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10.1371/journal.ppat.1004874 | Experimental Evolution of an RNA Virus in Wild Birds: Evidence for Host-Dependent Impacts on Population Structure and Competitive Fitness | Within hosts, RNA viruses form populations that are genetically and phenotypically complex. Heterogeneity in RNA virus genomes arises due to error-prone replication and is reduced by stochastic and selective mechanisms that are incompletely understood. Defining how natural selection shapes RNA virus populations is crit... | Viruses are constantly emerging into new areas and pose significant challenges to public health. Chikungunya and West Nile viruses (WNV), both mosquito-borne RNA viruses, are quintessential examples of how increased globalization has facilitated the expansion of viruses into new territories. Rapid evolution of both of ... | RNA viruses pose some of the most complex, persistent and challenging problems facing public health and medicine. The ongoing outbreaks of avian influenza A(H7N9) virus (Orthomyxoviridae) in China [1], Ebola virus (Filoviridae) in West Africa [2], and chikungunya virus (CHIKV, Togaviridae, Alphavirus) and West Nile vir... |
10.1371/journal.pntd.0007210 | Evaluation of a novel West Nile virus transmission control strategy that targets Culex tarsalis with endectocide-containing blood meals | Control of arbovirus transmission remains focused on vector control through application of insecticides directly to the environment. However, these insecticide applications are often reactive interventions that can be poorly-targeted, inadequate for localized control during outbreaks, and opposed due to environmental a... | West Nile virus (WNV) is a mosquito-borne virus that causes significant disease and death every year in humans, domesticated animals, and wildlife. Control of WNV transmission is focused on controlling the mosquito vector through applications of insecticides directly to the environment. In this study, we evaluate a nov... | West Nile virus (WNV) is an arthropod-borne flavivirus, and the leading cause of domestically acquired arboviral disease in the United States [1,2], resulting in significant disease and death every year in humans, domesticated animals, and wildlife. From 1999–2017, >48,000 cases of human WNV disease and >2000 deaths we... |
10.1371/journal.pntd.0005622 | Rapid deployment of a mobile biosafety level-3 laboratory in Sierra Leone during the 2014 Ebola virus epidemic | Ebola virus emerged in West Africa in December 2013. The high population mobility and poor public health infrastructure in this region led to the development of the largest Ebola virus disease (EVD) outbreak to date.
On September 26, 2014, China dispatched a Mobile Biosafety Level-3 Laboratory (MBSL-3 Lab) and a well-t... | A Mobile Biosafety Level-3 Laboratory (MBSL-3 Lab) and a well-trained diagnostic team were dispatched to Sierra Leone to assist in Ebola virus disease (EVD) diagnosis when the largest outbreak of EVD to date emerged in West Africa in 2014. This setup allowed for the diagnosis of suspected EVD cases in less than 4 hours... | Ebola virus belongs to the Filoviridae family of enveloped viruses and contains a non-segmented negative-strand RNA genome [1,2]. Infection in humans can cause Ebola hemorrhagic fever, with exceptionally high case-fatality rates of more than 50% [3,4]. The incubation period of Ebola virus disease (EVD) is 2 to 21 days ... |
10.1371/journal.ppat.0030058 | Identification of a CCR5-Expressing T Cell Subset That Is Resistant to R5-Tropic HIV Infection | Infection with HIV-1 perturbs homeostasis of human T cell subsets, leading to accelerated immunologic deterioration. While studying changes in CD4+ memory and naïve T cells during HIV-1 infection, we found that a subset of CD4+ effector memory T cells that are CCR7−CD45RO−CD45RA+ (referred to as TEMRA cells), was signi... | HIV-1 infection profoundly perturbs the immune system and is characterized by depletion of CD4+ T cells and chronic immune activation, which lead to AIDS. Although HIV-1 targets CD4+ T cells, it also requires a second receptor in order to infect the target cells. The majority of HIV-1 strains that are transmitted use a... | Chronic immune activation and homeostatic disturbance of T cell subsets that accompany viral replication are hallmarks of HIV-1 infection [1–4]. The cause and implications of these profound quantitative and qualitative changes in CD4+ memory T cell subsets during HIV-1 infection are still not well understood [2]. Eluci... |
10.1371/journal.ppat.1007876 | Structural mechanism for guanylate-binding proteins (GBPs) targeting by the Shigella E3 ligase IpaH9.8 | The guanylate-binding proteins (GBPs) belong to the dynamin superfamily of GTPases and function in cell-autonomous defense against intracellular pathogens. IpaH9.8, an E3 ligase from the pathogenic bacterium Shigella flexneri, ubiquitinates a subset of GBPs and leads to their proteasomal degradation. Here we report the... | Shigella flexneri is a Gram-negative bacteria that causes diarrhea in humans and leads to a million deaths every year. Once inside the cell, S. flexneri injects the host cell cytoplasm with effector proteins to suppress host defense. The guanylate-binding proteins (GBPs) have potent antimicrobial functions against a nu... | The guanylate-binding proteins (GBPs) play critical roles in cell-autonomous immunity against a diverse range of bacterial, viral, and protozoan pathogens. The charter member of this family is GBP1, which was identified as a protein that is strongly induced by the interferons and can specifically bind to the guanylate ... |
10.1371/journal.pgen.1003185 | Genetic Disruption of the Copulatory Plug in Mice Leads to Severely Reduced Fertility | Seminal fluid proteins affect fertility at multiple stages in reproduction. In many species, a male's ejaculate coagulates to form a copulatory plug. Although taxonomically widespread, the molecular details of plug formation remain poorly understood, limiting our ability to manipulate the structure and understand its r... | Male reproductive fitness is strongly affected by seminal fluid. In many animals, the male's ejaculate coagulates in the female's reproductive tract to form a structure known as the copulatory plug. Here, I show that male mice without a functional copy of the gene transglutaminase IV cannot form a plug and suffer sever... | The non-sperm component of an ejaculate can have large effects on male reproductive fitness. In internally fertilizing species, seminal proteins can modify female receptivity [1]–[3], egg laying behavior [4]–[6], implantation and gestation [7], and the female's immune response to sperm and embryo [7]–[11]. Seminal prot... |
10.1371/journal.pbio.2006601 | Heterogeneity and longevity of antibody memory to viruses and vaccines | Determining the duration of protective immunity requires quantifying the magnitude and rate of loss of antibodies to different virus and vaccine antigens. A key complication is heterogeneity in both the magnitude and decay rate of responses of different individuals to a given vaccine, as well as of a given individual t... | Immunological memory, mediated by antibodies, is a hallmark of immunity. A key problem for determining the longevity of protective immunity is heterogeneity in the responses of different individuals. We characterize the extent of this heterogeneity and determine how it affects the longevity of protection. We found that... | Immune memory is a cardinal feature of the adaptive immune response of vertebrates and is the principle that underlies vaccination [1–3]. Immunological memory arises as a consequence of the increase in the magnitude of the antigen-specific response, augmented by increases in the quality of the response [1,4].
A major ... |
10.1371/journal.ppat.1002062 | Bacteria-Induced Dscam Isoforms of the Crustacean, Pacifastacus leniusculus | The Down syndrome cell adhesion molecule, also known as Dscam, is a member of the immunoglobulin super family. Dscam plays an essential function in neuronal wiring and appears to be involved in innate immune reactions in insects. The deduced amino acid sequence of Dscam in the crustacean Pacifastacus leniusculus (PlDsc... | Invertebrate animals lack an adaptive immune system and have no antibodies. Vertebrate antibodies belong to the immunoglobulin super family of proteins, and one other member of this large family is the Down syndrome cell adhesion molecule or Dscam. Of specific interest is that Dscam proteins in invertebrates show a gre... | The immunoglobulin super family (IgSF) is composed of proteins that contain at least one immunoglobulin domain [1]. Several members of IgSF are expressed on the cell surface and there serve as receptors for diverse ligands, and contribute to a variety of cellular activities [2]. In vertebrates, many IgSF members play e... |
10.1371/journal.ppat.1005075 | Nanoformulations of Rilpivirine for Topical Pericoital and Systemic Coitus-Independent Administration Efficiently Prevent HIV Transmission | Vaginal HIV transmission accounts for the majority of new infections worldwide. Currently, multiple efforts to prevent HIV transmission are based on pre-exposure prophylaxis with various antiretroviral drugs. Here, we describe two novel nanoformulations of the reverse transcriptase inhibitor rilpivirine for pericoital ... | When taken consistently, PrEP has been shown to reduce the risk of HIV infection by up to 92% in people who are at high risk. However, PrEP is much less effective if it is not taken consistently. To improve adherence to the drug regimen, several new drug delivery systems, that include novel gel formulations and long-ac... | Although the annual number of new HIV infections continues to decline, the global HIV-1 pandemic remains an unprecedented public health problem, with 2.1 million new infections in 2013 and an estimated 35 million people already infected [1]. This highlights the urgent need for effective and safe prevention strategies f... |
10.1371/journal.ppat.1002361 | Signal Transduction through CsrRS Confers an Invasive Phenotype in Group A Streptococcus | The CsrRS (or CovRS) two component system controls expression of up to 15% of the genome of group A Streptococcus (GAS). While some studies have suggested that the sensor histidine kinase CsrS responds to membrane perturbations as a result of various environmental stresses, other data have implicated the human antimicr... | Group A Streptococcus (S. pyogenes or GAS) is exclusively a human pathogen that can inhabit the human throat as a harmless commensal, cause localized, self-limited infection in the form of pharyngitis or strep throat, or invade local tissues or the bloodstream to produce life-threatening disease states such as necrotiz... | Human beings are thought to be the principal if not exclusive host for group A Streptococcus (S. pyogenes, GAS). The organism's primary environmental niche is the human pharynx where GAS can colonize the epithelium without evoking any clinical symptoms, or it can produce local inflammation and symptomatic streptococcal... |
10.1371/journal.pgen.1003296 | Ancient DNA Reveals Prehistoric Gene-Flow from Siberia in the Complex Human Population History of North East Europe | North East Europe harbors a high diversity of cultures and languages, suggesting a complex genetic history. Archaeological, anthropological, and genetic research has revealed a series of influences from Western and Eastern Eurasia in the past. While genetic data from modern-day populations is commonly used to make infe... | The history of human populations can be retraced by studying the archaeological and anthropological record, but also by examining the current distribution of genetic markers, such as the maternally inherited mitochondrial DNA. Ancient DNA research allows the retrieval of DNA from ancient skeletal remains and contribute... | Our current knowledge of the origins of human populations and their migratory history relies on archaeological, anthropological, linguistic and genetic research. The study of genetic markers, especially the maternally inherited mitochondrial DNA (mtDNA), has allowed important events in the genetic history of humans to ... |
10.1371/journal.pcbi.1005962 | A comprehensive and quantitative comparison of text-mining in 15 million full-text articles versus their corresponding abstracts | Across academia and industry, text mining has become a popular strategy for keeping up with the rapid growth of the scientific literature. Text mining of the scientific literature has mostly been carried out on collections of abstracts, due to their availability. Here we present an analysis of 15 million English scient... | Text mining has become an integral part of all fields in science. Owing to the large number of articles published every day, it is necessary to employ automated systems to assist in curation, knowledge management and discovery. To date, most systems make use of information collected from abstracts only. Moreover, studi... | Text mining has become a widespread approach to identify and extract information from unstructured text. Text mining is used to extract facts and relationships in a structured form that can be used to annotate specialized databases, to transfer knowledge between domains and more generally within business intelligence t... |
10.1371/journal.ppat.1001106 | The HA and NS Genes of Human H5N1 Influenza A Virus Contribute to High Virulence in Ferrets | Highly pathogenic H5N1 influenza A viruses have spread across Asia, Europe, and Africa. More than 500 cases of H5N1 virus infection in humans, with a high lethality rate, have been reported. To understand the molecular basis for the high virulence of H5N1 viruses in mammals, we tested the virulence in ferrets of severa... | Highly pathogenic H5N1 influenza A viruses have caused more than 500 human infections with approximately 60% lethality in 15 countries and continue to pose a pandemic threat. The recent worldwide spread of pandemic H1N1 influenza A viruses raises the concern of reassortment between the H5N1 viruses and other influenza ... | In 1997, the first human case of influenza caused by an H5N1 virus occurred in Hong Kong [1], [2]. In 2003, a new outbreak of H5N1 virus was identified in Vietnam. Since then, H5N1 viruses have spread across Asia, Europe and Africa. As of July 22, 2010, 501 cases of H5N1 virus infections in humans have been reported by... |
10.1371/journal.ppat.1000312 | Molecular Evolution of a Viral Non-Coding Sequence under the Selective Pressure of amiRNA-Mediated Silencing | Plant microRNAs (miRNA) guide cleavage of target mRNAs by DICER-like proteins, thereby reducing mRNA abundance. Native precursor miRNAs can be redesigned to target RNAs of interest, and one application of such artificial microRNA (amiRNA) technology is to generate plants resistant to pathogenic viruses. Transgenic Arab... | RNA viruses are well-known for their tremendous capacity to evolve, a characteristic that threatens the development of effective antiviral strategies. A new antiviral strategy was recently proposed to control plant RNA viruses that relied on the expression in plants of artificial microRNAs (amiRNAs) targeting short seq... | Plant miRNAs regulate the abundance of target mRNAs by guiding their cleavage at the sequence complementary region. Previous reports have shown that changes of several nucleotides within a miRNA 21-nt sequence do not affect its biogenesis and maturation [1],[2]. This finding raises the possibility to redesign the miRNA... |
10.1371/journal.pntd.0007703 | Chikungunya virus requires cellular chloride channels for efficient genome replication | Chikungunya virus (CHIKV) is a re-emerging, pathogenic alphavirus that is transmitted to humans by Aedes spp. mosquitoes—causing fever and debilitating joint pain, with frequent long-term health implications and high morbidity. The CHIKV lifecycle is poorly understood and specific antiviral therapeutics or vaccines are... | Chikungunya virus (CHIKV) is a mosquito-borne virus that infects humans and causes chikungunya fever—characterized by fever, rash and chronic arthralgia. Treatment of chikungunya fever is limited to the alleviation of the symptoms and no vaccine is available to prevent infection. Consequently, new anti-CHIKV therapies ... | Chikungunya virus (CHIKV) is a mosquito-borne virus of the Alphavirus genus in the Togaviridae family. It was first isolated during an outbreak in Tanzania in 1952 [1], since which its geographic range has expanded globally to include almost 40 countries [2]. Following transmission, CHIKV replicates in the fibroblasts ... |
10.1371/journal.pcbi.1004494 | Predicting the Effect of Mutations on Protein-Protein Binding Interactions through Structure-Based Interface Profiles | The formation of protein-protein complexes is essential for proteins to perform their physiological functions in the cell. Mutations that prevent the proper formation of the correct complexes can have serious consequences for the associated cellular processes. Since experimental determination of protein-protein binding... | Few proteins carry out their tasks in isolation. Instead, proteins combine with each other in complicated ways that can be affected by either the natural genetic variation that occurs among people or by disease causing mutations such as those that occur in cancer or in genetic disorders. To understand how these mutatio... | The formation of protein-protein complexes plays an essential role in the regulation of various biological processes. Mutations play fundamental roles in evolution by introducing diversity into genomes that can either be selectively advantageous or cause a change in protein affinity that can result in malfunction of th... |
10.1371/journal.pbio.1002197 | Impaired Mitochondrial Energy Production Causes Light-Induced Photoreceptor Degeneration Independent of Oxidative Stress | Two insults often underlie a variety of eye diseases including glaucoma, optic atrophy, and retinal degeneration—defects in mitochondrial function and aberrant Rhodopsin trafficking. Although mitochondrial defects are often associated with oxidative stress, they have not been linked to Rhodopsin trafficking. In an unbi... | Mitochondrial dysfunction is associated with a number of metabolic and neurological diseases such as Leigh syndrome and progressive blindness. Increased oxidative stress, which is often associated with mitochondrial dysfunction, is thought to be a common cause of disease progression. Here, we identified nuclear genes t... | The causes of progressive dysfunction or death of photoreceptors (PRs) is genetically heterogeneous in humans [1]. PR degeneration is a complex process influenced by numerous genes and environmental factors. Although prolonged exposure to sunlight is one of the major causes of retinal degeneration, more than 200 genes ... |
10.1371/journal.pgen.1002197 | Trans-eQTLs Reveal That Independent Genetic Variants Associated with a Complex Phenotype Converge on Intermediate Genes, with a Major Role for the HLA | For many complex traits, genetic variants have been found associated. However, it is still mostly unclear through which downstream mechanism these variants cause these phenotypes. Knowledge of these intermediate steps is crucial to understand pathogenesis, while also providing leads for potential pharmacological interv... | Many genetic variants have been found associated with diseases. However, for many of these genetic variants, it remains unclear how they exert their effect on the eventual phenotype. We investigated genetic variants that are known to be associated with diseases and complex phenotypes and assessed whether these variants... | For many complex traits and diseases, numerous associated single nucleotide polymorphisms (SNPs) have been identified through genome-wide association studies (GWAS)through genome-wide association studies (GWAS) [1]. For many of these identified variants it is still unclear through which mechanism the association betwee... |
10.1371/journal.pcbi.1003442 | De Novo Prediction of PTBP1 Binding and Splicing Targets Reveals Unexpected Features of Its RNA Recognition and Function | The splicing regulator Polypyrimidine Tract Binding Protein (PTBP1) has four RNA binding domains that each binds a short pyrimidine element, allowing recognition of diverse pyrimidine-rich sequences. This variation makes it difficult to evaluate PTBP1 binding to particular sites based on sequence alone and thus to iden... | A key step in the regulation of mammalian genes is the splicing of the messenger RNA precursor to produce a mature mRNA that can be translated into a particular protein needed by the cell. Through the process of alternative splicing, mRNAs encoding different proteins can be derived from the same primary gene transcript... | Alternative splicing of pre-mRNA commonly determines the protein output of mammalian genes, with most genes generating multiple mRNA and protein products [1]. A typical alternative exon is affected by multiple pre-mRNA binding proteins that may either enhance or repress splicing [2]. The expression and activity of thes... |
10.1371/journal.pcbi.1002657 | Artificial Neural Networks Trained to Detect Viral and Phage Structural Proteins | Phages play critical roles in the survival and pathogenicity of their hosts, via lysogenic conversion factors, and in nutrient redistribution, via cell lysis. Analyses of phage- and viral-encoded genes in environmental samples provide insights into the physiological impact of viruses on microbial communities and human ... | Bacteriophages are extremely abundant and diverse biological entities. All phage particles are comprised of nucleic acids and structural proteins, with few other packaged proteins. Despite their simplicity and abundance, more than 70% of phage sequences in the viral Reference Sequence database encode proteins with unkn... | As modern sequencing technologies exponentially increase the amount of DNA sequence data available, the discovery of sequences that encode proteins with unknown functions continue to accumulate. For example, a large majority of microbial and viral metagenome sequences sampled from different environments have unknown fu... |
10.1371/journal.pbio.1001591 | Transcription-Factor-Mediated DNA Looping Probed by High-Resolution, Single-Molecule Imaging in Live E. coli Cells | DNA looping mediated by transcription factors plays critical roles in prokaryotic gene regulation. The “genetic switch” of bacteriophage λ determines whether a prophage stays incorporated in the E. coli chromosome or enters the lytic cycle of phage propagation and cell lysis. Past studies have shown that long-range DNA... | One mechanism cells use to regulate gene expression is DNA looping, whereby two distant DNA sites are brought together by regulatory proteins. The looping then either enhances interactions between other regulatory proteins bound at the separate sites or brings those regulatory proteins close to RNA polymerase at the pr... | Looping between two DNA sites, mediated by transcription factors, is a ubiquitous mechanism in prokaryotic transcription regulation [1]. DNA looping brings two distal DNA sites into close proximity, enhancing interactions between transcription factors bound at separate sites or bringing transcription factors close to R... |
10.1371/journal.pntd.0006682 | An exploratory study on rabies exposure through contact tracing in a rural area near Bengaluru, Karnataka, India | Rabies is a neglected zoonotic disease. Given the low incidence, apart from the existing reporting syst, there is a need to look for other means of case detection strategies for rabies. Contact tracing is one such method to efficiently capture information.
To find out the rabid status of biting animal through contact t... | In India, Rabies is a neglected zoonotic disease and the burden of rabies is usually not captured by the health system due to varied reasons. Hence, an exploratory study was attempted to find out the rabid status of the biting animal through contact tracing during the first quarter of 2017 in villages coming under thre... | Rabies is a 100% fatal viral zoonotic disease.[1] However, Rabies can be prevented if, health care providers are able to identify the type of exposure, categorize the wounds and provide post exposure prophylaxis(PEP) as early as possible.[2,3] South East Asia region accounts approximately for 60% of human rabies deaths... |
10.1371/journal.pgen.1007799 | Genetic regulation of the placental transcriptome underlies birth weight and risk of childhood obesity | GWAS identified variants associated with birth weight (BW), childhood obesity (CO) and childhood BMI (CBMI), and placenta is a critical organ for fetal development and postnatal health. We examined the role of placental transcriptome and eQTLs in mediating the genetic causes for BW, CO and CBMI, and applied integrative... | Genetic studies (e.g GWAS) revealed substantial heritability on birth weight (BW), childhood obesity (CO) and childhood body mass index (CBMI), however, the etiological mechanisms and relevant tissue(s) underlying these traits/conditions are not clear. We incorporated the data from largest GWASes to date and placenta e... | Birth weight (BW) is influenced by both fetal and maternal factors, including race, infant sex, plurality, altitude, education, and smoking [1], and is consistently associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease [2]. Childhood obesity (CO) has also eme... |
10.1371/journal.pcbi.1005001 | Isofunctional Protein Subfamily Detection Using Data Integration and Spectral Clustering | As increasingly more genomes are sequenced, the vast majority of proteins may only be annotated computationally, given experimental investigation is extremely costly. This highlights the need for computational methods to determine protein functions quickly and reliably. We believe dividing a protein family into subtype... | The knowledge of protein functions is central for understanding life at a molecular level and has huge biochemical and pharmaceutical implications. However, despite best research efforts, a substantial and ever-increasing number of proteins predicted by genome sequencing projects still lack functional annotations. Comp... | Despite the best research efforts, a substantial and ever-increasing amount of predicted proteins still lack functional annotation [1]. Indeed, the unprecedented increase in the number of new protein sequences being produced by genomics and proteomics projects, as well as the copious amounts of structures for proteins ... |
10.1371/journal.ppat.1002851 | Clonality Despite Sex: The Evolution of Host-Associated Sexual Neighborhoods in the Pathogenic Fungus Penicillium marneffei | Molecular genetic approaches typically detect recombination in microbes regardless of assumed asexuality. However, genetic data have shown the AIDS-associated pathogen Penicillium marneffei to have extensive spatial genetic structure at local and regional scales, and although there has been some genetic evidence that a... | Fungal pathogen populations show patterns ranging from globally recombining to endemic and clonal. Among the most genetically and spatially restricted fungi is the highly clonal pathogen Penicillium marneffei, an endemic AIDS-associated pathogen in Southeast Asia. Previous studies have shown that P. marneffei has a pat... | Hypotheses of globally continuous populations and strict clonality in putatively asexual microbial pathogens are rarely supported [1], [2], [3], [4], [5]. Instead, genetic approaches detect recombination in microbes regardless of assumed asexuality, and pathogens are surprisingly promiscuous despite strong population g... |
10.1371/journal.pcbi.1006196 | Simulations to benchmark time-varying connectivity methods for fMRI | There is a current interest in quantifying time-varying connectivity (TVC) based on neuroimaging data such as fMRI. Many methods have been proposed, and are being applied, revealing new insight into the brain’s dynamics. However, given that the ground truth for TVC in the brain is unknown, many concerns remain regardin... | Time-varying connectivity attempts to quantify the fluctuating covariance relationship between two or more regions through time. In recent years, it has become popular to do this with fMRI neuroimaging data. There have been many methods proposed to quantify time-varying connectivity, but very few attempts to systematic... | Time-varying connectivity (TVC) is being applied to an increasing number of topics studying the brain’s networks. Topics that have been explored with TVC include development [1], various pathologies [2, 3], affect [4], attention [5], levels of consciousness [6], and temporal properties of the brain’s networks [7–9]. Th... |
10.1371/journal.pntd.0004015 | Distribution of Peripheral Memory T Follicular Helper Cells in Patients with Schistosomiasis Japonica | Schistosomiasis is a helminthic disease that affects more than 200 million people. An effective vaccine would be a major step towards eliminating the disease. Studies suggest that T follicular helper (Tfh) cells provide help to B cells to generate the long-term humoral immunity, which would be a crucial component of su... | Schistosomiasis affects more than 200 million people worldwide and causes more than 280,000 deaths per year. Current control strategies are based on chemotherapy, but recurrent reinfection of people living in endemic areas makes researchers search for an effective vaccine to provide long-term protection against schisto... | Schistosomiasis remains a major public health problem in many developing countries. Estimates place the current number of infections at approximately 200 million people, with another 600 million considered at risk [1]. Although praziquantel remains highly effective in schistosomiasis treatment, it provides only short-t... |
10.1371/journal.pcbi.1003946 | The Amino Acid Alphabet and the Architecture of the Protein Sequence-Structure Map. I. Binary Alphabets | The correspondence between protein sequences and structures, or sequence-structure map, relates to fundamental aspects of structural, evolutionary and synthetic biology. The specifics of the mapping, such as the fraction of accessible sequences and structures, or the sequences' ability to fold fast, are dictated by the... | If we were to design a proteome, what types and what proportion of amino acids would we use in order to optimize properties such as the diversity of sequences and structures, their robustness to mutations, or their ability to fold efficiently? Here, I use simple models to study the sequence-structure map of proteins fr... | The implications of understanding the properties and organization of the sequence-structure map of proteins are broad, they range from explaining the diversity of known protein folds in the context of cellular physiology and their evolution [1], synthesize molecules of biomedical or industrial interest [2], to engineer... |
10.1371/journal.pbio.1001301 | Stitching together Multiple Data Dimensions Reveals Interacting Metabolomic and Transcriptomic Networks That Modulate Cell Regulation | Cells employ multiple levels of regulation, including transcriptional and translational regulation, that drive core biological processes and enable cells to respond to genetic and environmental changes. Small-molecule metabolites are one category of critical cellular intermediates that can influence as well as be a tar... | It is now possible to score variations in DNA across whole genomes, RNA levels and alternative isoforms, metabolite levels, protein levels and protein state information, protein–protein interactions, and protein–DNA interactions, in a comprehensive fashion in populations of individuals. Interactions among these molecul... | Cells are complex molecular machines that employ multiple levels of regulation that enable them to respond to genetic and environmental perturbations. Advances in biology over the past several years to elucidate the complexity of this regulation have been truly astonishing. However, despite transformative advances in t... |
10.1371/journal.ppat.1005611 | Antibiotic-Resistant Neisseria gonorrhoeae Spread Faster with More Treatment, Not More Sexual Partners | The sexually transmitted bacterium Neisseria gonorrhoeae has developed resistance to all antibiotic classes that have been used for treatment and strains resistant to multiple antibiotic classes have evolved. In many countries, there is only one antibiotic remaining for empirical N. gonorrhoeae treatment, and antibioti... | More and more infectious disease treatments fail because the causative pathogens are resistant to the drugs used for treatment. For the treatment of Neisseria gonorrhoeae, a sexually transmitted bacterium, drug resistance is a particularly big problem: there is only a single antibiotic left that is recommended for trea... | Antibiotic-resistant Neisseria gonorrhoeae can evolve and spread rapidly [1]. Resistance is commonly observed against the antibiotic classes penicillin, tetracycline and fluoroquinolones [2–4]. Resistance also emerged against cefixime, an oral third generation cephalosporin, in recent years [2, 3]. Since 2010, cefixime... |
10.1371/journal.pntd.0001519 | Therapeutic DNA Vaccine Encoding Peptide P10 against Experimental Paracoccidioidomycosis | Paracoccidioidomycosis (PCM), caused by Paracoccidioides brasiliensis, is the most prevalent invasive fungal disease in South America. Systemic mycoses are the 10th most common cause of death among infectious diseases in Brazil and PCM is responsible for more than 50% of deaths due to fungal infections. PCM is typicall... | Paracoccidioidomycosis (PCM) is the predominant systemic mycosis in Latin America causing half of the total deaths among systemic fungal infectious diseases in Brazil. Chemotherapy is the standard treatment, but the long time required, severe cases of immunosuppression and frequent relapses indicate that additional met... | Paracoccidioides brasiliensis is a thermally dimorphic fungus that causes a systemic granulomatous disease known as paracoccidioidomycosis (PCM). PCM is widespread in Latin America, mainly affecting rural workers, and its incidence has increased in recently deforested areas associated with soil churning [1]. Acquisitio... |
10.1371/journal.pgen.1007039 | The creation and selection of mutations resistant to a gene drive over multiple generations in the malaria mosquito | Gene drives have enormous potential for the control of insect populations of medical and agricultural relevance. By preferentially biasing their own inheritance, gene drives can rapidly introduce genetic traits even if these confer a negative fitness effect on the population. We have recently developed gene drives base... | Gene drives are selfish genetic elements that are able to bias their own inheritance among offspring. Starting from very low frequencies they can rapidly invade a population in just a few generations, even when imposing a fitness cost. Gene drives based on the precise DNA cutting enzyme CRISPR have been shown recently ... | Naturally occurring gene drives—selfish genetic elements that are able to bias their own inheritance and rapidly invade a population, even starting from very low frequencies—have inspired proposals to harness their power to spread into a population of insect disease vectors traits that manipulate their biology in ways ... |
10.1371/journal.pcbi.1002489 | Predictive Features of Persistent Activity Emergence in Regular Spiking and Intrinsic Bursting Model Neurons | Proper functioning of working memory involves the expression of stimulus-selective persistent activity in pyramidal neurons of the prefrontal cortex (PFC), which refers to neural activity that persists for seconds beyond the end of the stimulus. The mechanisms which PFC pyramidal neurons use to discriminate between pre... | Memory, referred to as the ability to retain, store and recall information, represents one of the most fundamental cognitive functions in daily life. A significant feature of memory processes is selectivity to particular events or items that are important to our survival and relevant to specific situations. For long-te... | Working memory reflects the temporary storage of information that is necessary for immediate decisions/actions. Delay-period activity, which corresponds to neural activity that persists after the end of the initiating stimulus, represents the cellular correlate of working memory [1], [2]. This activity, referred from n... |
10.1371/journal.ppat.1004284 | Paenibacillus larvae Chitin-Degrading Protein PlCBP49 Is a Key Virulence Factor in American Foulbrood of Honey Bees | Paenibacillus larvae, the etiological agent of the globally occurring epizootic American Foulbrood (AFB) of honey bees, causes intestinal infections in honey bee larvae which develop into systemic infections inevitably leading to larval death. Massive brood mortality might eventually lead to collapse of the entire colo... | American Foulbrood and its etiological agent, Paenibacillus larvae, pose a serious threat to global honey bee health. So far, molecular mechanisms of host-microbe interactions are poorly understood in this system and no key virulence factor for the entire species has been identified. Here, we demonstrate that P. larvae... | Vertebrates and invertebrates alike need to protect their intestinal epithelia against various chemical, physical and biological challenges while the transport of nutrients and water must remain uninterrupted to aid in digestion. For this purpose, mucosal secretions line the digestive tract of vertebrates, while in mos... |
10.1371/journal.ppat.1000963 | Cognitive Dysfunction Is Sustained after Rescue Therapy in Experimental Cerebral Malaria, and Is Reduced by Additive Antioxidant Therapy | Neurological impairments are frequently detected in children surviving cerebral malaria (CM), the most severe neurological complication of infection with Plasmodium falciparum. The pathophysiology and therapy of long lasting cognitive deficits in malaria patients after treatment of the parasitic disease is a critical a... | Cerebral malaria (CM) is a deadly consequence of Plasmodium falciparum infection. Severe neurologic deficits are frequent during CM. Although most resolve within 6 months, several retrospective studies have described high frequencies of long-lasting cognitive impairment after an episode of CM. We developed behavioral t... | Malaria, together with tuberculosis and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), is one of three most important infectious diseases worldwide, with devastating morbidity and mortality and deleterious economic consequences [1]. More than 400 million people suffer from malaria, which ca... |
10.1371/journal.pntd.0004204 | Comparison of Leishmania killicki (syn. L. tropica) and Leishmania tropica Population Structure in Maghreb by Microsatellite Typing | Leishmania (L.) killicki (syn. L. tropica), which causes cutaneous leishmaniasis in Maghreb, was recently described in this region and identified as a subpopulation of L. tropica. The present genetic analysis was conducted to explore the spatio-temporal distribution of L. killicki (syn. L. tropica) and its transmission... | Leishmania killicki (syn. L. tropica) was discovered in 1986. Few studies have been conducted on this parasite exclusively described in Maghreb. Consequently, many elements on its epidemiology, transmission, population structure and dynamics remain unknown.
To better understand the evolution of this parasite, its popul... | Leishmaniases are vector-borne diseases caused by several Leishmania species that cycle between their phlebotomine sandfly vectors and mammalian reservoir hosts [1]. Leishmania parasites, like many other microorganisms, have a high adaptation capacity that allows them to invade and survive in various ecosystems. The sp... |
10.1371/journal.pgen.1008332 | Reshuffling yeast chromosomes with CRISPR/Cas9 | Genome engineering is a powerful approach to study how chromosomal architecture impacts phenotypes. However, quantifying the fitness impact of translocations independently from the confounding effect of base substitutions has so far remained challenging. We report a novel application of the CRISPR/Cas9 technology allow... | Chromosomes are highly dynamic objects that often undergo large structural variations such as reciprocal translocations. Such rearrangements can have dramatic functional consequences, as they can disrupt genes, change their regulation or create novel fusion genes at their breakpoints. For instance, 90–95% of patients d... | Genetic polymorphisms are not restricted to base substitutions and indels but also include large-scale Structural Variations (SVs) of chromosomes. SVs comprise both unbalanced events, often designated as copy number variations (CNVs) including deletions and duplications, and balanced events that are copy number neutral... |
10.1371/journal.pcbi.1000387 | Drug Discovery Using Chemical Systems Biology: Identification of the Protein-Ligand Binding Network To Explain the Side Effects of CETP Inhibitors | Systematic identification of protein-drug interaction networks is crucial to correlate complex modes of drug action to clinical indications. We introduce a novel computational strategy to identify protein-ligand binding profiles on a genome-wide scale and apply it to elucidating the molecular mechanisms associated with... | Both the cost to launch a new drug and the attrition rate during the late stage of the drug discovery and development process are increasing. Torcetrapib is a case in point, having been withdrawn from phase III clinical trials after 15 years of development and an estimated cost of US $800 M. Torcetrapib represents a ne... | Identification of protein-ligand interaction networks on a proteome-wide scale is crucial to address a wide range of biological problems such as correlating molecular functions to physiological processes and designing safe and efficient therapeutics [1]. Recent protein-ligand interaction studies have revealed that prot... |
10.1371/journal.pntd.0005914 | Detecting and confirming residual hotspots of lymphatic filariasis transmission in American Samoa 8 years after stopping mass drug administration | The Global Programme to Eliminate Lymphatic Filariasis (LF) aims to eliminate the disease as a public health problem by 2020 by conducting mass drug administration (MDA) and controlling morbidity. Once elimination targets have been reached, surveillance is critical for ensuring that programmatic gains are sustained, an... | Lymphatic filariasis (LF) is caused by infection with filarial worms that are transmitted by mosquito bites. The Global Programme to Eliminate Lymphatic Filariasis aims to eliminate the disease as a public health problem by 2020. Once elimination targets have been reached, cost-effective surveillance strategies are req... | Lymphatic filariasis (LF) is a mosquito-borne parasitic infection caused by Wuchereria or Brugia species of helminths. Mosquito vectors vary between countries and regions, and include Aedes, Anopheles, Culex and Mansonia species. Globally, it is estimated that 68 million people are affected, comprising approximately 36... |
10.1371/journal.pbio.2006145 | JMJD5 links CRY1 function and proteasomal degradation | The circadian oscillator is a molecular feedback circuit whose orchestration involves posttranslational control of the activity and protein levels of its components. Although controlled proteolysis of circadian proteins is critical for oscillator function, our understanding of the underlying mechanisms remains incomple... | In mammals, circadian rhythms are generated by a molecular oscillator in which the circadian locomotor output cycles protein kaput (CLOCK)–brain and muscle ARNT-like protein 1 (BMAL1) transcription factors drive expression of the genes coding for their own repressors, the CRYPTOCHROME (CRY) and PERIOD (PER) proteins. A... | Circadian rhythms are endogenous, approximately 24-hour oscillations in behavior and physiology that evolved as an adaptation to the day–night cycle. These rhythms are generated by a cell-autonomous timekeeping mechanism known as the molecular circadian oscillator. At its most basic, the oscillator is a transcription–t... |
10.1371/journal.ppat.1002570 | A20 (Tnfaip3) Deficiency in Myeloid Cells Protects against Influenza A Virus Infection | The innate immune response provides the first line of defense against viruses and other pathogens by responding to specific microbial molecules. Influenza A virus (IAV) produces double-stranded RNA as an intermediate during the replication life cycle, which activates the intracellular pathogen recognition receptor RIG-... | Influenza virus or flu epidemics represent a recurrent threat to the public health, especially for individuals which are part of a high-risk group such as children, elderly or immune-compromised people. Sporadic pandemic flu outbreaks, such as the Spanish flu of 1918, may cause high grades of mortality among healthy pe... | Viruses are a class of highly diverse pathogens which depend on the host cell for their replication. The initiation of a protective innate antiviral immune response involves the action of specialized pattern recognition receptors (PRR), which detect conserved molecular structures of the invading pathogen. Triggering of... |
10.1371/journal.pntd.0003635 | What Drives the Occurrence of the Melioidosis Bacterium Burkholderia pseudomallei in Domestic Gardens? | Melioidosis is an often fatal infectious disease affecting humans and animals in tropical regions and is caused by the saprophytic environmental bacterium Burkholderia pseudomallei. Domestic gardens are not only a common source of exposure to soil and thus to B. pseudomallei, but they also have been found to contain mo... | Melioidosis cases are on the rise in endemic areas of northern Australia and Thailand. This potentially severe infectious disease affecting humans and animals in the tropical belt is caused by the gram negative bacterium Burkholderia pseudomallei. Domestic gardens are a common point of exposure to these environmental b... | Southeast Asia and tropical Australia have recently experienced a surge in melioidosis, an often fatal infectious disease caused by the saprophytic environmental bacterium Burkholderia pseudomallei [1,2]. Case numbers in the Top End of Australia have substantially increased in recent years. In the 20 years from 1989 un... |
10.1371/journal.pbio.2005761 | Reporting bias in the literature on the associations of health-related behaviors and statins with cardiovascular disease and all-cause mortality | Reporting bias in the literature occurs when there is selective revealing or suppression of results, influenced by the direction of findings. We assessed the risk of reporting bias in the epidemiological literature on health-related behavior (tobacco, alcohol, diet, physical activity, and sedentary behavior) and cardio... | In the scientific literature, reporting bias occurs when communication and publication of results are influenced by the direction of findings. Reporting bias can distort scientific evidence and may misguide subsequent clinical and public health efforts. Our study provided an assessment of the degree of reporting bias i... | The literature on the association between behavioral risk factors (e.g., smoking, alcohol, physical inactivity, and unhealthy diet) and cardiovascular diseases—the single largest cause of death globally [1]—has grown exponentially in the last decades [2–39]. Observational epidemiological studies are the dominant design... |
10.1371/journal.pgen.1005395 | Genome-Wide Reprogramming of Transcript Architecture by Temperature Specifies the Developmental States of the Human Pathogen Histoplasma | Eukaryotic cells integrate layers of gene regulation to coordinate complex cellular processes; however, mechanisms of post-transcriptional gene regulation remain poorly studied. The human fungal pathogen Histoplasma capsulatum (Hc) responds to environmental or host temperature by initiating unique transcriptional progr... | Eukaryotic cells alter their developmental programs in response to environmental signals. Histoplasma capsulatum (Hc), a ubiquitous fungal pathogen of humans, establishes unique transcriptional programs to specify growth in either a multicellular hyphal form or unicellular yeast form in response to temperature. Since h... | Environmental human pathogens have evolved the ability to survive in human hosts as well as diverse environmental reservoirs. Thus a hallmark of environmental pathogens is their capacity to adapt to varied growth conditions such as differences in temperature, alterations in nutrient sources, as well as exposure to the ... |
10.1371/journal.pntd.0006026 | RNA-seq transcriptional profiling of Leishmania amazonensis reveals an arginase-dependent gene expression regulation | Leishmania is a protozoan parasite that alternates its life cycle between the sand-fly vector and the mammalian host. This alternation involves environmental changes and leads the parasite to dynamic modifications in morphology, metabolism, cellular signaling and regulation of gene expression to allow for a rapid adapt... | Leishmania are auxotrophic for many essential nutrients, including amino acids. In this way, the parasite needs to uptake the amino acids from the environment. The uptake of amino acids is mediated by amino acid transporters that are unique for Leishmania. As part of polyamine pathway, the arginase converts L-arginine ... | Leishmania is a protozoan parasite that causes widespread human disease known as leishmaniases, characterized by cutaneous, mucosal or visceral manifestations. Leishmania alternates its life cycle between the sand-fly vector (promastigote form) and the mammalian host (amastigotes form) [1]. This alternation involves en... |
10.1371/journal.pntd.0004010 | Epidemiological and Molecular Characterization of Dengue Virus Circulating in Bhutan, 2013-2014 | Dengue is one of the most significant public health problems in tropical and subtropical countries, and is increasingly being detected in traditionally non-endemic areas. In Bhutan, dengue virus (DENV) has only recently been detected and limited information is available. In this study, we analyzed the epidemiological a... | We describe the epidemiological and molecular features of DENV currently circulating in the two southwestern districts of Bhutan, demonstrating a shift in serotype dominance from previous DENV-3 (2004–2006) to current DENV-1 (2013–2014). The presence of the dengue virus in Bhutan is a relatively recent one. Unfortunate... | Dengue is one of the most common infectious diseases in tropical and sub-tropical regions of the world [1, 2]. The World Health Organization (WHO) estimates 50–100 million infections per year globally; however, other studies have suggested a much higher figure [2]. Southeast Asia and Western Pacific represent about 75%... |
10.1371/journal.pbio.1002387 | Tel1 and Rif2 Regulate MRX Functions in End-Tethering and Repair of DNA Double-Strand Breaks | The cellular response to DNA double-strand breaks (DSBs) is initiated by the MRX/MRN complex (Mre11-Rad50-Xrs2 in yeast; Mre11-Rad50-Nbs1 in mammals), which recruits the checkpoint kinase Tel1/ATM to DSBs. In Saccharomyces cerevisiae, the role of Tel1 at DSBs remains enigmatic, as tel1Δ cells do not show obvious hypers... | Many tumors contain mutations that confer defects in repairing DNA double-strand breaks (DSBs). In both yeast and mammals, the MRX/MRN complex (Mre11-Rad50-Xrs2 in yeast; Mre11-Rad50-Nbs1 in mammals) plays critical functions in repairing a DSB by either nonhomologous end joining (NHEJ) or homologous recombination (HR).... | DNA double-strand breaks (DSBs) are among the most cytotoxic DNA lesions, because failure to repair them can lead to genome instability. DSBs can be repaired by either nonhomologous end joining (NHEJ) or homologous recombination (HR). While NHEJ directly ligates the DNA ends, HR requires the 5′ ends of a DSB to be nucl... |
10.1371/journal.pntd.0000202 | Microsatellites Reveal a High Population Structure in Triatoma infestans from Chuquisaca, Bolivia | For Chagas disease, the most serious infectious disease in the Americas, effective disease control depends on elimination of vectors through spraying with insecticides. Molecular genetic research can help vector control programs by identifying and characterizing vector populations and then developing effective interven... | Chagas disease is a protozoan infection caused by the parasite Trypanosoma cruzi. Chagas is prevalent throughout Central and South America, and it remains a chief concern in Bolivia. A movement that began in 1991 called the Southern Cone Initiative has been successful in reducing the incidence of Chagas disease in the ... | Chagas disease is a parasitic disease in which the pathogenic agent, Trypanosoma cruzi is transmitted by hematophagous insects of the sub-family Triatominae. Triatoma infestans is the major vector in the Andean highlands where the disease is endemic and has infected humans for over 9000 years [1]. Chagas disease is the... |
10.1371/journal.pcbi.1005792 | The structured ‘low temperature’ phase of the retinal population code | Recent advances in experimental techniques have allowed the simultaneous recordings of populations of hundreds of neurons, fostering a debate about the nature of the collective structure of population neural activity. Much of this debate has focused on the empirical findings of a phase transition in the parameter space... | Neurons encoding the natural world are correlated in their activities. The structure of this correlation fundamentally changes the population code, and these effects increase in larger neural populations. We experimentally recorded from populations of 100+ retinal ganglion cells and probed the structure of their joint ... | The past decade has witnessed a rapid development of new techniques for recording simultaneously from large populations of neurons [1–4]. As the experimentally accessible populations increase in size, a natural question arises: how can we model and understand the activity of large populations of neurons? In statistical... |
10.1371/journal.pntd.0007269 | Low population Japanese encephalitis virus (JEV) seroprevalence in Udayapur district, Nepal, three years after a JE vaccination programme: A case for further catch up campaigns? | The live attenuated Japanese encephalitis (JE) vaccine SA14-14-2 has been used in Nepal for catch-up campaigns and is now included in the routine immunisation schedule. Previous studies have shown good vaccine efficacy after one dose in districts with a high incidence of JE. The first well-documented dengue outbreak oc... | In Nepal, immunisation using a live attenuated vaccine is given against Japanese encephalitis (JE), caused by the mosquito-transmitted JE virus (JEV). JE immunisation has taken place via catch-up campaigns and is now part of the routine immunisation programme. Although previous studies have shown good vaccine efficacy ... | Japanese encephalitis virus (JEV), an arthropod-borne virus belonging to the genus Flavivirus of the family Flaviviridae, is transmitted by Culex mosquitoes, with birds and pigs acting as natural reservoirs and amplifying hosts. Humans are an accidental dead-end host [1]. JEV is enzootic in many parts of rural South an... |
10.1371/journal.pcbi.1004518 | A Pan-Cancer Catalogue of Cancer Driver Protein Interaction Interfaces | Despite their importance in maintaining the integrity of all cellular pathways, the role of mutations on protein-protein interaction (PPI) interfaces as cancer drivers has not been systematically studied. Here we analyzed the mutation patterns of the PPI interfaces from 10,028 proteins in a pan-cancer cohort of 5,989 t... | Until now, most efforts in cancer genomics have focused on identifying genes and pathways driving tumor development. Although this has been unquestionably a success, as evidenced by the fact that we now have an extensive catalogue of cancer driver genes and pathways, there is still a poor understanding of why patients ... | Cancer patients are extremely heterogeneous in their response to treatments and disease outcomes. The first step towards the understanding of this variability was the identification of the multitude of genes that cause cancer, the so-called cancer driver genes[1]. In that sense, the completion of The Cancer Genome Atla... |
10.1371/journal.pbio.2000942 | The Global Distribution and Drivers of Alien Bird Species Richness | Alien species are a major component of human-induced environmental change. Variation in the numbers of alien species found in different areas is likely to depend on a combination of anthropogenic and environmental factors, with anthropogenic factors affecting the number of species introduced to new locations, and when,... | The introduction of alien species is one of the primary ways in which human actions are changing the environment. Alien species have been responsible for numerous global and local extinctions and are eroding the uniqueness of many natural environments. There is thus a basic need to understand which areas end up with mo... | The number of species naturally inhabiting a location (native species richness [NSR]) is ultimately driven by the combined processes of speciation, extinction, and immigration, and proximately by the suite of environmental, ecological, historical, and evolutionary factors that determine the interplay of these processes... |
10.1371/journal.pntd.0005932 | Structural basis for the high specificity of a Trypanosoma congolense immunoassay targeting glycosomal aldolase | Animal African trypanosomosis (AAT) is a neglected tropical disease which imposes a heavy burden on the livestock industry in Sub-Saharan Africa. Its causative agents are Trypanosoma parasites, with T. congolense and T. vivax being responsible for the majority of the cases. Recently, we identified a Nanobody (Nb474) th... | Sub-Saharan Africa is plagued by many diseases, which impede its socio-economical development. One of these diseases, Animal African Trypanosomosis, affects livestock and is caused by the parasites of the Trypanosoma genus (T. vivax and T. congolense). Animal African Trypanosomosis leads to considerable economic losses... | The Trypanosoma genus represents a diverse group of extracellular hemoflagellated parasites of which some members can infect and cause disease in humans and livestock. An infection with African trypanosomes generally leads to the development of pathologies called Human African Trypanosomosis (HAT) and Animal African Tr... |
10.1371/journal.pcbi.1003562 | Atomistic Picture for the Folding Pathway of a Hybrid-1 Type Human Telomeric DNA G-quadruplex | In this work we studied the folding process of the hybrid-1 type human telomeric DNA G-quadruplex with solvent and ions explicitly modeled. Enabled by the powerful bias-exchange metadynamics and large-scale conventional molecular dynamic simulations, the free energy landscape of this G-DNA was obtained for the first t... | G-quadruplexes are high-order DNA/RNA structures. They are involved in the regulation of telomere maintenance, DNA replication, transcription and translation, and are also attractive drug designing targets for treating cancers and promising building blocks for molecular nanodevices. The knowledge of their formation pro... | G-quadruplexes are high-order DNA or RNA structures formed from guanine-rich sequences, and their building blocks are G-tetrads that arise from Hoogsten hydrogen-bonding between four guanines. The G-tetrads stack on top of each other and form four-stranded helical structures. Bioinformatics analysis suggests that G-qua... |
10.1371/journal.pgen.1002096 | The ISWI Chromatin Remodeler Organizes the hsrω ncRNA–Containing Omega Speckle Nuclear Compartments | The complexity in composition and function of the eukaryotic nucleus is achieved through its organization in specialized nuclear compartments. The Drosophila chromatin remodeling ATPase ISWI plays evolutionarily conserved roles in chromatin organization. Interestingly, ISWI genetically interacts with the hsrω gene, enc... | Chromatin structure and function are regulated by the concerted activity of covalent modifiers of chromatin, nucleosome remodeling factors, and several emerging classes of non-coding RNAs. ISWI is an evolutionarily conserved ATP-dependent chromatin remodeler playing essential roles in chromosome condensation, gene expr... | ISWI, the catalytic subunit of several ATP-dependent chromatin remodeling complexes, is highly conserved during evolution and is essential for cell viability [1]. ISWI-containing complexes play central roles in DNA replication, gene expression and chromosome organization [2]. ISWI uses ATP hydrolysis to catalyze nucleo... |
10.1371/journal.ppat.1002014 | Lung Adenocarcinoma Originates from Retrovirus Infection of Proliferating Type 2 Pneumocytes during Pulmonary Post-Natal Development or Tissue Repair | Jaagsiekte sheep retrovirus (JSRV) is a unique oncogenic virus with distinctive biological properties. JSRV is the only virus causing a naturally occurring lung cancer (ovine pulmonary adenocarcinoma, OPA) and possessing a major structural protein that functions as a dominant oncoprotein. Lung cancer is the major cause... | The identification of cells that give origin to cancer is critical in order to design effective therapeutic strategies. To this end, the early stages of cancer are the most informative but they are seldom associated with clinical symptoms and therefore pass unnoticed in human patients. Studies on animal tumors are inva... | Retroviruses have been instrumental in understanding the genetic basis and the fundamental molecular mechanisms leading to cancer [1]. Studies on the pathogenesis of retrovirus induced malignancies have also contributed to our understanding of the cells that give origin to cancer and the role played by stem and progeni... |
10.1371/journal.ppat.1006542 | Human cytomegalovirus IE1 downregulates Hes1 in neural progenitor cells as a potential E3 ubiquitin ligase | Congenital human cytomegalovirus (HCMV) infection is the leading cause of neurological disabilities in children worldwide, but the mechanisms underlying these disorders are far from well-defined. HCMV infection has been shown to dysregulate the Notch signaling pathway in human neural progenitor cells (NPCs). As an impo... | Congenital human cytomegalovirus (HCMV) infection is the leading cause of neurological disabilities in children, but the underlying pathogenesis of this infection remains unclear. Hes1, an important effector of Notch signaling, governs the fate of neural progenitor cells (NPCs) and fetal brain development. Here we demo... | As a leading cause of birth defects, congenital human cytomegalovirus (HCMV) infection causes irreversible maldevelopment of the central nervous system (CNS) in newborns and children [1–4]. To understand how HCMV interferes with neurodevelopment, neural progenitor cells (NPCs) have been utilized as a clinically relevan... |
10.1371/journal.pgen.1005754 | Gene Regulatory Mechanisms Underlying the Spatial and Temporal Regulation of Target-Dependent Gene Expression in Drosophila Neurons | Neuronal differentiation often requires target-derived signals from the cells they innervate. These signals typically activate neural subtype-specific genes, but the gene regulatory mechanisms remain largely unknown. Highly restricted expression of the FMRFa neuropeptide in Drosophila Tv4 neurons requires target-derive... | Nerve cells extend long processes that grow out to contact the target cells with which they communicate. When the nerve cell makes initial contact, the target cells send a retrograde signal back to the nerve cell. Such target-derived signals activate and maintain important genes that make the nerve cell functional, suc... | Nervous system development requires the differentiation of diverse neuronal subtypes under the direction of combinatorially acting transcription factors [1, 2]. However, target-derived signaling from axo-dendritic targets, in the form of retrograde bone morphogenetic protein (BMP), transforming growth factor β (TGFβ), ... |
10.1371/journal.pcbi.1005625 | Identifying direct contacts between protein complex subunits from their conditional dependence in proteomics datasets | Determining the three dimensional arrangement of proteins in a complex is highly beneficial for uncovering mechanistic function and interpreting genetic variation in coding genes comprising protein complexes. There are several methods for determining co-complex interactions between proteins, among them co-fractionation... | Proteins physically associate into complexes in order to carry out the essential functions of life. Knowing how proteins are physically arranged three dimensionally in these complexes provides clues towards how they work. In principle, the associations between proteins in large-scale proteomics datasets should often re... | Many proteins assemble into large macromolecular complexes with essential cellular functions. The three dimensional arrangement of proteins in a complex is vital to the complex’s function and knowledge of this arrangement would be highly valuable in understanding the mechanism of function. Conserved protein complexes a... |
10.1371/journal.pcbi.1000131 | Modeling the Violation of Reward Maximization and Invariance in Reinforcement Schedules | It is often assumed that animals and people adjust their behavior to maximize reward acquisition. In visually cued reinforcement schedules, monkeys make errors in trials that are not immediately rewarded, despite having to repeat error trials. Here we show that error rates are typically smaller in trials equally distan... | Theories of rational behavior are built on a number of principles, including the assumption that subjects adjust their behavior to maximize their long-term returns and that they should work equally hard to obtain a reward in situations where the effort to obtain reward is the same (called the invariance principle). Hum... | In studying reward-seeking behavior it is often assumed that animals attempt to maximize long term returns. This postulate often forms the basis of normative models of decision making [1], choice behavior [2]–[4], and motivation [5], and plays a prominent role in the field of Reinforcement Learning (RL; see, e.g., [6])... |
10.1371/journal.pcbi.1002649 | Assessing the Relative Stability of Dimer Interfaces in G Protein-Coupled Receptors | Considerable evidence has accumulated in recent years suggesting that G protein-coupled receptors (GPCRs) associate in the plasma membrane to form homo- and/or heteromers. Nevertheless, the stoichiometry, fraction and lifetime of such receptor complexes in living cells remain topics of intense debate. Motivated by expe... | G Protein-Coupled Receptors (GPCRs) are the largest family of membrane proteins targeted by drugs in clinical practice. Despite being at the forefront of biomedical research for many years, there is still considerable uncertainty about how GPCRs function at a molecular level. Although substantial evidence exists in sup... | G Protein-Coupled Receptors (GPCRs) have been reported to associate in the cell membrane to form dimers/oligomers. While incontrovertible evidence exists for the constitutive dimerization of disulfide-linked family C GPCRs [1], the interpretation of oligomerization studies of members of the largest subfamily A of GPCRs... |
10.1371/journal.pcbi.1000455 | Identifying Currents in the Gene Pool for Bacterial Populations Using an Integrative Approach | The evolution of bacterial populations has recently become considerably better understood due to large-scale sequencing of population samples. It has become clear that DNA sequences from a multitude of genes, as well as a broad sample coverage of a target population, are needed to obtain a relatively unbiased view of i... | The study of bacterial population biology is complicated by the fact that, although bacteria are largely asexual, they can also exchange genetic materials through homologous recombination. Unlike eukaryotes, recombination in bacteria is not an obligatory process. Furthermore, the recombination mechanisms are subject to... | It has become increasingly evident that recombination plays a major role in shaping the genetic structure of bacterial populations. Whether or not certain populations (as defined by allele frequencies) are more likely than others to undergo recombination, either as donors or recipients of DNA, is not well understood, t... |
10.1371/journal.pcbi.1000148 | Coordinate Regulation of G Protein Signaling via Dynamic Interactions of Receptor and GAP | Signal output from receptor–G-protein–effector modules is a dynamic function of the nucleotide exchange activity of the receptor, the GTPase-accelerating activity of GTPase-activating proteins (GAPs), and their interactions. GAPs may inhibit steady-state signaling but may also accelerate deactivation upon removal of st... | Throughout the eukaryotes, G proteins convey information from receptors for diverse stimuli—neurotransmitters, hormones, light, odors, and pheromones—to intracellular regulatory proteins collectively known as effectors. G proteins function by transiting a dynamic cycle of activation and deactivation. Receptors accelera... | G protein-mediated signaling modules display a variety of dynamic input-output behaviors despite their use of a single, relatively simple biochemical mechanism. Signal amplification, the ratio of effector proteins activated to agonist-bound receptors, can vary from unity to hundreds. Activating ligands may bind recepto... |
10.1371/journal.pgen.1003088 | The Genomes of the Fungal Plant Pathogens Cladosporium fulvum and Dothistroma septosporum Reveal Adaptation to Different Hosts and Lifestyles But Also Signatures of Common Ancestry | We sequenced and compared the genomes of the Dothideomycete fungal plant pathogens Cladosporium fulvum (Cfu) (syn. Passalora fulva) and Dothistroma septosporum (Dse) that are closely related phylogenetically, but have different lifestyles and hosts. Although both fungi grow extracellularly in close contact with host me... | We compared the genomes of two closely related pathogens with very different lifestyles and hosts: C. fulvum (Cfu), a biotroph of tomato, and D. septosporum (Dse), a hemibiotroph of pine. Some differences in gene content were identified that can be directly related to their different hosts, such as the presence of a ge... | Cladosporium fulvum and Dothistroma septosporum are two related fungal species belonging to the class Dothideomycetes. C. fulvum is a biotrophic pathogen of tomato that has served as a model system for plant-microbe interactions since its first effector gene, Avr9, was cloned in 1991 [1]. It is not related to species i... |
10.1371/journal.pcbi.1005807 | A machine learning approach for predicting CRISPR-Cas9 cleavage efficiencies and patterns underlying its mechanism of action | The adaptation of the CRISPR-Cas9 system as a genome editing technique has generated much excitement in recent years owing to its ability to manipulate targeted genes and genomic regions that are complementary to a programmed single guide RNA (sgRNA). However, the efficacy of a specific sgRNA is not uniquely defined by... | The CRISPR-Cas9 system, a microbial adaptive immune system, was recently exploited for modulating DNA sequences within the endogenous genome in many organisms. This system has emerged as a technology of choice for genome editing with promising therapeutic and research advancements. However, these exciting developments ... | The Clustered, Regularly InterSpaced, Palindromic Repeats (CRISPR), and its associated protein 9 (Cas9) constitute a microbial adaptive immune system that was exploited in recent years for modulating DNA sequences within the endogenous genome in cultured cells and whole organisms [1–6]. The Cas9 endonuclease is directe... |
10.1371/journal.ppat.1003609 | Human Cytomegalovirus Gene UL76 Induces IL-8 Expression through Activation of the DNA Damage Response | Human cytomegalovirus (HCMV), a β-herpesvirus, has evolved many strategies to subvert both innate and adaptive host immunity in order to ensure its survival and propagation within the host. Induction of IL-8 is particularly important during HCMV infection as neutrophils, primarily attracted by IL-8, play a key role in ... | The importance of herpesviruses is evident by their prevalence in the human population and the diverse range of diseases that they provoke. Their ability to establish latency provides a compelling example of how herpesviruses successfully evade the immune system and manipulate cellular biology. One promising approach f... | Human cytomegalovirus (HCMV) is a β-herpesvirus that infects healthy individuals, usually asymptomatically, but can cause severe or fatal disease in immunocompromised individuals. Primary HCMV infection, as with other herpesviruses, is followed by establishment of lifelong latency with periodic reactivation and, in ord... |
10.1371/journal.pcbi.1000194 | The Inactivation Principle: Mathematical Solutions Minimizing the
Absolute Work and Biological Implications for the Planning of Arm Movements | An important question in the literature focusing on motor control is to determine
which laws drive biological limb movements. This question has prompted numerous
investigations analyzing arm movements in both humans and monkeys. Many theories
assume that among... | When performing reaching and grasping movements, the brain has to choose one
trajectory among an infinite set of possibilities. Nevertheless, because human
and animal movements provide highly stereotyped features, motor strategies used
by the brain were assume... | In order to perform accurate goal-directed movements, the Central Nervous System
(CNS) has to compute neural commands according to the initial state of the body, the
location of the target, and the external forces acting on the limbs. Arm movement
planning requires solvin... |
10.1371/journal.pcbi.0030171 | Pathway Switching Explains the Sharp Response Characteristic of Hypoxia Response Network | Hypoxia induces the expression of genes that alter metabolism through the hypoxia-inducible factor (HIF). A theoretical model based on differential equations of the hypoxia response network has been previously proposed in which a sharp response to changes in oxygen concentration was observed but not quantitatively expl... | A complex biomolecular network utilizes different pathways to perform different functions. However, the interactions within the network are typically so complicated that the pathway structure is usually hidden. By some mathematical techniques, the pathways can be identified and possibly decoupled, whereby the insightfu... | Molecular oxygen is the terminal electron acceptor in the mitochondrial electron transport chain. Hypoxia, or oxygen deficiency, induces a number of metabolic changes with rapid and profound consequences on cell physiology. A hypoxia-induced shortage of energy alters gene expression, energy consumption, and cellular me... |
10.1371/journal.pgen.1005520 | FLCN and AMPK Confer Resistance to Hyperosmotic Stress via Remodeling of Glycogen Stores | Mechanisms of adaptation to environmental changes in osmolarity are fundamental for cellular and organismal survival. Here we identify a novel osmotic stress resistance pathway in Caenorhabditis elegans (C. elegans), which is dependent on the metabolic master regulator 5’-AMP-activated protein kinase (AMPK) and its neg... | The ability of an organism to adapt to sudden changes in environmental osmolarity is critical to ensure growth, propagation, and survival. The synthesis of organic osmolytes is a common adaptive strategy to survive hyperosmotic stress. However, it was not well understood, which biosynthetic pathways and storage strateg... | Water is a fundamental molecule for life and the ability of an organism to adapt to changes in water content is essential to ensure survival. Hyperosmotic stress promotes water efflux, causing cellular shrinkage, protein and DNA damage, cell cycle arrest and cell death. All living organisms encounter hyperosmotic envir... |
10.1371/journal.pgen.1003538 | SPO11-Independent DNA Repair Foci and Their Role in Meiotic Silencing | In mammalian meiotic prophase, the initial steps in repair of SPO11-induced DNA double-strand breaks (DSBs) are required to obtain stable homologous chromosome pairing and synapsis. The X and Y chromosomes pair and synapse only in the short pseudo-autosomal regions. The rest of the chromatin of the sex chromosomes rema... | Meiosis is a special cell division that generates genetically divergent haploid germ cells. At the very beginning of this process, during meiotic prophase, the enzyme SPO11 generates hundreds of DNA double-strand breaks (DSBs). Meiotic DSBs are repaired via a mechanism that requires the presence of an intact homologous... | During meiotic prophase in yeast and mammals, the induction of DNA double-strand breaks (DSBs) by the transesterase SPO11 precedes stable pairing and synapsis of homologous chromosomes [1], [2]. Synapsis between chromosomes is achieved by the formation of a specific protein complex, consisting of lateral elements along... |
10.1371/journal.pcbi.1006360 | ggsashimi: Sashimi plot revised for browser- and annotation-independent splicing visualization | We present ggsashimi, a command-line tool for the visualization of splicing events across multiple samples. Given a specified genomic region, ggsashimi creates sashimi plots for individual RNA-seq experiments as well as aggregated plots for groups of experiments, a feature unique to this software. Compared to the exist... | Efficient visualization of splicing events from RNA sequencing data is key for the computational analysis of alternative splicing. This process, that results in a single gene giving rise to multiple transcripts, is usually illustrated through sashimi plots: a representation of the read coverage and the support of each ... | Alternative splicing is the process through which different combinations of exons of the same gene are selected to produce a variety of mature coding and non-coding transcripts [1]. The genome-wide landscape of alternative splicing can be easily profiled by RNA sequencing (RNA-seq) and tens of thousands of different RN... |
10.1371/journal.pcbi.1004185 | Machine Learning Methods Enable Predictive Modeling of Antibody Feature:Function Relationships in RV144 Vaccinees | The adaptive immune response to vaccination or infection can lead to the production of specific antibodies to neutralize the pathogen or recruit innate immune effector cells for help. The non-neutralizing role of antibodies in stimulating effector cell responses may have been a key mechanism of the protection observed ... | Antibodies are one of the central mechanisms that the human immune system uses to eliminate infection: an antibody can recognize a pathogen or infected cell using its Fab region while recruiting additional immune cells through its Fc that help destroy the offender. This mechanism may have been key to the reduced risk o... | Antibodies provide the correlate of protection for most vaccines [1]. This correlation is often thought to be mechanistic, as in numerous disease settings passively transferred antibodies provide protection from infection [2]. Yet, the fact that some vaccines that induce an antibody response do not provide protection i... |
10.1371/journal.ppat.1002213 | Significant Effects of Antiretroviral Therapy on Global Gene Expression in Brain Tissues of Patients with HIV-1-Associated Neurocognitive Disorders | Antiretroviral therapy (ART) has reduced morbidity and mortality in HIV-1 infection; however HIV-1-associated neurocognitive disorders (HAND) persist despite treatment. The reasons for the limited efficacy of ART in the brain are unknown. Here we used functional genomics to determine ART effectiveness in the brain and ... | HAND is a common complication of HIV-1 infection in the nervous system presenting a varied spectrum of clinical manifestations with cognitive, motor and behavioral symptoms. Introduction of ART has greatly reduced morbidity and mortality in HIV-1 infection; however HAND persists and its overall prevalence appears to ha... | HAND is a common complication of HIV-1 infection in the nervous system presenting a varied spectrum of clinical manifestations with cognitive, motor and behavioral symptoms. Currently three conditions of increasing severity are recognized as components of HAND: HIV-1-associated asymptomatic neurocognitive impairment, H... |
10.1371/journal.ppat.1005783 | TPL-2 Regulates Macrophage Lipid Metabolism and M2 Differentiation to Control TH2-Mediated Immunopathology | Persistent TH2 cytokine responses following chronic helminth infections can often lead to the development of tissue pathology and fibrotic scarring. Despite a good understanding of the cellular mechanisms involved in fibrogenesis, there are very few therapeutic options available, highlighting a significant medical need... | Chronic helminth infections can cause significant morbidity and organ damage in their definitive mammalian hosts. Managing this collateral damage can reduce morbidity and preserve vital tissues for normal organ function. One particular consequence of some chronic helminth infections is the deposition of fibrotic scar t... | Immune-mediated pathologies and fibrotic scarring are a major cause of global morbidity and mortality. This is due, in part, to a shortage of available drugs and a lack of novel therapeutic targets to limit fibrogenesis, highlighting a major unmet medical need [3, 4]. Chronic infection resulting in recurring inflammati... |
10.1371/journal.ppat.0040003 | Yersinia Controls Type III Effector Delivery into Host Cells by Modulating Rho Activity | Yersinia pseudotuberculosis binds to β1 integrin receptors, and uses the type III secretion proteins YopB and YopD to introduce pores and to translocate Yop effectors directly into host cells. Y. pseudotuberculosis lacking effectors that inhibit Rho GTPases, YopE and YopT, have high pore forming activity. Here, we pres... | The type III secretion system (TTSS) is essential for the virulence of a number of Gram-negative human pathogens of enormous clinical significance. The molecular mechanisms by which TTSS effector proteins are translocated into the host cell are not well understood. The work presented here proposes a new model in which ... | A great spectrum of Gram-negative bacteria depends on a specialized secretion mechanism to establish a successful infection in the host. This machinery is known as the type III secretion system (TTSS), and is present in organisms that are pathogenic for animals or plants, as well as in symbiotic bacteria [1]. In pathog... |
10.1371/journal.ppat.1003247 | Brain Inositol Is a Novel Stimulator for Promoting Cryptococcus Penetration of the Blood-Brain Barrier | Cryptococcus neoformans is the most common cause of fungal meningitis, with high mortality and morbidity. The reason for the frequent occurrence of Cryptococcus infection in the central nervous system (CNS) is poorly understood. The facts that human and animal brains contain abundant inositol and that Cryptococcus has ... | Cryptococcus neoformans is an AIDS-associated human fungal pathogen that annually causes over 1 million cases of meningitis world-wide, and more than 600,000 attributable deaths. Cryptococcus often causes lung and brain infection and is the leading cause of fungal meningitis in immunosuppressed patients. Why Cryptococc... | Cryptococcus neoformans is a basidiomycetous yeast pathogen that often causes life-threatening infections. It causes the most common fungal infection of the central nervous system (CNS) in HIV-infected persons and may present as encephalitis, meningitis, or cerebral-space-occupying lesions [1], [2], [3], [4], [5], [6].... |
10.1371/journal.pcbi.1000620 | Design Principles for Ligand-Sensing, Conformation-Switching Ribozymes | Nucleic acid sensor elements are proving increasingly useful in biotechnology and biomedical applications. A number of ligand-sensing, conformational-switching ribozymes (also known as allosteric ribozymes or aptazymes) have been generated by some combination of directed evolution or rational design. Such sensor elemen... | Aptamers are nucleic acids that bind their cognate ligands (ranging from metal ions to small molecules to proteins) specifically and tightly. Through rational design and/or directed evolution, aptamers can be engineered into allosteric nucleic acids whose conformations can be regulated by their ligands. Aptamer beacons... | Nucleic acid binding species (aptamers) have emerged as a powerful tool for molecular recognition, and have begun to be widely adapted as biosensors, in drug-delivery systems, and as regulatory elements that control gene expression [1]–[4]. Naturally occurring nucleic acid regulatory elements, riboswitches, have been d... |
10.1371/journal.ppat.1004403 | Ontogeny of Recognition Specificity and Functionality for the Broadly Neutralizing Anti-HIV Antibody 4E10 | The process of antibody ontogeny typically improves affinity, on-rate, and thermostability, narrows polyspecificity, and rigidifies the combining site to the conformer optimal for binding from the broader ensemble accessible to the precursor. However, many broadly-neutralizing anti-HIV antibodies incorporate unusual st... | 4E10 is an antibody that neutralizes a broad variety of HIV strains. However, 4E10 is uncommon in infected patients and has not been successfully elicited by any vaccine approach attempted. Hurdles to re-eliciting 4E10 include the accumulation of many mutations during development, demonstrated reactivity against host p... | An effective HIV vaccine will likely need to elicit broadly-neutralizing antibodies (bnAbs) that target the viral envelope protein (Env) as part of a protective immune response [1]–[6]. Env-derived and reverse-engineered immunogen-based vaccines, however, have consistently failed to elicit bnAbs. Possible explanations ... |
10.1371/journal.ppat.1002379 | A Novel Role for the NLRC4 Inflammasome in Mucosal Defenses against the Fungal Pathogen Candida albicans | Candida sp. are opportunistic fungal pathogens that colonize the skin and oral cavity and, when overgrown under permissive conditions, cause inflammation and disease. Previously, we identified a central role for the NLRP3 inflammasome in regulating IL-1β production and resistance to dissemination from oral infection wi... | In this manuscript we describe a new role for a group of molecules termed the “inflammasome” that process key immune response proteins including interleukin-1-β. In previous work, we and others have shown that the NLRP3 inflammasome is important in protecting from severe fungal infections. We now show that, in addition... | Candida sp. are dimorphic fungi that commonly colonize the oral cavity of adult humans, with overgrowth prevented by competing commensal bacteria as well as local host immune responses. Perturbations of the normal oral flora through antibiotic treatment, for example, or immunocompromised states can lead to mucosal Cand... |
10.1371/journal.pntd.0000721 | Structural Optimization and De Novo Design of Dengue Virus Entry Inhibitory Peptides | Viral fusogenic envelope proteins are important targets for the development of inhibitors of viral entry. We report an approach for the computational design of peptide inhibitors of the dengue 2 virus (DENV-2) envelope (E) protein using high-resolution structural data from a pre-entry dimeric form of the protein. By us... | Virus surface proteins mediate interactions with target cells during the initial events in the process of infection. Inhibiting these proteins is therefore a major target for the development of antiviral drugs. However, there are a very large number of different viruses, each with their own distinct surface proteins an... | Fusogenic viral envelope glycoproteins are multimeric proteins that facilitate the fusion of viral and target cell lipid membranes during the initiation of infection. The membrane fusion process is energetically favorable and essentially irreversible, but has a considerable kinetic energy barrier [1]. These proteins al... |
10.1371/journal.pntd.0003034 | Patterns and Risks of Trichinella Infection in Humans and Pigs in Northern Laos | Several outbreaks of trichinellosis associated with the consumption of raw pork have occurred in Laos since 2004. This cross-sectional study was conducted in four provinces of northern Laos to investigate the seroepidemiology of trichinellosis in the human population and determine the prevalence and species of Trichine... | Trichinellosis is one of the most widely distributed parasitic zoonoses worldwide and is caused by infection with nematodes of the genus Trichinella. Infection occurs after consuming larvae in the muscle of infected animals. Several outbreaks of trichinellosis have occurred in Laos since 2004, resulting in a substantia... | Trichinellosis is one of the most widely distributed zoonoses worldwide and is caused by infection with nematodes of the genus Trichinella [1]. Infection occurs after consuming larvae in the muscle of infected animals with domestic and wild pigs the most common vehicles of human infections [2]. The severity of human di... |
10.1371/journal.pbio.1001477 | Strength of Gamma Rhythm Depends on Normalization | Neuronal assemblies often exhibit stimulus-induced rhythmic activity in the gamma range (30–80 Hz), whose magnitude depends on the attentional load. This has led to the suggestion that gamma rhythms form dynamic communication channels across cortical areas processing the features of behaviorally relevant stimuli. Recen... | Brain signals often show a stimulus-induced rhythm in the “gamma” band (30–80 Hz) whose magnitude depends on attentional load, leading to suggestions that gamma rhythm plays a functional role in routing signals across cortical areas. However, gamma power also depends on simple stimulus features such as size or contrast... | Modulations in gamma rhythms have consistently been observed during high-level cognitive processes such as attention [1]–[5], memory [6], feature-binding [7],[8], or conscious perception [9], leading to the suggestion that these rhythms play a functional role in high-level cognitive processing [7],[10]. However, severa... |
10.1371/journal.pntd.0007303 | Comparative accuracy of typhoid diagnostic tools: A Bayesian latent-class network analysis | Typhoid fevers are infections caused by the bacteria Salmonella enterica serovar Typhi (Salmonella Typhi) and Paratyphi A, B and C (Salmonella Paratyphi). Approximately 17.8 million incident cases of typhoid fever occur annually, and incidence is highest in children. The accuracy of current diagnostic tests of typhoid ... | Typhoid fever is an infection caused by the bacterium Salmonella Typhi. Typhoid fever is rare in developed countries but remains high in the developing world. Effective treatment is available but accurate diagnosis of typhoid fever is challenging as typhoid fever can be difficult to distinguish from other infections. B... | Typhoid fever (also known as enteric fever) is a systemic infection caused by the Gram-negative bacteria Salmonella enterica serotypes Typhi or Paratyphi A,B and C[1],[2]. While rare in developed countries, the burden of typhoid remains high in developing countries. Recent annual estimates of typhoid fever cases in low... |
10.1371/journal.pntd.0002072 | Activities of Daily Living Associated with Acquisition of Melioidosis in Northeast Thailand: A Matched Case-Control Study | Melioidosis is a serious infectious disease caused by the Category B select agent and environmental saprophyte, Burkholderia pseudomallei. Most cases of naturally acquired infection are assumed to result from skin inoculation after exposure to soil or water. The aim of this study was to provide evidence for inoculation... | Melioidosis is a serious infectious disease caused by the environmental saprophyte, Burkholderia pseudomallei. The infection is potentially preventable, but developing prevention guidelines is hampered by a lack of evidence on which to base them. The purpose of this study was to provide evidence for inoculation, inhala... | Burkholderia pseudomallei is a Category B select agent and the cause of naturally acquired melioidosis in South and East Asia, Northern Australia, the Indian subcontinent and areas of South America [1]–[3]. Northeast Thailand is a hotspot for this infection, with an annual incidence of 21.0 per 100,000 population and a... |
10.1371/journal.pgen.1000239 | Genetic and Linguistic Coevolution in Northern Island Melanesia | Recent studies have detailed a remarkable degree of genetic and linguistic diversity in Northern Island Melanesia. Here we utilize that diversity to examine two models of genetic and linguistic coevolution. The first model predicts that genetic and linguistic correspondences formed following population splits and isola... | The coevolution of genes and languages has been a subject of enduring interest among geneticists and linguists. Progress has been limited by the available data and by the methods employed to compare patterns of genetic and linguistic variation. Here, we use high-quality data and novel methods to test two models of gene... | In On the Origin of Species [1] and The Descent of Man [2], Darwin suggested that patterns of global biological and linguistic variation might correspond because of their parallel evolution in isolated human groups. Recently, Cavalli-Sforza and colleagues [3]–[5] described a more formal version of this process in which... |
10.1371/journal.ppat.1001330 | SLO-1-Channels of Parasitic Nematodes Reconstitute Locomotor Behaviour and Emodepside Sensitivity in Caenorhabditis elegans slo-1 Loss of Function Mutants | The calcium-gated potassium channel SLO-1 in Caenorhabditis elegans was recently identified as key component for action of emodepside, a new anthelmintic drug with broad spectrum activity. In this study we identified orthologues of slo-1 in Ancylostoma caninum, Cooperia oncophora, and Haemonchus contortus, all importan... | In parasitic nematodes, experiments at the molecular level are currently not feasible, since in vitro culture and genetic engineering are still in their infancy. In the present study we chose the model organism Caenorhabditis elegans not only as a mere expression system for genes from parasitic nematodes, but used the ... | Infections with parasitic nematodes heavily affect the well-being, health, and productivity of humans and animals worldwide [1]. Since the 1960s several broad spectrum anthelmintic compounds have been available. During decades of frequent and sometimes inappropriate use of these anthelmintics, resistance to currently a... |
10.1371/journal.pgen.1005569 | LINE-1 Mediated Insertion into Poc1a (Protein of Centriole 1 A) Causes Growth Insufficiency and Male Infertility in Mice | Skeletal dysplasias are a common, genetically heterogeneous cause of short stature that can result from disruptions in many cellular processes. We report the identification of the lesion responsible for skeletal dysplasia and male infertility in the spontaneous, recessive mouse mutant chagun. We determined that Poc1a, ... | Severe short stature in humans has many causes including defects in skeletal and hormonal growth regulation. Primordial dwarfisms are congenital growth defects that involve mutations in genes for DNA repair, DNA replication, splicing of U12 introns, and centrosome dynamics. We discovered that the spontaneous, dwarf mou... | Normal adult stature in humans is achieved primarily through regulation of long bone growth, which occurs through endochondral ossification [1,2]. This process begins with the differentiation of mesenchymal stem cells into chondrocytes in regions of the body where skeletal elements will eventually reside. Hypertrophic ... |
10.1371/journal.pntd.0004778 | Improvement of POC-CCA Interpretation by Using Lyophilization of Urine from Patients with Schistosoma mansoni Low Worm Burden: Towards an Elimination of Doubts about the Concept of Trace | Accurate diagnostic techniques for schistosomiasis are essential for prevalence determination and identification of positive patients. A point-of-care test for detecting schistosome circulating cathodic antigen (POC-CCA) has been evaluated for its accuracy in different endemic regions. This reagent strip/dipstick based... | Schistosomiasis mansoni is a relevant disease affecting millions of individuals in different countries, in particular countries in Africa, and Brazil. Diagnosis performed by Kato-Katz technique for the detection of eggs in stool and a point-of-care test for circulating cathodic antigen detection in urine (POC-CCA) has ... | World Health Organization (WHO) guidelines for control and elimination of schistosomiasis require pre-treatment evaluations of the prevalence of Schistosoma infections to inform decisions on how often to treat within endemic areas [1]. The WHO has articulated goals to control the disease by 2020 [2]. Accurate diagnosti... |
10.1371/journal.pbio.0050300 | Distinct Mammalian Precursors Are Committed to Generate Neurons with Defined Dendritic Projection Patterns | The mechanisms that regulate how dendrites target different neurons to establish connections with specific cell types remain largely unknown. In particular, the formation of cell-type–specific connectivity during postnatal neurogenesis could be either determined by the local environment of the mature neuronal circuit o... | The mammalian brain contains a large number of different classes of neurons that are connected in a specific manner. A long-standing question is how such stereotyped connections emerge during the assembly of the brain. Here, we investigated whether neonatal and adult brain stem cells give rise to neurons whose connecti... | Dendrites are the major source of synaptic input for neurons. Thus, the specific computation that a neuron can accomplish is largely determined by the synaptic partners that contact its dendrites. In many regions of the central nervous system, including the cortex, spinal cord, retina, and olfactory bulb [1–4], neurons... |
10.1371/journal.pgen.1007759 | Balancing selection at a premature stop mutation in the myostatin gene underlies a recessive leg weakness syndrome in pigs | Balancing selection provides a plausible explanation for the maintenance of deleterious alleles at moderate frequency in livestock, including lethal recessives exhibiting heterozygous advantage in carriers. In the current study, a leg weakness syndrome causing mortality of piglets in a commercial line showed monogenic ... | Lameness is an important problem in livestock production for both animal welfare and economic reasons. A severe piglet lameness syndrome was observed in a commercial pig population. The incidence of the condition was low (6.3%), but was higher in affected families (~25%), which suggested a genetic basis and a recessive... | Leg weakness is a heterogeneous condition causing lameness in pigs, and has negative impacts on both animal welfare and productivity [1, 2]. Significant heritability estimates have been reported for leg weakness traits [reviewed in 3], with moderate to high estimates in certain pig breeds, e.g. h2 = 0.45 in Landrace [4... |
10.1371/journal.ppat.1002161 | Glycosaminoglycans and Sialylated Glycans Sequentially Facilitate Merkel Cell Polyomavirus Infectious Entry | Merkel cell polyomavirus (MCV or MCPyV) appears to be a causal factor in the development of Merkel cell carcinoma, a rare but highly lethal form of skin cancer. Although recent reports indicate that MCV virions are commonly shed from apparently healthy human skin, the precise cellular tropism of the virus in healthy su... | Strong evidence suggests that Merkel cell polyomavirus (MCV or MCPyV) is a causative factor in the development of a large proportion of cancers arising from epidermal Merkel cells. While Merkel cell carcinoma is rare, it appears that infection with MCV is common, and many healthy people chronically shed MCV virions fro... | The viral family Polyomaviridae consists of a diverse group of non-enveloped DNA viruses that infect humans as well as a range of other vertebrates. The family name is derived from the observation that murine polyomavirus causes tumors in various tissues in experimentally infected animals. The apparently broad tissue t... |
10.1371/journal.ppat.1007957 | Dietary zinc and the control of Streptococcus pneumoniae infection | Human zinc deficiency increases susceptibility to bacterial infection. Although zinc supplementation therapies can reduce the impact of disease, the molecular basis for protection remains unclear. Streptococcus pneumoniae is a major cause of bacterial pneumonia, which is prevalent in regions of zinc deficiency. We repo... | Zinc deficiency affects one-third of the world’s population and is associated with an increased susceptibility to bacterial infection. Despite this, the molecular basis for how zinc deficiency compromises host control of infection remains to be understood. We show that dietary zinc deficiency impacts host tissue zinc a... | Zinc (Zn) is the second most abundant transition metal ion in humans and has crucial importance in immune function [1]. Although severe Zn deficiency is rare, mild to moderate Zn deficiency is estimated to affect one third of the world’s population [2]. The impact on human health accounts for ~1.4% of annual global mor... |
10.1371/journal.pcbi.1005892 | Optimal occlusion uniformly partitions red blood cells fluxes within a microvascular network | In animals, gas exchange between blood and tissues occurs in narrow vessels, whose diameter is comparable to that of a red blood cell. Red blood cells must deform to squeeze through these narrow vessels, transiently blocking or occluding the vessels they pass through. Although the dynamics of vessel occlusion have been... | Arterial trees shuttle red blood cells from the heart to billions of capillaries distributed throughout the body. These trees have long been thought to be organized to minimize transport costs. Yet red blood cells are tightly squeezed within the finest vessels, meaning that these vessels account for as much as half of ... | Vascular networks transport oxygen, carbon dioxide and sugars within animals. Exchange of both nutrients and gases occurs primarily in narrow vessels (e.g. capillaries) that are typically organized into reticulated networks. The narrowest vessels are comparable in diameter to red blood cells, forcing cells to squeeze t... |
10.1371/journal.pbio.2004303 | Communication across the bacterial cell envelope depends on the size of the periplasm | The cell envelope of gram-negative bacteria, a structure comprising an outer (OM) and an inner (IM) membrane, is essential for life. The OM and the IM are separated by the periplasm, a compartment that contains the peptidoglycan. The OM is tethered to the peptidoglycan via the lipoprotein, Lpp. However, the importance ... | Antibiotic resistance is one of the greatest threats that humanity faces today. In particular, the emergence of multidrug-resistant gram-negative bacteria has become a pressing issue. Infections caused by resistant gram-negative bacteria are indeed difficult to treat because of the presence of a double-membraned envelo... | Although the multilayered architecture of the cell envelope of gram-negative bacteria was first described in the 1960s, we are still unraveling the links between the structure of this cellular component and its functions in the cell. The envelope of these bacteria consists of an inner membrane (IM), a classical phospho... |
10.1371/journal.pntd.0004768 | Accuracy of Mobile Phone and Handheld Light Microscopy for the Diagnosis of Schistosomiasis and Intestinal Protozoa Infections in Côte d’Ivoire | Handheld light microscopy using compact optics and mobile phones may improve the quality of health care in resource-constrained settings by enabling access to prompt and accurate diagnosis.
Laboratory technicians were trained to operate two handheld diagnostic devices (Newton Nm1 microscope and a clip-on version of the... | Handheld light microscopes are new technologies that may be helpful in enabling better access to diagnostic testing for people living in resource-constrained settings in tropical and subtropical countries. Recent studies evaluating the accuracy of such devices have focused on their use by expert microscopists and were ... | Neglected tropical diseases have considerable detrimental impacts in resource-constrained settings as they can result in chronic disability and stigmatization, and have profound negative economic consequences [1,2]. Microscopy is an essential tool in the diagnosis and surveillance of many neglected tropical diseases an... |
10.1371/journal.ppat.1000131 | HIV-1 Nef Targets MHC-I and CD4 for Degradation Via a Final Common β-COP–Dependent Pathway in T Cells | To facilitate viral infection and spread, HIV-1 Nef disrupts the surface expression of the viral receptor (CD4) and molecules capable of presenting HIV antigens to the immune system (MHC-I). To accomplish this, Nef binds to the cytoplasmic tails of both molecules and then, by mechanisms that are not well understood, di... | HIV is unique among viral pathogens in its capacity to cause chronic and progressive disease in almost all infected people. To accomplish this, HIV must evade the host immune response, especially cytotoxic T lymphocytes (CTLs), which normally function to lyse virally infected cells. HIV encodes a factor, Nef, which pro... | The HIV-1 accessory protein, Nef, affects the biology of the infected cell in several ways to achieve conditions optimal for viral replication and spread. Nef alters the intracellular trafficking of important immune molecules, such as class I and II major histocompatibility complex proteins (MHC-I and MHC-II), CD4, CD2... |
10.1371/journal.pcbi.1002193 | Ligand-Induced Modulation of the Free-Energy Landscape of G Protein-Coupled Receptors Explored by Adaptive Biasing Techniques | Extensive experimental information supports the formation of ligand-specific conformations of G protein-coupled receptors (GPCRs) as a possible molecular basis for their functional selectivity for signaling pathways. Taking advantage of the recently published inactive and active crystal structures of GPCRs, we have imp... | G protein-coupled receptors (GPCRs) constitute one of the most important classes of cellular targets owing to their known response to a host of extracellular stimuli, and consequent involvement in numerous vital biological processes. Compelling evidence herein referred to as ‘functional selectivity’ shows that ligands ... | G-protein coupled receptors (GPCRs) are versatile signaling proteins that functionally couple a host of extracellular stimuli to intracellular effectors, thus mediating several vital cellular responses. The majority of marketed drugs act as agonists, inverse agonists, or antagonists at these receptors depending on whet... |
10.1371/journal.pgen.1003582 | Joint Molecule Resolution Requires the Redundant Activities of MUS-81 and XPF-1 during Caenorhabditis elegans Meiosis | The generation and resolution of joint molecule recombination intermediates is required to ensure bipolar chromosome segregation during meiosis. During wild type meiosis in Caenorhabditis elegans, SPO-11-generated double stranded breaks are resolved to generate a single crossover per bivalent and the remaining recombin... | Meiotic recombination generates joint molecules that ensure chromosomes segregate correctly. Failure to generate or resolve joint molecules can have profound effects on fertility and on the viability of resulting progeny. The generation and resolution of joint molecules is carefully regulated. Generation of joint molec... | Meiotic recombination generates chiasmata that join homologous chromosomes together to ensure proper meiotic chromosome segregation. The efficient generation and resolution of joint molecules (JM) is essential for meiosis; therefore, JM formation and resolution is carefully regulated. In most organisms, meiotic recombi... |
10.1371/journal.pgen.1001079 | Identification of the Bovine Arachnomelia Mutation by Massively Parallel Sequencing Implicates Sulfite Oxidase (SUOX) in Bone Development | Arachnomelia is a monogenic recessive defect of skeletal development in cattle. The causative mutation was previously mapped to a ∼7 Mb interval on chromosome 5. Here we show that array-based sequence capture and massively parallel sequencing technology, combined with the typical family structure in livestock populatio... | Arachnomelia is a defect in skeletal development of cattle. Affected calves are born dead with elongated limbs and facial deformities. The causative mutation for this recessive condition had previously been mapped to a ∼7 Mb interval. We exploited the special structure of cattle families to identify the causative mutat... | Arachnomelia is a genetic disease in cattle characterized by skeletal abnormalities. Affected calves are usually stillborn with a spidery appearance and an abnormally shaped skull (Figure 1). The bones of the limbs are prolonged (dolichostenomelia) with marked thinning of the diaphyses that fracture easily in the cours... |
10.1371/journal.pcbi.1003190 | A General Model for Toxin-Antitoxin Module Dynamics Can Explain Persister Cell Formation in E. coli | Toxin-Antitoxin modules are small operons involved in stress response and persister cell formation that encode a “toxin” and its corresponding neutralizing “antitoxin”. Regulation of these modules involves a complex mechanism known as conditional cooperativity, which is supposed to prevent unwanted toxin activation. He... | Bacterial persistence plays an important role in many chronic infections. Persisters are subpopulations of bacteria which are tolerant to biological stresses such as antibiotics because they are in a dormant, non-dividing state. Toxin-antitoxin (TA) modules play a pivotal role in persister generation and bacterial stre... | Stress response is an important aspect of the physiology of bacteria, allowing them to deal with a continuously changing environment and exposure to altering and fluctuating food sources as well as life-threatening chemicals such as antibiotics. Among the elements involved in bacterial stress response are the type II t... |
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