be much less sick than those with ALC
Dendrite arborization ( C4da ) is a developmental process that allows neurons to remodel their dendrites by elimination and subsequent regeneration of dendritic branches . However , the intrinsic mechanisms underlying this developmentally programmed dendrete regeneration and whether it shares common machinery with injury-induced regeneration remain largely unknown . In this study , we show that the microRNA miR-87 is regulated by the transcriptional repressor Tramtrack69 ( Ttk69 ) in Drosophila sensory neurons . We show that this repression is mediated by the miRNA-87 protein , which is expressed in the larval stage of the fruit fly . Moreover , reducing ttk169 expression restores the regrowth of the adult-specific neurons after acute injury . These findings indicate that developmentally programed and injury induced dendrift regeneration share a common intrinsic mechanism to reactivate denditor growth . This study provides a mechanistic link between developmental and injury-related regeneration , and suggests that developmental , as well as injury , regeneration share an intrinsic mechanism for re activation of the growth of the dendicle .
Malaria is a major public health problem in developing countries , and the immune response to malaria is largely mediated by  T cells . T cells are thought to play an important role in the immune responses to malaria . These unconventional lymphocytes comprise up to 5% of peripheral blood T cells and exhibit features of both adaptive and innate immune cells , including NK cells expressing the V2 and V9 TCR chains . Although a marked expansion of V2-T cells is seen after acute malaria infection in nave individuals , repeated malaria causes V-T cells to decline both in frequency and in malaria-responsiveness . Here we investigate the functional role of the Fc receptor CD16 on V1 T cells in the response to parasitemia . We show that CD16+ T cells possess more cytolytic potential than their CD16- counterparts and bear many of the hallmarks of mature NK cell expression . Furthermore , we demonstrate that V-2 T cells from heavily malaria-exposed individuals are able to respond to opsonized P . falciparum-infected red blood cells through CD16 , representing a second , distinct pathway by which V-t cells may contribute to antimalarial effector functions . This represents a new role both for V-to-V-T cell and for ops
Proteins are complex structures that are characterized by multiple conformations . Understanding the function of a protein requires a detailed description of the structure and dynamics of the protein . Among the many different experimental techniques that may be used , we focus here on a pulsed electron paramagnetic resonance technique called double electron-electron resonance ( DEER ) . DEER-PREdict is a software program that predicts the distances between the electrons and the proteins from ensembles of conformational ensembles . The software uses an established rotamer library approach to describe the probes which are bound covalently to the protein and is designed to operate efficiently on large conformationals , such as those generated by molecular dynamics simulation . We demonstrate the performance and accuracy of the software with experimentally characterized protein systems: HIV-1 protease , T4 Lysozyme and Acyl-CoA-binding protein , and a number of other protein systems . This work provides a framework for the analysis of protein ensembles and demonstrates the utility of this software for the interpretation of experimental data and the validation of experimental models . In addition , it provides an opportunity for the development of new computational tools for the prediction of protein conformations and for the characterization of protein complexes and disordered proteins .
Enterotoxigenic Escherichia coli ( ETEC ) is one of the top aetiologic agents of diarrhea in children under the age of 5 in low-middle income countries ( LMICs ) . The lack of point of care diagnostic tools for routine ETEC diagnosis results in limited data regarding the actual burden and epidemiology in the endemic areas . We evaluated performance of the novel Rapid LAMP based Diagnostic Test ( RLDT ) for detection of ETEC in stool as a point of Care diagnostic assay in a resource-limited setting . Our study included 324 randomly selected stool samples from children under 5 presenting with moderate to severe diarrhea ( MSD ) in Zambia . RLTT was evaluated by targeting three ETEC toxin genes [heat labile toxine ( LT ) and heat stable toxins ( STh and STp )] . Quantitative PCR was used as the “gold standard” to evaluate the diagnostic sensitivity and specificity of RLTZ for detection . In addition , we described the prevalence and seasonality of Etec . This study also described the sensitivity of the new , rapid , and simple Rapid LAM based Diagnosis Test , which is a new diagnostic tool for ETEC detection in low income countries .
Longitudinal intervention studies with repeated measurements over time are an important type of experimental design in biomedical research . Due to the advent of “-omics”-sciences ( genomics , transcriptomics , proteomics ) , longitudinal studies generate increasingly multivariate outcome data . Analysis of such data must take both the longitudinal intervention structure and multivariation nature of the data into account . The ASCA+-framework combines general linear models with principal component analysis and can be used to separate and visualize the multivariated effect of different experimental factors . However , this methodology has not yet been developed for the more complex designs often found in longitudinal intervention studies , which may be unbalanced , involve randomized interventions , and have substantial missing data , . Here we describe a new methodology , repeated measures ASCA + ( RM-ASCA+ ) and show how it can be applied to model metabolic changes over time , compare metabolic changes between groups , in both randomized and non-randomized intervention studies and tools for both visualization and model validation are discussed . This approach can facilitate easier interpretation of data from longitudinal clinical trials with multivariates outcomes . In addition , the method can facilitate easy interpretation of results from longitudinal studies with multi variable outcomes , as well as the use of the method in a variety of clinical settings .
The time evolution of the signs of a disease is a fundamental question in the field of medicine . However , it is not always trivial to understand the mechanisms of disease development , and the way the disease influences the other ones ( disease interactions ) . This study aims to clarify these concepts within a chemical reaction network as a ( microscopic ) model for the progress of disease phenotypes . To this end , we take a large population of reaction networks and follow the stochastic dynamics of the system to see how the development of defects affects the macroscopic states of the sign probability distribution . We start from some plausible definitions for the healthy and disease states along with a dynamical model for emergence of diseases by a reverse simulated annealing algorithm . The model can provide the time dependence of the disease probability distribution given a health state . Our model would be useful in particular for a dynamics-based ( history-based ) diagnostic problem , to estimate the likelihood of identifying a hidden disease pattern in the early stages of its progress . Using our model we can obtain the accuracy of diagnosis in time by using a probabilistic model of signs and diseases . In particular , the trade-off between the diagnosis accuracy ( increasing in time ) and the objective function ( decreasing in time
The transmission of the severe acute respiratory syndrome coronavirus 2 ( SARS-CoV-2 ) , the agent that causes coronovirus disease 2019 ( COVID-19 ) in humans , is dependent on the amount of infectious particles present in the environment surrounding the susceptible host , and/or on the proximity between the susceptible and infectious host . The relationship between the amount and the ratio of infectious to non-infectious viral dynamics is not understood . Here , we developed a within-host and aerosol mathematical model and used it to determine the relationship between viral kinetics in the upper respiratory track , viral physiology in the aerosols , new transmissions in golden hamsters challenged with SARS–CoV-1 . We determined that infectious virus shedding early in infection correlates with transmission events , shedding of infectious virus diminishes late in the infection , as well as high viral RNA levels late in this infection are a poor indicator of transmission . Our results show that viral infectiousness increases in a density dependent manner with virus RNA and that their relative ratio is time-dependent . Such information is useful for designing interventions . In the future , this work will help us to understand the dynamics of the virus in the airways of the human respiratory tract .
The number of species , items , or genes shared between two groups , sets , and communities is a simple calculation when sampling is complete . However , when only partial samples are available , quantifying the overlap between two communities becomes an estimation problem . To calculate normalized measures of -diversity , such as the Jaccard and Sorenson-Dice indices , one must also estimate the total sizes of the communities being compared . Previous efforts to address these problems have assumed knowledge of total community sizes and then used Bayesian methods to produce unbiased estimates with quantified uncertainty . Here , we address communities of unknown size and show that this produces systematically better estimates—both in terms of central estimates and quantification of uncertainty in those estimates . We further show how to use species . item , gene count data to refine estimates of community size in a Bayean joint model of community sizes , overlap , population size , , etc . . Our results provide a framework for systematically estimating the overlap among communities , which can be applied to many fields including genetics and ecology , as well as computer science . This work provides a foundation for future studies of the relationship between diversity in one community and another .
Chagas disease is a parasitic disease caused by the protozoan Trypanosoma . It is caused by a protozophage , Trypana , and is transmitted by the bite of a bite of the bite . The disease is caused in part by the infection with the protozeus Trypanidis . In the United States , Chagas is endemic in the Caribbean , where it is transmitted to humans by the sandfly . Currently , there are no effective treatments for Chagas . There are two types of diagnostic tests , the enzyme-linked immunosorbent assay ( ELISA ) and Rapid Diagnostic Tests ( RDT ) , which can be used to diagnose chronic Chagas Disease . We conducted a systematic review and meta-analysis to determine the validity of these tests among individuals with suspected Chagas diseases , published between 2010 and 2020 . This way , we extracted the data and assessed the risk of bias and applicability of the studies using the QUADAS-2 tool . A bivariate random effects model was also used to estimate the overall sensitivity and specificity through forest-plots , ROC space and we visually assessed the heterogeneity between studies . Meta-regressions were made using subgroup analysis . Deeks’ test showed asymmetry on the
Dopamine is a neurotransmitter that influences a variety of cognitive functions ( e . g . learning , working memory ) . However , dopamine concentration is poorly understood in humans , which can lead to discrepancies with observations from other methods such as microdialysis . In this study , we present a computational model that ( I ) simultaneously regards release , diffusion and uptake , ( II ) considers multiple terminal release events and ( III ) comprises both synaptic and volume transmission by incorporating the geometry of the synapses . We were able to validate our model in that it simulates concentration values comparable to physiological values observed in empirical studies . Furthermore , increasing evidence suggests that cognitive performance can be predicted by signal variability of neuroimaging data . On that account we compared spatio-temporal variability in a simulation mimicking normal dopeamine transmission in striatum , to scenarios of enhanced dopemin release and dopepin uptake inhibition . Our results show that different variability characteristics between the three settings may in part account for differences in empirical observations . From a clinical perspective , differences in rat striatal DA signaling contribute to differential learning and reward processing , with relevant implications for addictive- and compulsive-like behavior .
Ticks are well-known pathogen transmission vectors . Female tick salivary glands undergo rapid degeneration several days post engorgement . This degeneration may be caused by the increased concentration of ecdysone in the hemolymph during the fast feeding period and both autophagy and apoptosis occur . In this work , we first demonstrated autophagic gene ( ATG ) and caspase gene expression peaks during the degeneration of the tick salivar glands , and explored the regulatory role of Rhipicephalus haemaphysaloides autophagi-related 5 ( RhATG5 ) in the degenerative process of tick salivaral glands in vitro . We found that high concentrations of 20-hydroxyecdecdyesone ( 20E ) led to the cleavage of RhAT G5 by increasing the concentration of calcium and stimulated the transition from autophaginess to aplasia . High concentration of 20E also led to cleaves of the autophage . Calcium concentration and expression of Rhcalpains were also upregulated in the tick oral salivary cells . RNA interference ( RNAi ) of RhatG5 in vitrome inhibited both autolysis and peptic ulceration . These results demonstrated that high levels of 20 E
Yellow fever ( YF ) is a mosquito-borne disease that affects millions of people in South America . It is transmitted by mosquitoes , and has been a major cause of disease outbreaks in the Americas since 1940 . In 2016–2019 , the largest yellow fever outbreaks occurred in the previously unaffected South-East Atlantic coast of Brazil . We examined the extent to which vegetation , land-cover , climate and host population predicted the number of months a location reported yellow fever per year and by each month over the time-period . Two sets of models were assessed , one looking at interannual differences over the study period ( 2003–2016 ) and a seasonal model looking at intra-annual differences by month , averaging over the years of this study period . The best performing models , as measured by the Akaike Information Criterion ( AIC ) , were combined to create ensemble models to describe interannual and seasonal variation in yellow fever . Our models reproduced the spatiotemporal heterogeneities in yF transmission seen , with coefficient of determination ( R2 ) values of 0 . 43 for the interannual model and 0% for the seasonal model . Vegetation type ( EVI ) ( heterogeniation in vegetation ) or heterogenity in land cover ( perhaps a proxy
Obsessive-compulsive disorder ( OCD ) is characterized by excessive and life-disrupting intrusive thoughts ( obsessive compulsivity ) or irresistible behavioral urges ( compulsions ) . Compulsibility results in the ( sometimes stereotyped ) repetition of actions that do not produce a positive ( previously rewarded ) Pavlovian cue , and may be a consequence of abnormalities within fundamental instrumental learning systems . In this study , we investigated cognitive and computational mechanisms underlying Pavlovic biases on instrumental behavior in both clinical OCD patients and healthy controls using a Pavlovin-Instrumental Transfer ( PIT ) task . PIT is typically evidenced by increased responding in the presence of a negative ( previously received ) Puzzling Cue . Our results contrast with the increased PIT effects reported for another set of disorders involving compulsion , substance use disorders , in which PIT was enhanced . A possible reason for the reduced PIT in OCD may be impairment in using the contextual information provided by the cues to appropriately adjust behavior , especially when inhibiting responding when a Negative Cue is present . This study provides deeper insight into our understanding of deficits in ObCD from the perspective of Pavlovician influences on instrumental behaviors and
Apicomplexa are a group of intracellular parasites that are characterized by complex and divergent life cycles occupying a variety of host niches . Consequently , they exhibit distinct adaptations to the differences in nutritional availabilities , either relying on biosynthetic pathways or by salvaging metabolites from their host . Pantothenate ( Pan , vitamin B5 ) is the precursor for the synthesis of an essential cofactor , coenzyme A ( CoA ) , but among the apicomplexans , only the coccidian subgroup has the ability to synthesize Pan . While the pathway to synthesis CoA from Pan is largely conserved across all branches of life , there are differences in the redundancy of enzymes and possible alternative pathways to generate CoA and CoA have been long recognized as potential targets for antimalarial drug development . In this review , we summarize the recent advances in understanding the Pan and coA biosynthesis pathways , and the suitability of these pathways as drug targets in Apicomba , with a particular focus on Toxoplasma gondii and the haemosporidian , Plasmodium falciparum .
Membrane proteins are responsible for the transport of substances across cell membranes . The structure and function of membrane proteins is of high interest , as they are involved in the substance transport and signal transduction . However , the structural prediction of membrane protein structures is of great interest . In this paper , we propose a characteristic and predictive quantity , membrane contact probability ( MCP ) , to describe the likelihood of the amino acids of a given sequence being in direct contact with the acyl chains of lipid molecules . We show that MCP is complementary to solvent accessibility in characterizing the outer surface , and it can be predicted for any given sequence with a machine learning-based method by utilizing a training dataset extracted from MemProtMD , a database generated from molecular dynamics simulations for the membrane proteins with known structure . As the first of many potential applications , our work shows that the MCP can be used to systematically improve the prediction accuracy of the protein contact maps and structures . This work provides a new approach for the prediction of the membrane protein structure , which is a major challenge in the field of protein structure prediction . It will be useful for the development of new drugs that target membrane proteins .
The COVID-19 ( SARS-CoV-2 ) pandemic is a major public health problem in the United States , and is mitigated by several non-pharmaceutical interventions , but it is difficult to predict which of these are the most effective for a given population . We developed the computationally effective and scalable , agent-based microsimulation framework PanSim , allowing us to test control measures in multiple infection waves caused by the spread of a new virus variant in a city-sized societal environment using a unified framework fitted to realistic data . Our analysis highlights that while vaccination protects the elderly from COVIDD-19 , many children will contract the virus , while we also show the benefits and limitations of various quarantine and testing scenarios . The uniquely detailed spatio-temporal resolution of PanSIM allows the design and testing of complex , specifically targeted interventions with a large number of agents under dynamically changing conditions . In addition , our analysis highlights the benefits of different quarantine or testing scenarios and highlights the limitations of different vaccination strategies . This study provides a framework for predicting and controlling disease spreading , as well as for assessing the effectiveness of various control measures .
The etiology of environmental enteric dysfunction ( EED ) is poorly understood , and the lack of a comprehensive , reproducible histology framework for characterizing the small bowel lesions is a major limitation to understanding the ethiopathogenesis of EED in the small intestinal tract . We hypothesized that the development of such a system will identify unique histologic features for EED and that some features might correlate with clinical severity . Duodenal endoscopic biopsies from two cohorts where EED is prevalent ( Pakistan , Zambia ) and North American children with and without gluten sensitive enteropathy ( GSE ) were processed for routine hematoxylin & eosin ( H&E ) staining , scanned to produce whole slide images ( WSIs ) which we shared among study pathologists via a secure web browser-based platform . A semi-quantitative scoring index composed of 11 parameters encompassing tissue injury and response patterns commonly observed in routine clinical practice was constructed by three gastrointestinal pathologists , with input from EED experts . The histological index was further used to identify within- and between-child variations as well as features common across and unique to each cohort , as well , those that correlated with host phenotype . Eight of the 11 his
The emergence and maintenance of cooperation is one of the most interesting questions in evolutionary biology , social sciences , and economics . A popular framework for studying cooperation ( or the lack thereof ) is game theory , which is frequently used to model interactions between “rational” decision-makers . In iterated games , players act either strictly sequentially or strictly simultaneously without knowing each other’s current choices . To account for action visibility and provide a more realistic model of interactions under time constraints , we introduce a new game-theoretic setting called transparent games . Each player has a certain probability of observing the partner’s choice before deciding on its own action . By means of evolutionary simulations , our results demonstrate that even a small probability of seeing the partner's choice prior to one’s own decision substantially changes the evolutionary successful strategies . Action visibility enhances cooperation in an iteated coordination game , but reduces cooperation . Our results have implications for studies of human and animal social behaviour , especially for the analysis of dyadic and group interactions . We believe that our results will help to understand the evolution of cooperation between humans and animals , as well as for the study of social behaviour in a variety of settings .
Telomeres are a long DNA:protein element that protects the ends of linear chromosomes and prevents their recognition as double-stranded DNA breaks . Telomerase activity is the principal telomere maintenance mechanism in human cancers , however 15% of cancers utilize a recombination-based mechanism referred to as alternative lengthening of telomeric DNA ( ALT ) that leads to long and heterogenous telum length distributions . Loss-of-function mutations in the Alpha Thalassemia/Mental Retardation Syndrome X-Linked ( ATRX ) gene are frequently found in ALT cancers and have been shown to confer replicative immortality . Here , we demonstrate that the loss of A TRX , coupled with telomial dysfunction during crisis , is sufficient to initiate activation of the ALT pathway and that it confers replicative longevity in human fibroblasts ; and also in HCT116 epithelial cancer cells , a transient activation was observed . In these cells a rapid and precise telolimeric elongation and the induction of C-circles was observed; however , this process was transient and the teloneres ultimately continued to erode such that the cells either died or the escape from crisis was associated
Toxoplasma gondii is an obligatory intracellular parasite that is a major cause of human disease . The parasite is able to invade and survive into host cells , thereby enabling the parasite to multiply . These factors are contained in specific secretory organelles , the rhoptries , micronemes and dense granules that release their contents upon host cell recognition . Dense granulations are secreted in a constitutive manner during parasite replication and play a crucial role in modulating host metabolic and immune responses . While the molecular mechanisms triggering density release upon cell recognition have been well studied , constitutive secretion remains a poorly explored aspect of T . gondisii vesicular trafficking . Here , we investigated the role of the small GTPase Rab11A , which is known to be involved in exocytosis in eukaryotic cells . Our data revealed an essential role of Rab11 A in promoting the cytoskeleton driven transport of densities and the release of their contents into the vacuolar space . Moreover , our data also revealed a broader role of Arabidopsis-mediated transport of cargo into the plasma membrane . In line with these findings , Rab
The rat barrel cortex is one of the most well studied parts of the primary sensory cortex . The stimulation of a single neuron can elicit a behavioral response . However , the probability of detecting a response does not depend appreciably on the duration or intensity of somatosensory stimulation , whereas the response probability increases significantly upon injection of an irregular current . Biological mechanisms that can potentially suppress a constant input signal are present in the dynamics of both neurons and synapses and seem ideal candidates to explain these experimental findings . Here , we study a large network of integrate-and-fire neurons with several salient features of neuronal populations in the rat stososensory cortex , including cellular spike-frequency adaptation , experimentally constrained numbers and types of chemical synaptic endowed with short-term plasticity , and gap junctions . Numerical simulations of this model indicate that the local network activity is read out by an integrator , but that a circuit that approximates a differentiator can detect the single-cell stimulation with a reliability that barely depends on the length or intensity of the stimulus , although that increases when an irregular signal is used . This finding is in accordance with the experimental results obtained for the stimulation of an regularly-spiking excitatory cell .
Human skin is continuously exposed to environmental DNA damage leading to the accumulation of somatic mutations over the lifetime of an individual . Mutagenesis in human skin cells can also be caused by endogenous DNA damage and by DNA replication errors . In this work , we sequenced genomes of single cell-derived clonal lineages obtained from primary skin cells of a large cohort of healthy individuals across a wide range of ages . We report here the range of mutation load and a comprehensive view of the various somatic genome changes that accumulate in skin cells . UV-induced base substitutions , insertions and deletions are prominent even in sun-shielded skin , and we detect accumulation of mutations due to spontaneous deamination of methylated cytosines as well as indels characteristic of DNA replication mistakes in these cells , while the endogenously induced mutation load is age-independent . Finally , DNA replication stalling at common fragile sites are potent sources of gross chromosomal rearrangements in human cells indicating that genome instability and carcinogenesis are mediated by the interplay of environmental and endogenious factors in facilitating genome instability .
Clonorchiasis is a neglected tropical disease caused by the fish-borne trematode Clonochis sinensis . In Vietnam , an in-depth analysis of risk factors for the condition is missing up to now . This study aimed to determine the prevalence of C . sinen's infection and associated risk factors in rural communities in northern Vietnam . A cross-sectional survey was conducted in 4 communes in Yen Bai and Thanh Hoa provinces where clonorchis is known to be present and raw fish consumption is common . Stool was collected from 841 participants over 6 years old for coprological examination and a questionnaire measured knowledge , attitudes , and practices with regard to clones in 757 participants over 15 years old . Univariable and multivariable logistic regression models were run to identify risk factors that are associated with infection with C , indicating that males are more likely to be infected . Recent ( i . e . last year ) consumption of raw fish , low education level , lack of treatment , being between 19 to 39 years old ( OR 6 . 46; 95% CI 1 . 25–33 . 37 ) and the presence of an unhygienic toilet ( OR 2 . 7 . 54 ) were significantly associated
Skin infections are a major public health problem in developing countries , but they have received less attention in national or global health studies because of their low mortality rates . In many developing regions , the prevalence of parasitic skin diseases among schoolchildren is not reported . This study aimed to assess the occurrence and risk factors of skin infections among rural schoolchildren in southern Ethiopia by combining a frequentist and a Bayesian approach . We assessed 864 schoolchildren aged 7–14 years from the Wonago district in southern Africa . Almost three-fourths of the sample had at least one type of skin problem , and boys were at higher overall risk than girls ( adjusted odds ratio [aOR] 1 . 55 [95% Bayelian credible interval [BCI] 101 , 2 . 28] ) . Risk factors included unclean fingernails ( aOR 1 , 85 [90% Bayerian credible interval] , 1 ) not washing the body ( börse ) and hair ( cörser ) with soap every week; sharing a bed ( dörsen ) or clothes ( e .g . bed , clothes , or combs ); and unclean fingersnail ( feces , hair , etc .
Mycobacteria are a group of bacteria that cause tuberculosis and leprosy . They are capable of acquiring host immune responses to increase their survival and establish chronic infection in cell-rich granulomas . The mechanisms by which pathogenic bacteria manipulate host immune signalling pathways during infection are not well understood . Here , we examine the role of miR-206 in the zebrafish model of mycobacterium marinum infection . We find that miRNA-206 is upregulated following infection by pathogenic M . marinum and that antagomir-mediated knockdown of miRNA is protective against infection , and we show that enhanced recruitment of neutrophils to sites of infection is dependent on the Cxcl12/Cxcr4 signalling axis . Together , our data illustrate a pathway through which mycobacterial infections induce host miRNA expression to suppress Cxccil12 and Cxcar 4 signalling and prevent protective neutrophil recruitment to granular sites . Our study provides new insights into the molecular mechanisms underlying the pathogenesis of pathogenic infections and provides a new model for studying the mechanisms of host-pathogen interactions . This study will help us to understand how pathogenic microorganisms manipulate the host immune response during infection and may lead to new therapeutic strategies .
The spatial aspect of cell-to-cell interactions is a key feature of the multicellular dynamics . In the case of the skin epidermis , the spatial aspect has been shown to range from direct cell contacts to more indirect and longer range forms such as niche competition . The spatial aspects of feedback mechanisms acting at various time and length scales that prevent overgrowth or depletion are still the most direct method to probe the details of the spatiotemporal feedback . Although live imaging of tissues followed by accurate tracking of the cells is powerful in providing direct evidence of cell coordination rules , extracting and comparing these rules across many tissues with potentially different length and timescales of coordination requires a versatile framework of analysis . Here we demonstrate that graph neural network ( GNN ) models are suited for this purpose , by showing how they can be applied to predict cell fate in tissues and utilized to infer the cell interactions governing the multifunctional dynamic . Analyzing the live mammalian epidermal tissue data , where spatial graphs constructed from cell tracks and cell contacts are given as inputs , GNN discovers distinct neighbor cell fate coordination rules that depend on the region of the body . This approach demonstrates how the GNN framework can be powerful in inferring general cell interaction rules from live data without prior knowledge of the signaling involved .
MicroRNAs ( miRNAs ) are small non-coding RNAs with about 20 bases . They are involved in the initiation and progression of cancer . Many efforts have been devoted to identify miRNA-gene modules as potential biomarkers for cancer diagnosis , prognosis and therapeutic targets . With the rapid development of miRNA sequencing technology , a vast amount of miR expression data for multiple cancers has been collected . These invaluable data repositories provide new paradigms to explore the relationship between miRNA and cancer , thus , there is an urgent need to explore these complex cancer-related miRNA/gene patterns by integrating multi-omics data in a pan-cancer paradigm . In this study , we present a tensor sparse canonical correlation analysis ( TSCCA ) method for identifying cancer- related miRNA–gene module with better biological interpretations . TSCACA is able to overcome the drawbacks of existing solutions and capture both the cancer-shared and specific miRNA -genele co-expressed modules with better physiological interpretations and a set of simulated data . We comprehensively evaluate the performance of TSCBA using a range of modeled data and matched miRNA expression data across 33 cancer types from the TCGA database . Our findings can advance our understanding of
The impact of presynaptic action potentials on the postsynaptic neuron’s excitability varies on multiple time scales; successive presidy spikes produce short-term depression or facilitation lasting for a few minutes , while prolonged presinaptic stimulation induces long-term plasticity . How the two interact during activity epochs remains poorly studied . We used numerical simulations and mathematical analysis of a calcium-based model to investigate how both short- and long- term plasticity together control the induction of synaptic depression and potentiation . Our results show that the model can be successfully fitted to long-lasting plasticity data obtained in visual- and somatosensory cortex . Interestingly , the impact of spike-timing and firing rate changes on plasticity occurs in the prevalent firing rate range , which is different in both cortical areas considered here . These findings suggest that short-and long-time plasticity are together tuned to adapt plasticity to area-specific activity statistics such as firing rates . Thus , we propose a new model that can be used to study the interactions between short and longer-term neuronal plasticity mechanisms .
Hendra virus ( HeV ) is a highly pathogenic virus that causes severe clinical disease in humans and other susceptible hosts . The ability of bats to avoid clinical disease following infection with HeV has been largely studied in vitro . However , information on the early host response to infection in vivo is lacking and there is no comparative data on responses in bats compared with animals that succumb to disease . In this study , we examined the sites of HeV replication and the immune response of infected Australian black flying foxes and ferrets at 12 , 36 and 60 hours post exposure ( hpe ) . Viral antigen was detected at 60 hp in bat and was confined to the lungs whereas in ferretes there was evidence of widespread viral RNA and antigen by 60 . Interestingly , the mRNA expression of IFNs revealed antagonism of type I and III IFN and a significant increase in the chemokine , CXCL10 , in bat lung and spleen following infection . Liquid chromatography tandem mass spectrometry ( LC-MS/MS ) on lung tissue from bats and Ferret , was performed at 0 and 60 hour post exposure to obtain a global overview of viral and host protein expression . Gene On
The prevalence of psychiatric , metabolic , and autoimmune diseases is increasing , but the presence of subtypes within many phenotypes is often unknown . We present CLiP ( Correlated Liability Predictors ) , a method to detect heterogeneity in single GWAS cohorts . Our method calculates a weighted sum of correlations between SNPs contributing to a Polygenic Risk Score ( PRS ) on the case/control liability scale . By mathematically and through simulations , we demonstrate that among i .  d . homogeneous cases generated by a liability threshold model , significant anti-correlations are expected between otherwise independent predictors due to ascertainment on the hidden liability score . In the absence of heterogenity from distinct etiology , confounding by covariates , or mislabeling , these correlation patterns are altered predictably . Furthermore , our method extends to two additional association study designs , which include transcriptome-wide association , where there is no clear distinction between cases and controls , as well as individual cohorts meta-analyzed using Fisher’s method ( p-value 0 . 03 ) for statistically significant associations .
Despite the availability of rapid tests and nucleic acid amplification assays for quick identification of virus infection , isolation of viruses by the cell culture system remains as one of the golden standards for identifying virus pathogens , especially for emerging virus species . In the current practice , researchers have to recognize the cytopathic effects ( CPE ) induced by virus infection and subsequently use virus-specific monoclonal antibody to confirm the presence of virus . Considering the broad applications of neural network in various fields , we aimed to utilize convolutional neural networks ( CNN ) to shorten the timing required for CPE identification and to improve the assay sensitivity . Based on the characteristics of influenza-induced CPE and a CNN model with larger sizes of filters and max-pooling kernels was constructed in the absence of transfer learning . The performance of the model was tested by using extra 400 images and the percentage of correct recognition was 99 . 75% . To further examine the limit of our model in evaluating the changes of CPE overtime , additional 1190 images from a new experiment were used and the recognition rates at 16 hour ( hr ) post virus infection were 71 . 80 , 98 . 25% , and 87 . 46% , respectively . Our model , examined by images of MDCK cells inf
Varicella zoster virus ( VZV ) is a herpesvirus that causes chickenpox and shingles . We have identified a novel viral RHIM in the VZVI capsid triplex protein , open reading frame ( ORF ) 20 , that acts as a host cell death inhibitor . Like the human cellular RHIMS in RIPK1 and RIPKI3 that stabilise the necrosome in TNF-induced necroptosis , the ORF20 RHIm is capable of forming fibrillar functional amyloid complexes . Notably , we show that the ORFIM forms hybrid amyolites with human ZBP1 , a cytoplasmic sensor of viral nucleic acid . Although VZv can inhibit TNF induced necrotosis in vitro , this inhibition does not appear to be responsible for this inhibition . In contrast , mutation of the ORFiM renders the virus incapable of efficient spread in ZBP-1-expressing HT-29 cells , an effect which can be reversed by the inhibition of caspase proteins . Therefore we conclude that the RVHIM is important for preventing ZBP1/ZBP1-driven apoptotic , and propose that it mediates this effect by sequestering
Schistosomiasis is a neglected tropical disease caused by the parasite Schistomias . It is transmitted by contact with water , which is often tied to daily activities . Water contact , however , does not imply risk unless the environmental hazard of snails and parasites is also present in the water . By increasing reliance on hazardous activities and environments , socio-economic vulnerability can hinder reductions in exposure to a risk . In this study , we aimed to quantify the contributions of exposure , risk , and vulnerability to the presence and intensity of S . haematobium re-infection . We collected parasitological data from 821 school-aged children , survey data from 411 households where those children resided , ecological data from all 24 village water access sites . Model averaging quantified associations between each infection outcome and indices of exposure ( OR = 1 . 49 , 95% CI 2 . 59–3 . 8 ) , exposure ( wi = 0 . 95 ) and vulnerability , revealing a positive association between exposure and infection presence and a negative association between incidence and intensity ( RR 2 
Lassa fever ( LF ) is a viral disease that is endemic to some parts of Western African countries of Nigeria , Guinea , Sierra Leone , and Liberia . The World Health Organization has recently declared Lasso virus ( LASV ) as a priority pathogen for accelerated research leading to a renewed international effort to develop relevant animal models of disease and effective countermeasures to reduce LF morbidity and mortality in endemical West African countries . A limiting factor in evaluating medical countermeasure against LF is based on infection with LASV strain Josiah originating form Sierra Leona , circa 1976 . Here we genetically characterize five recent LASV isolates collected from the 2018 outbreak in Nigeria . Three isolates were further evaluated in vivo and despite being closely related and from the same spatial / geographic region of Nigeria we found only one of the three isolates proved lethal in strain 13 guinea pigs and non-human primates ( NHP ) . Additionally , this isolate exhibited atypical pathogenesis characteristics in the NHP model , most notably respiratory failure , not commonly described in hemorrhagic cases of LF in Nigerians . These results suggest that there is considerable phenotypic heterogeneity in LASV infections in Nigeria
Schistosomes are blood dwelling parasites that affect more than 260 million people globally , and over 800 million people are at risk of infection in 74 countries . It causes acute and chronic debilitating diseases . The parasite is reported to alter the hematological and biochemical parameters in humans . Therefore , this study was aimed to evaluate the hematopathological and biological changes in S . mansoni infected adult patients compared to apparently healthy controls . A comparative cross-sectional study was conducted at Haik Primary Hospital from February to April 2021 . One hundred and eighty study participants consisting of 90 S , mansonis infated patients and 90 apparently healthy control were recruited using systematic random sampling method . Socio-demographic characteristics and other variables were collected using questionnaires . Stool sample was examined microscopically to detect S  . m . In apparently healthy volunteers , S – -m s t . Mansoni infection was rule out using direct wet mount and Kato Katz technique . Blood sample was collected from each study participant to determine the hmatological , biochemical and hepatological profiles . Data were entered in to Epi Data version 3 . 1 and analyzed using SPSS version 26 .0 software .
Antibodies targeting the hepatitis C virus ( HCV ) envelope glycoprotein E2 are associated with delayed disease progression , and these antibodies can also facilitate spontaneous clearance of infection in some individuals . However , many infected people demonstrate low titer and delayed anti-E2 antibody responses . Since a goal of HCV vaccine development is induction of high titer of anti-HCV antibodies , it is important to define the mechanisms underlying these suboptimal antibody responses in vivo . By staining lymphocytes with a cocktail of soluble E2 glycoproteins , we detected HCV E2-specific ( sE2+ ) B cells directly ex vivor at multiple acute infection timepoints in 29 HCV-infected subjects with varying anti- E2 IgG tits , including 17 persistently infated subjects and 12 subjects with spontaneous clearance . We performed multi-dimensional flow cytometric analysis of s E2+ and E2-nonspecific ( SEC ) class-switched B cells ( csBC ) . In sEC+ cSC from both persistence and clearance subjects , frequencies of resting memory B cells were reduced , frequency of activated MBC ( actMBC ) and tissue-like MBC were increased , expression of