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10.1371/journal.pntd.0002370 | Non-peptidic Cruzain Inhibitors with Trypanocidal Activity Discovered by Virtual Screening and In Vitro Assay | A multi-step cascade strategy using integrated ligand- and target-based virtual screening methods was developed to select a small number of compounds from the ZINC database to be evaluated for trypanocidal activity. Winnowing the database to 23 selected compounds, 12 non-covalent binding cruzain inhibitors with affinit... | Chagas disease (American trypanosomiasis) is a parasitic infection that kills millions of mostly poverty-stricken people in Latin America. In recent years it has also spread to nonendemic countries – the United States, Canada, Europe, Australia and Japan – as a result of immigration. The only available drugs for its tr... | Chagas disease, widespread in Latin America, is caused by the kinetoplastid protozoan parasite Trypanosoma cruzi. Despite efforts to reduce the transmission of the parasite by controlling the hematophagous triatomine insect vector, the World Health Organization estimates that 10 million people are infected worldwide, w... |
10.1371/journal.pcbi.1004921 | Conservation in Mammals of Genes Associated with Aggression-Related Behavioral Phenotypes in Honey Bees | The emerging field of sociogenomics explores the relations between social behavior and genome structure and function. An important question is the extent to which associations between social behavior and gene expression are conserved among the Metazoa. Prior experimental work in an invertebrate model of social behavior... | Sociogenomics explores the relationship between social behavior and the genome. An important issue is the extent to which results from social insects can be used to understand social behavior in other animals. We address this question through computational studies of previously published experimental data on patterns o... | Social behavior, like phenotypes of any level of complexity, is regulated by the activity of genomic networks and resulting gene expression. At the same time that specific examples of genes influencing behavior were being discovered empirically[1,2], the field of systems biology was developing[3]. The essence of system... |
10.1371/journal.pcbi.1006395 | Balance of mechanical forces drives endothelial gap formation and may facilitate cancer and immune-cell extravasation | The formation of gaps in the endothelium is a crucial process underlying both cancer and immune cell extravasation, contributing to the functioning of the immune system during infection, the unfavorable development of chronic inflammation and tumor metastasis. Here, we present a stochastic-mechanical multiscale model o... | Transmigration of immune cells into and out of the blood vessels is a crucial process for the functioning of the immune system during infections and acute inflammations, and aberrant transmigration may contribute to chronic inflammations. Likewise, cancer metastasis critically depends on intra-and extravasation of canc... | Immune and cancer cells alike are characterized by their ability to migrate within the vasculature and then to leave the vasculature into different tissues. These processes are crucial for a functioning immune system to fight acute infections [1] or participate in wound healing [2]. However, chronic inflammation or tum... |
10.1371/journal.ppat.1006663 | Effects of glutamate and ivermectin on single glutamate-gated chloride channels of the parasitic nematode H. contortus | Ivermectin (IVM) is a widely-used anthelmintic that works by binding to and activating glutamate-gated chloride channel receptors (GluClRs) in nematodes. The resulting chloride flux inhibits the pharyngeal muscle cells and motor neurons of nematodes, causing death by paralysis or starvation. IVM resistance is an emergi... | IVM is a gold standard anti-parasitic drug that is used extensively to control invertebrate parasites pest species. The drug targets the glutamate-gated chloride channel receptor (GluClR) found on neurons and muscle cells of these organisms, causing paralysis and death. However, IVM resistance is becoming a serious pro... | Pentameric ligand gated ion channels (pLGICs) are membrane-bound receptors that facilitate the diffusion of ions across cell membranes in response to the binding of agonists. The glutamate-gated chloride channel receptor (GluClR), first identified in arthropods, such as insects and crustaceans [1–3], is an anion-select... |
10.1371/journal.pgen.1000939 | DNA Adenine Methylation Is Required to Replicate Both Vibrio cholerae Chromosomes Once per Cell Cycle | DNA adenine methylation is widely used to control many DNA transactions, including replication. In Escherichia coli, methylation serves to silence newly synthesized (hemimethylated) sister origins. SeqA, a protein that binds to hemimethylated DNA, mediates the silencing, and this is necessary to restrict replication to... | Bacteria usually have one chromosome but can have extrachromosomal replicons, called plasmids. Although normally dispensable, plasmids can confer adaptive advantage to cells in stressful environments. Bacteria can also have multiple chromosomes, each carrying essential genes, as in eukaryotes. In all organisms, chromos... | The regulatory potential of canonical DNA sequences can be greatly expanded by epigenetic modifications. Methylation is the most common modification of DNA and is widely used to control many cellular processes [1]. In bacteria, DNA methylation is restricted to adenine and cytosine residues [2], and can facilitate or in... |
10.1371/journal.pntd.0004568 | Cost-Effectiveness of Antivenoms for Snakebite Envenoming in 16 Countries in West Africa | Snakebite poisoning is a significant medical problem in agricultural societies in Sub Saharan Africa. Antivenom (AV) is the standard treatment, and we assessed the cost-effectiveness of making it available in 16 countries in West Africa.
We determined the cost-effectiveness of AV based on a decision-tree model from a p... | Antivenom is the main intervention against snakebite poisoning but is relatively scarce, unaffordable and the situation has been compounded further by the recent cessation of production of effective antivenoms and marketing of inappropriate products. Given this crisis, we assessed the cost effectiveness of providing an... | Snakebite poisoning is a significant cause of death and disability in rural West Africa [1,2,3,4,5,6,7]. The exact burden of snakebite is difficult to ascertain and is often undereported. A study by Jean-Philippe Chippaux reported an estimate of over 314, 000 envenomations, 7300 mortality and nearly 6000 amputations oc... |
10.1371/journal.pgen.1000151 | Off-Target Effects of Psychoactive Drugs Revealed by Genome-Wide Assays in Yeast | To better understand off-target effects of widely prescribed psychoactive drugs, we performed a comprehensive series of chemogenomic screens using the budding yeast Saccharomyces cerevisiae as a model system. Because the known human targets of these drugs do not exist in yeast, we could employ the yeast gene deletion c... | Neuropsychiatric disorders such as depression and psychosis affect one-quarter of all individuals during their lifetime, and despite efforts to improve the selectivity of psychoactive drugs, all are associated with side effects. Drug efficacy and tolerance are known to be linked to an individual's genetic profile, but ... | Neuropsychiatric disorders will effect 25% of all individuals at some point in their lives, with devastating social and economic consequences [1]. This constellation of diseases encompasses schizophrenia, depression, age-related memory and cognition decline, and the degeneration of neuromuscular function. Most prescrib... |
10.1371/journal.ppat.1005780 | Ecological Contexts of Index Cases and Spillover Events of Different Ebolaviruses | Ebola virus disease afflicts both human and animal populations and is caused by four ebolaviruses. These different ebolaviruses may have distinct reservoir hosts and ecological contexts that determine how, where, and when different ebolavirus spillover events occur. Understanding these virus-specific relationships is i... | Multiple Ebola virus disease outbreaks have occurred over the past 40 years, yet we still do not know the geographical distributions, definitive host species, and suitable habitats for animal-to-human transmission of different ebolaviruses. Each Ebola virus disease outbreak has started with at least one transmission ev... | From the first recognized outbreak of Ebola virus disease (EVD) in 1976 to the recent outbreak beginning in 2013, our knowledge about the molecular biology and epidemiology of viruses belonging to the genus Ebolavirus has increased dramatically. Yet after nearly 40 years of research, we still have a limited understandi... |
10.1371/journal.pcbi.1003830 | Baseline CD4+ T Cell Counts Correlates with HIV-1 Synonymous Rate in HLA-B*5701 Subjects with Different Risk of Disease Progression | HLA-B*5701 is the host factor most strongly associated with slow HIV-1 disease progression, although risk of progression may vary among patients carrying this allele. The interplay between HIV-1 evolutionary rate variation and risk of progression to AIDS in HLA-B*5701 subjects was studied using longitudinal viral seque... | The clinical course of HIV-1 infection is characterized by considerable variability in the rate of progression to acquired immunodeficiency syndrome (AIDS) among patients with different genetic background. The human leukocyte antigen (HLA) B*5701 is the host factor most strongly associated with slow HIV-1 disease progr... | The clinical course of HIV-1 infection is characterized by considerable variability in the rate of disease progression among patients with different genetic background [1]–[3]. It has been shown that the likelihood of progressing to AIDS for subjects with baseline viral load (VL) around or lower than 10,000 copies/mL i... |
10.1371/journal.pcbi.1004211 | Optimising and Communicating Options for the Control of Invasive Plant Disease When There Is Epidemiological Uncertainty | Although local eradication is routinely attempted following introduction of disease into a new region, failure is commonplace. Epidemiological principles governing the design of successful control are not well-understood. We analyse factors underlying the effectiveness of reactive eradication of localised outbreaks of ... | Increases in global trade and travel suggest outbreaks of plant disease caused by invasive pathogens will increase in frequency. We use mathematical modelling to show how control of such disease outbreaks can be optimised. Although our methods and analyses are generic, we use the attempted eradication of citrus canker ... | Impacts of invading pathogens can be extremely severe, and so understanding how controls can be optimised is imperative [1]. We focus here on plant disease, motivated by the serious and potentially irreparable ecological damage that can follow introductions of plant pathogens into natural host populations [2], and the ... |
10.1371/journal.pcbi.1001113 | Consensus-Phenotype Integration of Transcriptomic and Metabolomic Data Implies a Role for Metabolism in the Chemosensitivity of Tumour Cells | Using transcriptomic and metabolomic measurements from the NCI60 cell line panel,
together with a novel approach to integration of molecular profile data, we show
that the biochemical pathways associated with tumour cell chemosensitivity to
platinum-based drug... | Resistance to chemotherapy drugs in cancer sufferers is very common. Using a
panel of 59 cell lines obtained from different types of cancer we study the
links between the genes and metabolites measured in these cells and the
resistance the cells show to common... | In the quest to understand complex biological systems at multiple levels of
biological organization, the need arises to combine knowledge from experiments of
different types to create a full picture of a system's behavior. Modern
molecular profiling (“omics”) methods, suc... |
10.1371/journal.pgen.1004324 | Genetic Interactions Involving Five or More Genes Contribute to a Complex Trait in Yeast | Recent research suggests that genetic interactions involving more than two loci may influence a number of complex traits. How these ‘higher-order’ interactions arise at the genetic and molecular levels remains an open question. To provide insights into this problem, we dissected a colony morphology phenotype that segre... | Although it is well known that interactions among genetic variants contribute to many complex traits, the forms of these interactions have not been fully characterized. Most work on this problem to date has focused on relatively simple cases involving two or three loci. However, higher-order interactions involving larg... | Understanding the genetic basis of complex traits is critical for advancing medicine, evolutionary biology, and agriculture [1], [2]. A challenge to progress in this area is that genetic variants can interact, resulting in unexpected phenotypic consequences [3]–[7]. Most of our knowledge about these genetic interaction... |
10.1371/journal.pbio.1001283 | Presynaptically Localized Cyclic GMP-Dependent Protein Kinase 1 Is a Key Determinant of Spinal Synaptic Potentiation and Pain Hypersensitivity | Synaptic long-term potentiation (LTP) at spinal neurons directly communicating pain-specific inputs from the periphery to the brain has been proposed to serve as a trigger for pain hypersensitivity in pathological states. Previous studies have functionally implicated the NMDA receptor-NO pathway and the downstream seco... | Pain is an important physiological function that protects our body from harm. Pain-sensing neurons, called nociceptors, transduce harmful stimuli into electrical signals and transmit this information to the brain via the spinal cord. When nociceptors are persistently activated, such as after injury, the connections the... | Plasticity in peripheral nociceptors and their synapses with spinal neurons has been proposed as a cellular basis for the development and maintenance of pain hypersensitivity following peripheral inflammation or nerve injury [1]–[3]. Activation of nociceptive nerve afferents at frequencies relevant to pathological pain... |
10.1371/journal.ppat.1006248 | Synergy between the classical and alternative pathways of complement is essential for conferring effective protection against the pandemic influenza A(H1N1) 2009 virus infection | The pandemic influenza A(H1N1) 2009 virus caused significant morbidity and mortality worldwide thus necessitating the need to understand the host factors that influence its control. Previously, the complement system has been shown to provide protection during the seasonal influenza virus infection, however, the role of... | The pandemic influenza A(H1N1) 2009 virus is now circulating seasonally and causing a significant disease burden worldwide. Hence, it is important to delineate the immune components required for protection against its infection. Here we demonstrate that presence of intact complement is essential for clearing the pandem... | Influenza viruses, the members of the family Orthomyxoviridae, are globally important acute respiratory pathogens known to cause significant morbidity and mortality [1–3]. These negative sense RNA viruses possess a segmented genome encompassing a constellation of genes, which facilitate genetic reassortment upon infect... |
10.1371/journal.pgen.0030207 | Activation of Inflammation/NF-κB Signaling in Infants Born to Arsenic-Exposed Mothers | The long-term health outcome of prenatal exposure to arsenic has been associated with increased mortality in human populations. In this study, the extent to which maternal arsenic exposure impacts gene expression in the newborn was addressed. We monitored gene expression profiles in a population of newborns whose mothe... | Arsenic is an environmental pollutant and known human carcinogen. Chronic exposure to arsenic-contaminated water is an important public health hazard around the world, including the United States, with millions exposed to drinking water with levels that far exceed World Health Organization (WHO) guidelines. Given the i... | Arsenic is a ubiquitous environmental pollutant and a known human carcinogen [1]. Chronic arsenic exposure is an important public health hazard around the world, with millions of people exposed to drinking water with levels far exceeding the guideline of 10 μg/l established by the WHO. Exposure to arsenic-contaminated ... |
10.1371/journal.pgen.1004186 | Within-Host Spatiotemporal Dynamics of Plant Virus Infection at the Cellular Level | A multicellular organism is not a monolayer of cells in a flask; it is a complex, spatially structured environment, offering both challenges and opportunities for viruses to thrive. Whereas virus infection dynamics at the host and within-cell levels have been documented, the intermediate between-cell level remains poor... | A great deal is understood about how a virus infects an individual cell and manages to replicate. Patterns of disease progression in plant and animal hosts, such as virus titers and the appearance of symptoms, have also been described in great detail. On other hand, very little is known about what is happening at the i... | For obligate intra-cellular micro-parasites such as viruses, the cell is the fundamental and minimal unit of infection. Important macro-scale phenomena in viral infection – immunity, virulence, transmission, and evolution – all depend on the infection outcome in individual cells. The biochemical and molecular bases of ... |
10.1371/journal.ppat.1002999 | Glycoprotein N of Human Cytomegalovirus Protects the Virus from Neutralizing Antibodies | Herpes viruses persist in the infected host and are transmitted between hosts in the presence of a fully functional humoral immune response, suggesting that they can evade neutralization by antiviral antibodies. Human cytomegalovirus (HCMV) encodes a number of polymorphic highly glycosylated virion glycoproteins (g), i... | Herpes viruses are transmitted between individuals in cell free form and successful spread benefits from mechanisms that limit the loss of infectivity by the activity of virus neutralizing antibodies. Human cytomegalovirus (HCMV) is an important pathogen and understanding how the virus can evade antiviral antibodies ma... | Cytomegaloviruses (CMV) have co-evolved with their respective hosts. During this long and continuing co-evolution these viruses have adapted to the host defense systems and vice versa to allow the life-long persistence of these viruses. As a result, infections in immunocompetent hosts are generally asymptomatic and a l... |
10.1371/journal.pgen.1002649 | Transcriptional Regulation of Rod Photoreceptor Homeostasis Revealed by In Vivo NRL Targetome Analysis | A stringent control of homeostasis is critical for functional maintenance and survival of neurons. In the mammalian retina, the basic motif leucine zipper transcription factor NRL determines rod versus cone photoreceptor cell fate and activates the expression of many rod-specific genes. Here, we report an integrated an... | The rod and cone photoreceptors in the retina are highly specialized neurons that capture photons under dim and bright light, respectively. Loss of rod photoreceptors is an early clinical manifestation in most retinal neurodegenerative diseases that eventually result in cone cell death and blindness. The transcription ... | Molecular mechanisms underlying neuronal differentiation and generation of complex sensory and behavioral circuits in the mammalian central nervous system are still poorly elucidated. Gene regulatory networks (GRNs) integrate key control elements that guide the development of distinct cell types [1], [2], [3] and contr... |
10.1371/journal.ppat.1003861 | STING-Dependent Type I IFN Production Inhibits Cell-Mediated Immunity to Listeria monocytogenes | Infection with Listeria monocytogenes strains that enter the host cell cytosol leads to a robust cytotoxic T cell response resulting in long-lived cell-mediated immunity (CMI). Upon entry into the cytosol, L. monocytogenes secretes cyclic diadenosine monophosphate (c-di-AMP) which activates the innate immune sensor STI... | Current vaccines are successful at generating neutralizing antibodies, however there is a pressing medical need to find adjuvants that yield long-lived memory T cells. Immunization with the bacterium Listeria monocytogenes induces a robust protective immune response mediated by cytotoxic lymphocytes that are efficient ... | Cell-mediated immunity (CMI) is a critical component for protection against intracellular pathogens. Upon infection, the innate immune response provides resistance and initiates the development of antigen-specific lymphocytes including cytotoxic CD8+ T cells, which ultimately kill host cells harboring pathogens [1]. Th... |
10.1371/journal.ppat.1005594 | Crystal Structure of Human Herpesvirus 6B Tegument Protein U14 | The tegument protein U14 of human herpesvirus 6B (HHV-6B) constitutes the viral virion structure and is essential for viral growth. To define the characteristics and functions of U14, we determined the crystal structure of the N-terminal domain of HHV-6B U14 (U14-NTD) at 1.85 Å resolution. U14-NTD forms an elongated he... | Human herpesvirus 6B (HHV-6B), a causative agent of exanthema subitum for children and immunocompromised adults, encodes numerous tegument proteins that constitute the viral matrix. HHV-6B U14 is a tegument protein essential for viral propagation, and additionally it interacts with host factors such as tumor suppressor... | Human herpesvirus 6B (HHV-6B) and the closely-related virus HHV-6A are classified as Roseolovirus genus of beta herpesvirus subfamily [1] [2] [3] [4], which also includes human herpesvirus 7 (HHV-7) and human cytomegalovirus (HCMV). HHV-6B is a causative agent of exanthema subitum for children [5] [6] by primary infect... |
10.1371/journal.pntd.0006776 | Implementing active community-based surveillance-response system for Buruli ulcer early case detection and management in Ghana | Buruli Ulcer (BU) is one of the most neglected debilitating tropical diseases caused by Mycobacterium ulcerans, which causes considerable morbidity and disability. Building on earlier findings that community-based interventions could enhance case detection and reduce treatment dropout and defaulter rates, we establishe... | The study revealed that it is feasible to train periphery health workers and community-based volunteers to implement a community-based active surveillance–response system for early buruli ulcer (BU) case detection, diagnosis and treatment at outpatient clinics. At the end of 12 months follow-up, there were 36084 survei... | Buruli ulcer (BU) is one of the most neglected debilitating tropical diseases caused by Mycobacterium ulcerans. Though, BU-related fatality is very rare, it causes considerable morbidity and disability [1–3], which lead to stigma and anguish among infected individuals and affected families. The disease occurs mainly in... |
10.1371/journal.pcbi.1004130 | Neuroblastoma Tyrosine Kinase Signaling Networks Involve FYN and LYN in Endosomes and Lipid Rafts | Protein phosphorylation plays a central role in creating a highly dynamic network of interacting proteins that reads and responds to signals from growth factors in the cellular microenvironment. Cells of the neural crest employ multiple signaling mechanisms to control migration and differentiation during development. I... | Neuroblastoma is a childhood cancer for which therapeutic progress has been slow. We analyzed a large number phosphorylated proteins in neuroblastoma cells to discern patterns that indicate functional signal transduction pathways. To analyze the data, we developed novel techniques that resolve data structure and visual... | Neuroblastoma arises from cells of the neural crest, a population of multipotent, migrating cells that differentiate into neurons in the peripheral nervous system, melanocytes, and structural cells [1]. Neuroblastoma represents 7–10% of childhood cancers and about half of all infant cancers. Positive prognosis ranges f... |
10.1371/journal.pntd.0000894 | Viral and Epidemiological Determinants of the Invasion Dynamics of Novel Dengue Genotypes | Dengue has become a major concern for international public health. Frequent epidemic outbreaks are believed to be driven by a complex interplay of immunological interactions between its four co-circulating serotypes and large fluctuations in mosquito densities. Viral lineage replacement events, caused for example by di... | Dengue fever and the more severe dengue haemorrhagic fever and dengue shock syndrome are mosquito borne viral infections that have seen a major increase in terms of global distribution and total case numbers over the last few decades. There are currently four antigenically distinct and potentially co-circulating dengue... | Dengue virus (DENV) is the most wide-spread arbovirus affecting human populations. During the last decades it has increasingly become a major public health problem with significant economic and social impact [1]–[3]. It is transmitted between humans in urban and peri-urban settings predominantly by the Aedes aegypti an... |
10.1371/journal.pntd.0003803 | Antiviral Biologic Produced in DNA Vaccine/Goose Platform Protects Hamsters Against Hantavirus Pulmonary Syndrome When Administered Post-exposure | Andes virus (ANDV) and ANDV-like viruses are responsible for most hantavirus pulmonary syndrome (HPS) cases in South America. Recent studies in Chile indicate that passive transfer of convalescent human plasma shows promise as a possible treatment for HPS. Unfortunately, availability of convalescent plasma from survivo... | Our studies show the utility of combining DNA vaccination with the goose platform for the development of polyclonal avian antibodies for use as candidate medical countermeasures. We demonstrate that these antibodies have potent anti-viral neutralizing activity in cell culture and are efficacious in preventing hantaviru... | Andes virus (ANDV) is a New World hantavirus from the genus Hantavirus within the family Bunyaviridae, an etiological agent of hantavirus pulmonary syndrome (HPS). Hantaviruses are enveloped viruses with trisegmented single-stranded, negative-sense RNA genomes. The three genome segments S, M, and L encode for three str... |
10.1371/journal.pbio.2006387 | Classes and continua of hippocampal CA1 inhibitory neurons revealed by single-cell transcriptomics | Understanding any brain circuit will require a categorization of its constituent neurons. In hippocampal area CA1, at least 23 classes of GABAergic neuron have been proposed to date. However, this list may be incomplete; additionally, it is unclear whether discrete classes are sufficient to describe the diversity of co... | Single-cell RNA sequencing allows scientists to count the number of copies of each gene expressed in multiple individually isolated cells. Because different cell types express genes in different amounts, “clusters” of cells with similar expression patterns are likely to correspond to different cell types. As well as di... | Cortical circuits are composed of highly diverse neurons, and a clear definition of cortical cell types is essential for the explanation of their contribution to network activity patterns and behavior. Cortical neuronal diversity is strongest amongst GABAergic neurons. In hippocampal area CA1—one of the architecturally... |
10.1371/journal.pntd.0001618 | Untargeted Metabolomics Reveals a Lack Of Synergy between Nifurtimox and Eflornithine against Trypanosoma brucei | A non-targeted metabolomics-based approach is presented that enables the study of pathways in response to drug action with the aim of defining the mode of action of trypanocides. Eflornithine, a polyamine pathway inhibitor, and nifurtimox, whose mode of action involves its metabolic activation, are currently used in co... | Understanding drug mode of action is of fundamental importance. Of the five drugs in use against human African trypanosomiasis (HAT), convincing evidence on a specific mode of action has been proposed only for the polyamine pathway inhibitor eflornithine. Eflornithine is currently used with nifurtimox as first line tre... | Human African trypanosomiasis (HAT) is a parasitic infection in sub-Saharan Africa transmitted by tsetse flies. Its causative agent is the flagellated protozoan Trypanosoma brucei, with two sub-species, T. b. gambiense and T. b. rhodesiense responsible for human disease [1], [2].
There are five drugs in use agai... |
10.1371/journal.ppat.1003611 | Dual Analysis of the Murine Cytomegalovirus and Host Cell Transcriptomes Reveal New Aspects of the Virus-Host Cell Interface | Major gaps in our knowledge of pathogen genes and how these gene products interact with host gene products to cause disease represent a major obstacle to progress in vaccine and antiviral drug development for the herpesviruses. To begin to bridge these gaps, we conducted a dual analysis of Murine Cytomegalovirus (MCMV)... | We have conducted a comprehensive analysis of the murine cytomegalovirus and host cell transcriptomes during lytic infection. We identify numerous novel spliced and unspliced transcripts of MCMV. Unexpectedly, the most abundantly transcribed viral genes are of unknown function. We found that the most abundant viral tra... | The cytomegaloviruses, classified within the Betherpesvirinae subfamily, are a group of species-specific herpes viruses that establish life-long infection of their hosts. Human cytomegalovirus (HCMV) can cause devastating disease and death in congenitally-infected infants, and long-term neurological complications in su... |
10.1371/journal.ppat.1005979 | Pheromone Recognition and Selectivity by ComR Proteins among Streptococcus Species | Natural transformation, or competence, is an ability inherent to bacteria for the uptake of extracellular DNA. This process is central to bacterial evolution and allows for the rapid acquirement of new traits, such as antibiotic resistance in pathogenic microorganisms. For the Gram-positive bacteria genus Streptococcus... | Bacteria transmit chemical signals to each other in a process known as quorum sensing. This adaptation is central to pathogenesis as it allows bacteria to coordinate a group response, such as when to form a biofilm, secrete virulence factors, or uptake new DNA. Quorum sensing in many species of Gram-positive bacteria u... | Competence, or the ability of bacteria to import extracellular DNA, is a trait widely conserved across both Gram-negative and Gram-positive bacteria. This natural transformation process allows bacteria to acquire new genes that increase genetic diversity and fitness, such as the gain of antibiotic-resistance determinan... |
10.1371/journal.pntd.0005749 | Geographic strain differentiation of Schistosoma japonicum in the Philippines using microsatellite markers | Microsatellites have been found to be useful in determining genetic diversities of various medically-important parasites which can be used as basis for an effective disease management and control program. In Asia and Africa, the identification of different geographical strains of Schistosoma japonicum, S. haematobium a... | Schistosomiasis is one of the important neglected tropical diseases endemic in 78 countries throughout the world. The disease is caused by the parasitic worms known as schistosomes. In the Philippines, S. japonicum is the causative agent of the disease. The prevalence of the disease varies in endemic areas, suggesting ... | Schistosomiasis is one of the most important neglected tropical diseases affecting almost 240 million people throughout the world with more than 700 million considered to be at risk of infection [1]. Five species of schistosomes are known to cause human infection: Schistosoma haematobium, S. mansoni, S. mekongi, S. int... |
10.1371/journal.pcbi.1004808 | Reconstruction of Tissue-Specific Metabolic Networks Using CORDA | Human metabolism involves thousands of reactions and metabolites. To interpret this complexity, computational modeling becomes an essential experimental tool. One of the most popular techniques to study human metabolism as a whole is genome scale modeling. A key challenge to applying genome scale modeling is identifyin... | Cellular metabolism is defined by a large, intricate network of thousands of components, and plays a fundamental role in many diseases. To study this network in its entirety, metabolic models have been built which encompass all known biochemical reactions in the human metabolism. However, since not all metabolic reacti... | Genome-wide Metabolic Reconstructions (GEMs) computationally model the molecules and reactions responsible for metabolism in any given organism, and have been applied across a variety of fields including metabolic engineering and evolutionary analysis [1]. Computational methods developed to study GEMs [2] have generate... |
10.1371/journal.pntd.0002030 | Naturally Occurring Incompatibilities between Different Culex pipiens pallens Populations as the Basis of Potential Mosquito Control Measures | Vector-borne diseases remain a threat to public health, especially in tropical countries. The incompatible insect technique has been explored as a potential control strategy for several important insect vectors. However, this strategy has not been tested in Culex pipiens pallens, the most prevalent mosquito species in ... | Population suppression is an important component of mosquito control measures. The incompatible insect technique exploits the monogamous mating behavior of female mosquitoes to decrease the percentage of females inseminated by compatible males and hence reduce overall fecundity. Previous studies used genetically engine... | Vector-borne diseases especially those transmitted by mosquitoes such as malaria, dengue fever, Japanese encephalitis, West Nile fever, Chikungunya and lymphatic filariasis are still important scourges responsible for millions of deaths each year, especially in tropical and developing countries. The lack of effective v... |
10.1371/journal.pcbi.1000938 | Drug Off-Target Effects Predicted Using Structural Analysis in the Context of a Metabolic Network Model | Recent advances in structural bioinformatics have enabled the prediction of protein-drug off-targets based on their ligand binding sites. Concurrent developments in systems biology allow for prediction of the functional effects of system perturbations using large-scale network models. Integration of these two capabilit... | Pharmaceutical science is only beginning to scratch the surface on the exact mechanisms of drug action that lead to a drug's breadth of patient responses, both intended and side effects. Decades of clinical trials, molecular studies, and more recent computational analysis have sought to characterize the interactions be... | Despite the advantages gained from drug therapy in medicine, drug development has historically presented an expensive and frequently perplexing challenge for researchers. Identifying useful drug targets for treating disease and matching them to chemical compounds that can elicit the desired effect through drug-target i... |
10.1371/journal.pbio.0050292 | A sex-ratio Meiotic Drive System in Drosophila simulans. I: An Autosomal Suppressor | Sex ratio distortion (sex-ratio for short) has been reported in numerous species such as Drosophila, where distortion can readily be detected in experimental crosses, but the molecular mechanisms remain elusive. Here we characterize an autosomal sex-ratio suppressor from D. simulans that we designate as not much yang (... | Genetic conflicts among genes happen when their modes of transmission differ. Genes in the heterogametic (XY) sex can be grouped as X-linked, Y-linked, autosomal, or cytoplasmic. Sex ratio in the progeny greatly affects the transmission advantage of each of the four types of genes, with the optimal sex ratio for each t... | As a rule, most dioecious species produce equal numbers of male and female progeny because the rarer sex has a mating advantage. R. A. Fisher in 1930, as well as Carl Düsing in 1884 before him, framed arguments based on parental expenditure that mandates an equilibrium sex ratio of 50% female [1,2]. This so-called Fish... |
10.1371/journal.pntd.0003162 | In Situ Immune Response in Human Chromoblastomycosis – A Possible Role for Regulatory and Th17 T Cells | Chromoblastomycosis is a chronic fungal infection that affects skin and subcutaneous tissue. Lesions can be classified in tumorous, verrucous, cicatricial and plaque type. The cellular immune response in the severe form of the disease seems to correlate with a Th2 pattern of cytokines. The humoral immune response also ... | Chromoblastomycosis (CBM) is a chronic infection that affects skin and subcutaneous tissue, caused by some fungi which have a brownish color due to the presence of melanin pigments. The most frequent lesions are of verrucous type. Here we describe the participation of regulatory T cells and cells with the Th17 pattern ... | Chromoblastomycosis (CBM) is a chronic granulomatous fungal infection that affects skin and subcutaneous tissue, especially the lower limbs. It is a cosmopolitan disease, but classically it is found in tropical and subtropical regions [1].
The causative agents of CBM are dimorphic fungi [2], [3] which have a brownish ... |
10.1371/journal.pgen.1005870 | Systems Level Analyses Reveal Multiple Regulatory Activities of CodY Controlling Metabolism, Motility and Virulence in Listeria monocytogenes | Bacteria sense and respond to many environmental cues, rewiring their regulatory network to facilitate adaptation to new conditions/niches. Global transcription factors that co-regulate multiple pathways simultaneously are essential to this regulatory rewiring. CodY is one such global regulator, controlling expression ... | Bacterial pathogens sense multiple host-related metabolic signals that alert them of host localization and result in induction of virulence traits. The Gram-positive foodborne pathogen Listeria monocytogenes activates the transcription of its virulence genes in response to low levels of branch-chained amino acids (BCAA... | Listeria monocytogenes is a Gram-positive facultative intracellular pathogen transmitted by ingesting contaminated foods. L. monocytogenes causes a disease termed listeriosis associated with a mortality rate of up to 30%. Listeriosis typically manifests as a mild gastroenteritis in healthy people, however it can lead t... |
10.1371/journal.pcbi.1005824 | Tracking urban human activity from mobile phone calling patterns | Timings of human activities are marked by circadian clocks which in turn are entrained to different environmental signals. In an urban environment the presence of artificial lighting and various social cues tend to disrupt the natural entrainment with the sunlight. However, it is not completely understood to what exten... | For humans living in urban areas, the modern daily life is very different from that of people who lived in ancient times, from which todays’ societies evolved. Mainly due to the availability of artificial lighting, modern humans have been able to modify their natural daily cycles. In addition, social rules, like those ... | The daily activity of people varies across space and time from place to place, date to date, and hour to hour as a result of biological, societal, economic, and environmental factors, shaping the society where they live. Roughly speaking, each day humans do certain activities at specific times. There are many environme... |
10.1371/journal.pgen.1003178 | MTERF3 Regulates Mitochondrial Ribosome Biogenesis in Invertebrates and Mammals | Regulation of mitochondrial DNA (mtDNA) expression is critical for the control of oxidative phosphorylation in response to physiological demand, and this regulation is often impaired in disease and aging. We have previously shown that mitochondrial transcription termination factor 3 (MTERF3) is a key regulator that rep... | One of the main functions of the mitochondrial network is to provide the energy currency ATP to drive a large array of cellular metabolic processes. The formation of the mitochondrial respiratory chain, which allows this energy supply, is under the control of two separate genetic systems, the nuclear and the mitochondr... | There is a growing interest in molecular mechanisms regulating oxidative phosphorylation capacity because of the increasing number of diseases associated with mitochondrial dysfunction [1] and as aging is associated with mitochondrial functional decline [2], [3]. Regulation of mitochondrial gene expression has an impor... |
10.1371/journal.pmed.1002425 | Perinatal mortality associated with induction of labour versus expectant management in nulliparous women aged 35 years or over: An English national cohort study | A recent randomised controlled trial (RCT) demonstrated that induction of labour at 39 weeks of gestational age has no short-term adverse effect on the mother or infant among nulliparous women aged ≥35 years. However, the trial was underpowered to address the effect of routine induction of labour on the risk of perinat... | National guidelines recommend that induction of labour is carried out between 41 and 42 weeks of gestation to prevent the risks associated with prolonged pregnancy. However, women having their first baby at age 35 years or over are at increased risk of pregnancy complications, including perinatal death.
A recent random... | Across industrialised nations, the proportion of births to women aged ≥35 years is rising [1,2]. In England and Wales, births to women aged ≥35 years have increased from 6% of all births in 1975 to 21% in 2015 [3]. There has also been an increase in the number of babies born to first-time mothers aged ≥35 years, which ... |
10.1371/journal.pntd.0003501 | Minipool Caprylic Acid Fractionation of Plasma Using Disposable Equipment: A Practical Method to Enhance Immunoglobulin Supply in Developing Countries | Immunoglobulin G (IgG) is an essential plasma-derived medicine that is lacking in developing countries. IgG shortages leave immunodeficient patients without treatment, exposing them to devastating recurrent infections from local pathogens. A simple and practical method for producing IgG from normal or convalescent plas... | Plasma-derived immunoglobulin G (IgG) is on WHO’s Essential Medicines List, yet developing countries face severe shortages of this critical treatment. Infusion of IgG prepared from locally-collected plasma provides an advantageous mix of antibodies to viral and bacterial pathogens found in the living environment, and t... | Plasma products to treat congenital bleeding and immunological diseases are made in industrialized countries using complex technologies unavailable in the developing world [1]. Low- to medium-income countries may have little or no access to these life-saving products; these nations urgently need practical processing me... |
10.1371/journal.pntd.0007647 | Negligible exposure to nifurtimox through breast milk during maternal treatment for Chagas Disease | Treatment with nifurtimox (NF) for Chagas disease is discouraged during breast-feeding because no information on NF transfer into breast milk is available. NF is safe and effective for paediatric and adult Chagas disease. We evaluated the degree of NF transfer into breast milk in lactating women with Chagas disease.
Pr... | It is not known whether Nifurtimox, a drug for Chagas disease, is significantly transferred into breast milk, and no clinical trials were conducted to evaluate this topic. Treatment with nifurtimox is safe and effective in children and newborns with Chagas disease. Treatment of young women before pregnancy prevents con... | Chagas disease (CD) or American trypanosomiasis, is a parasitic zoonosis caused by infection with Trypanosome cruzi of worldwide distribution, endemic to the Americas, predominantly affecting the poor and medically underserved [1, 2, 3]. Most CD patients are asymptomatic during the acute phase, but progress to a chroni... |
10.1371/journal.ppat.1005688 | Nonclassical MHC Ib-restricted CD8+ T Cells Recognize Mycobacterium tuberculosis-Derived Protein Antigens and Contribute to Protection Against Infection | MHC Ib-restricted CD8+ T cells have been implicated in host defense against Mycobacterium tuberculosis (Mtb) infection. However, the relative contribution of various MHC Ib-restricted T cell populations to anti-mycobacterial immunity remains elusive. In this study, we used mice that lack MHC Ia (Kb-/-Db-/-), MHC Ia/H2-... | Tuberculosis, the disease caused by Mycobacterium tuberculosis (Mtb), remains a major global health burden. As T cells are crucial to the control of Mtb infection, it is imperative to decipher the role of different T cell subsets in anti-Mtb immunity for the development of more effective vaccines. While the contributio... | Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb), remains one of the world’s deadliest communicable diseases, with 1.5 million deaths annually [1]. Due to the emergence of multidrug-resistant Mtb strains, co-infection with HIV, and the failure of BCG vaccine to control adult pulmonary... |
10.1371/journal.pgen.1002675 | The DSIF Subunits Spt4 and Spt5 Have Distinct Roles at Various Phases of Immunoglobulin Class Switch Recombination | Class-switch recombination (CSR), induced by activation-induced cytidine deaminase (AID), can be divided into two phases: DNA cleavage of the switch (S) regions and the joining of the cleaved ends of the different S regions. Here, we show that the DSIF complex (Spt4 and Spt5), a transcription elongation factor, is requ... | Class switch recombination (CSR) in B cells is required for interaction with different effector molecules while retaining the affinity for the same antigens. CSR mechanism involves the orchestrated steps of transcription, DNA break, and repair of the target loci. Within the cells, these processes occur at the chromatin... | Immunoglobulin (Ig) class switch recombination (CSR), which takes place in activated B lymphocytes, alters antibody effector functions by changing the Ig heavy-chain constant region (CH) from Cμ (IgM) to other CHs (namely, IgGs, IgE, or IgA). CSR is initiated by the cleavage of two DNA switch (S) regions, a donor and a... |
10.1371/journal.pbio.1000584 | Clusters of Temporal Discordances Reveal Distinct Embryonic Patterning Mechanisms in Drosophila and Anopheles | Evolutionary innovations can be driven by spatial and temporal changes in gene expression. Several such differences have been documented in the embryos of lower and higher Diptera. One example is the reduction of the ancient extraembryonic envelope composed of amnion and serosa as seen in mosquitoes to the single amnio... | Linking genotype to phenotype is a major undertaking in modern biological research. A variety of strategies are used but have generally failed to explain the maintenance and acquisition of new phenotypic traits in changing populations. We propose that whole-genome cross-species comparisons can be used to identify gene ... | During the 1980s and 1990s methods of molecular genetics were used to determine the contributions of individual genes to different developmental processes, such as the segmentation of the Drosophila embryo [1]. However, during the past decade post-genome technologies have opened the door to identifying all of the genes... |
10.1371/journal.pntd.0003974 | Determinants of Health Service Responsiveness in Community-Based Vector Surveillance for Chagas Disease in Guatemala, El Salvador, and Honduras | Central American countries face a major challenge in the control of Triatoma dimidiata, a widespread vector of Chagas disease that cannot be eliminated. The key to maintaining the risk of transmission of Trypanosoma cruzi at lowest levels is to sustain surveillance throughout endemic areas. Guatemala, El Salvador, and ... | Elimination of domiciliated vectors led to a decreased prevalence of Chagas disease in parts of Latin America. In Central America, where the domiciliated vector Rhodnius prolixus has been almost eliminated, Triatoma dimidiata, which cannot be eliminated, continues to threaten the population in vast areas. To maintain t... | The prevalence of Chagas disease in Central America decreased from 1.7 million in the 1990s to 0.4 million in 2010 as a result of successful vector control [1, 2]. Of the two main vectors, Rhodnius prolixus is almost eliminated, but Triatoma dimidiata remains widespread in the region despite greatly reduced rates of ho... |
10.1371/journal.ppat.1007974 | Humoral immunity prevents clinical malaria during Plasmodium relapses without eliminating gametocytes | Plasmodium relapses are attributed to the activation of dormant liver-stage parasites and are responsible for a significant number of recurring malaria blood-stage infections. While characteristic of human infections caused by P. vivax and P. ovale, their relative contribution to malaria disease burden and transmission... | Plasmodium vivax contributes significantly to global malaria morbidity and remains a major obstacle for malaria elimination due to its ability to form dormant stages in the liver. These forms can become activated to cause relapsing blood-stage infections. Relapses remain poorly understood because it is difficult to ver... | Due to their ability to establish dormant forms in the liver called hypnozoites, relapsing malaria parasites pose a significant obstacle to malaria elimination [1]. Hypnozoites can become activated, resulting in repeat blood-stage infections, and these relapses account for the majority of P. vivax blood-stage parasitem... |
10.1371/journal.pntd.0000621 | Identification by PCR of Non-typhoidal Salmonella enterica Serovars Associated with Invasive Infections among Febrile Patients in Mali | In sub-Saharan Africa, non-typhoidal Salmonella (NTS) are emerging as a prominent cause of invasive disease (bacteremia and focal infections such as meningitis) in infants and young children. Importantly, including data from Mali, three serovars, Salmonella enterica serovar Typhimurium, Salmonella Enteritidis and Salmo... | The genus Salmonella has more than 2500 serological variants (serovars), such as Salmonella enterica serovar Typhi and Salmonella Paratyphi A and B, that cause, respectively, typhoid and paratyphoid fevers (enteric fevers), and a large number of non-typhoidal Salmonella (NTS) serovars that cause gastroenteritis in heal... | In industrialized countries, non-typhoidal Salmonella (NTS) constitute a well recognized public health problem that in healthy subjects is overwhelmingly encountered clinically as self-limited gastroenteritis [1],[2]. In immunocompromised and debilitated hosts, NTS can become invasive, leading to bacteremia, sepsis and... |
10.1371/journal.pgen.1003762 | Two Portable Recombination Enhancers Direct Donor Choice in Fission Yeast Heterochromatin | Mating-type switching in fission yeast results from gene conversions of the active mat1 locus by heterochromatic donors. mat1 is preferentially converted by mat2-P in M cells and by mat3-M in P cells. Here, we report that donor choice is governed by two portable recombination enhancers capable of promoting use of their... | The state of chromatin, heterochromatin or euchromatin, affects homologous recombination in eukaryotes. We study mating-type switching in fission yeast to learn how recombination is regulated in heterochromatin. Fission yeast exists as two mating-types, P or M, determined by the allele present at the expressed mat1 loc... | Fission yeast cells switch mating type by directed recombination events where the information in the expressed mat1 locus is replaced with information copied from one of two silent loci, mat2 or mat3 (reviewed in [1]). The system allows investigating multiple facets of recombination, including effects of chromatin stru... |
10.1371/journal.pbio.2007097 | Serotonin receptor HTR6-mediated mTORC1 signaling regulates dietary restriction–induced memory enhancement | Dietary restriction (DR; sometimes called calorie restriction) has profound beneficial effects on physiological, psychological, and behavioral outcomes in animals and in humans. We have explored the molecular mechanism of DR-induced memory enhancement and demonstrate that dietary tryptophan—a precursor amino acid for s... | Optimized dietary intake is crucial for maintaining cognitive performance. A mild reduction (between 20% and 40%) in food intake—called dietary restriction (DR) or calorie restriction—has been shown to extend life span and to improve cognitive ability in various species through a mechanism that is not fully understood.... | Nutritional status is closely linked to cognitive performance. Whereas high-calorie intake increases the risk for neurodegenerative diseases [1, 2], food shortage can disable costly memory formation in order to favor survival [3]. An adequate but reduced dietary intake, such as dietary restriction (DR; 20%–40% reductio... |
10.1371/journal.pgen.1004003 | The CCR4-NOT Complex Mediates Deadenylation and Degradation of Stem Cell mRNAs and Promotes Planarian Stem Cell Differentiation | Post-transcriptional regulatory mechanisms are of fundamental importance to form robust genetic networks, but their roles in stem cell pluripotency remain poorly understood. Here, we use freshwater planarians as a model system to investigate this and uncover a role for CCR4-NOT mediated deadenylation of mRNAs in stem c... | Although transcriptional regulation in stem cells is a very active subject, much less is known about how post-transcriptional mechanisms of gene expression affect stem cells. Here, we use freshwater planarians in order to address this question. Planarians have a striking regenerative capacity driven by a population of ... | Post-transcriptional control is central for the regulation of gene expression in stem cells [1]. A key post-transcriptional process is mRNA degradation [2]–[4] the control of which is believed to be as important as transcriptional regulation [5], [6]. Although transcriptional regulation has been extensively studied, le... |
10.1371/journal.pcbi.1005158 | Machine Learning for Characterization of Insect Vector Feeding | Insects that feed by ingesting plant and animal fluids cause devastating damage to humans, livestock, and agriculture worldwide, primarily by transmitting pathogens of plants and animals. The feeding processes required for successful pathogen transmission by sucking insects can be recorded by monitoring voltage changes... | Insect vectors acquire and transmit pathogens causing infectious diseases through probing on host tissues and ingesting host fluids. By connecting insects and their food source via an electrical circuit, computers, using machine learning algorithms, can learn to recognize insect feeding patterns involved in pathogen tr... | The invention of an electronic method for monitoring the feeding behavior of sucking insects [1–4] provided a potentially powerful tool to describe the cryptic behavior of the mouthparts of fluid-feeding phytophagous insects inside a host plant (Fig 1). Coupled with histological studies to correlate specific waveforms ... |
10.1371/journal.pgen.1005764 | Histamine Recycling Is Mediated by CarT, a Carcinine Transporter in Drosophila Photoreceptors | Histamine is an important chemical messenger that regulates multiple physiological processes in both vertebrate and invertebrate animals. Even so, how glial cells and neurons recycle histamine remains to be elucidated. Drosophila photoreceptor neurons use histamine as a neurotransmitter, and the released histamine is r... | Neurotransmitter transporters that remove neurotransmitters and recycle them after their release have particular importance at visual synapses, which must signal at high frequencies and therefore required rapid clearance of neurotransmitters from the synaptic cleft. In this study, we identified a SLC22 family transport... | Histamine is an important chemical messenger known to be involved in a broad spectrum of biological processes such as inflammation and gastric acid secretion. It is also recognized as an important neurotransmitter [1]. Recycling histamine at histaminergic synapses is a key event both in maintaining synaptic transmissio... |
10.1371/journal.pntd.0004228 | Trachoma and Relative Poverty: A Case-Control Study | Trachoma is widely considered a disease of poverty. Although there are many epidemiological studies linking trachoma to factors normally associated with poverty, formal quantitative data linking trachoma to household economic poverty within endemic communities is very limited.
Two hundred people with trachomatous trich... | Trachoma has long been considered a disease of poverty. However, there is surprisingly little direct data that formally quantifies the relationship between trachoma and economic poverty, and none that specifically focuses on trichiasis. We compared 200 people with trachomatous trichiasis (TT) to 200 people (controls) w... | Trachoma is leading infectious cause of blindness worldwide [1]. Trachomatous trichiasis (TT) is the late stage consequence of repeated conjunctival Chlamydia trachomatis infection in which eyelashes turn towards the eye, causing pain and eventually irreversible blinding corneal opacification (CO). About 229 million pe... |
10.1371/journal.pcbi.1000574 | Dynamic Allostery in the Methionine Repressor Revealed by Force Distribution Analysis | Many fundamental cellular processes such as gene expression are tightly regulated by protein allostery. Allosteric signal propagation from the regulatory to the active site requires long-range communication, the molecular mechanism of which remains a matter of debate. A classical example for long-range allostery is the... | Proteins carry out most of the cellular processes, from metabolic reactions to the regulation and expression of genes. Tight and effective regulation of the executing protein machinery is commonly achieved by allostery. The only general requirement for allosteric communication is the transmission of a signal, e.g., the... | Protein allostery plays a key role in the regulation of cellular functions such as transcription or enzymatic action [1]. It crucially governs the formation of protein or protein-DNA complexes as well as the functional activity of individual proteins. Allosteric signals used by nature are diverse, ranging from ligand b... |
10.1371/journal.pcbi.1000318 | Accurate Detection of Recombinant Breakpoints in Whole-Genome Alignments | We propose a novel method for detecting sites of molecular recombination in multiple alignments. Our approach is a compromise between previous extremes of computationally prohibitive but mathematically rigorous methods and imprecise heuristic methods. Using a combined algorithm for estimating tree structure and hidden ... | In viral and bacterial pathogens, recombination has the ability to combine fitness-enhancing mutations. Accurate characterization of recombinant breakpoints in newly sequenced strains can provide information about the role of this process in evolution, for example, in immune evasion. Of particular interest are situatio... | Recombination is the process by which a child inherits a mosaic of genes or sequences from multiple parents. Though most species participate in some form of genetic mixing or recombination, the mechanics by which this occurs varies greatly among them. In higher order organisms, crossing over occurs in meiosis along the... |
10.1371/journal.pgen.1005916 | Cdkn1c Boosts the Development of Brown Adipose Tissue in a Murine Model of Silver Russell Syndrome | The accurate diagnosis and clinical management of the growth restriction disorder Silver Russell Syndrome (SRS) has confounded researchers and clinicians for many years due to the myriad of genetic and epigenetic alterations reported in these patients and the lack of suitable animal models to test the contribution of s... | Silver Russell syndrome is a severe developmental disorder characterised by low birth weight, sparing of the head and neonatal hypoglycemia. SRS adults are small and can be extremely thin, lacking body fat. Numerous genetic and epigenetic mutations have been linked to SRS primarily involving imprinted genes, but progre... | Silver-Russell syndrome (SRS; MIM 180860), Beckwith Weidemann Syndrome (BWS; MIM 130650) and IMAGe syndrome (MIM 614732) are all rare imprinted developmental disorders that occur as a result of genetic or epigenetic alterations primarily at human chromosome 11p15 [1, 2]. Recent studies highlight the potential involveme... |
10.1371/journal.pmed.1002818 | Iron deficiency, elevated erythropoietin, fibroblast growth factor 23, and mortality in the general population of the Netherlands: A cohort study | Emerging data in chronic kidney disease (CKD) patients suggest that iron deficiency and higher circulating levels of erythropoietin (EPO) stimulate the expression and concomitant cleavage of the osteocyte-derived, phosphate-regulating hormone fibroblast growth factor 23 (FGF23), a risk factor for premature mortality. T... | Iron deficiency, one of the most common nutritional disorders worldwide, is known to be associated with increased risk of death in the general population, although a clear mechanism has not been identified.
In patient populations, it has been shown that higher levels of erythropoietin (EPO) are associated with adverse ... | Iron deficiency is one of the most common nutritional disorders worldwide [1]. In addition to its effect on quality of life and functional capacity, iron deficiency has previously been associated with an increased risk of all-cause and cardiovascular mortality in the general population [2]. However, the underlying mech... |
10.1371/journal.pcbi.1005568 | On the effects of alternative optima in context-specific metabolic model predictions | The integration of experimental data into genome-scale metabolic models can greatly improve flux predictions. This is achieved by restricting predictions to a more realistic context-specific domain, like a particular cell or tissue type. Several computational approaches to integrate data have been proposed—generally ob... | Recent methodological developments have facilitated the integration of high-throughput data into genome-scale models to obtain context-specific metabolic reconstructions. A unique solution to this data integration problem often may not be guaranteed, leading to a multitude of context-specific predictions equally concor... | Genome-scale metabolic models (GEMs) have proven instrumental in characterizing the activity of metabolic pathways in different biological scenarios. The activity of all metabolic reactions is specified by the flux distribution, which can be readily inferred from GEMs through the usage of constraint-based approaches [1... |
10.1371/journal.pgen.0030214 | Rrp1b, a New Candidate Susceptibility Gene for Breast Cancer Progression and Metastasis | A novel candidate metastasis modifier, ribosomal RNA processing 1 homolog B (Rrp1b), was identified through two independent approaches. First, yeast two-hybrid, immunoprecipitation, and functional assays demonstrated a physical and functional interaction between Rrp1b and the previous identified metastasis modifier Sip... | Metastasis, which is defined as the spread of malignant tumor cells from their original site to other parts of the body, accounts for the vast majority of solid cancer-related mortality. Our laboratory has previously shown that host germline-encoded variation modifies primary tumor metastatic capacity. Here, we detail ... | Most cancer-related mortality is a consequence of metastasis, and the vast majority of deaths from breast cancer, the most common malignancy of women in the United States [1], are attributable to disseminated disease. Disseminated breast cancer is still considered incurable in spite of therapeutic advances [2], and a m... |
10.1371/journal.pgen.1000273 | Gamma-Linolenic and Stearidonic Acids Are Required for Basal Immunity in Caenorhabditis elegans through Their Effects on p38 MAP Kinase Activity | Polyunsaturated fatty acids (PUFAs) form a class of essential micronutrients that play a vital role in development, cardiovascular health, and immunity. The influence of lipids on the immune response is both complex and diverse, with multiple studies pointing to the beneficial effects of long-chain fatty acids in immun... | Polyunsaturated fatty acids are vital for optimal physiological functions, including immunity. Much of these effects are mediated by eicosanoids, which are metabolites of arachidonic acid (AA) and eicosapentaenoic acid (EPA). In mammals, PUFAs cannot be synthesized de novo. They are produced from essential dietary fatt... | Polyunsaturated fatty acids (PUFAs) are a class of long chain fatty acids of 18 carbon atoms or more in length that contain two or more double bonds. PUFAs are classified into two groups, the omega-6 (n-6) or the omega-3 (n-3) fatty acids, depending on the position of the double bond (n) closest to the methyl end of th... |
10.1371/journal.pgen.1003527 | Strong Purifying Selection at Synonymous Sites in D. melanogaster | Synonymous sites are generally assumed to be subject to weak selective constraint. For this reason, they are often neglected as a possible source of important functional variation. We use site frequency spectra from deep population sequencing data to show that, contrary to this expectation, 22% of four-fold synonymous ... | Synonymous mutations do not alter the sequence of amino acids encoded by the gene in which they occur. These synonymous mutations were thus long thought to have no effect on the function of the ensuing protein or the fitness of the organism. At four-fold degenerate sites, every possible mutation is synonymous. For this... | As there are 64 codons and only 20 amino acids, most amino acids can be encoded by more than a single codon. Mutations that alter coding sequences (CDS), but do not alter amino acid sequences are referred to as synonymous mutations. Synonymous sites are then the collection of potential synonymous mutations present in a... |
10.1371/journal.pgen.1006727 | Trans-ethnic predicted expression genome-wide association analysis identifies a gene for estrogen receptor-negative breast cancer | Genome-wide association studies (GWAS) have identified more than 90 susceptibility loci for breast cancer, but the underlying biology of those associations needs to be further elucidated. More genetic factors for breast cancer are yet to be identified but sample size constraints preclude the identification of individua... | Although individual genetic variant-based genome-wide association studies have greatly increased our understanding of the genetic susceptibility to breast cancer, the genetic variants identified to date account for a relatively small proportion of the heritability. Shifting the focus of analysis from individual genetic... | Breast cancer is the most common cancer in women in the United States and in the world [1]. It is a heterogeneous disease and the two main subgroups of breast cancer are estrogen receptor (ER)-positive and ER-negative cancer. Genome-wide association studies (GWAS) have identified more than 90 susceptibility loci for br... |
10.1371/journal.pcbi.1004635 | Melanoma Cell Colony Expansion Parameters Revealed by Approximate Bayesian Computation | In vitro studies and mathematical models are now being widely used to study the underlying mechanisms driving the expansion of cell colonies. This can improve our understanding of cancer formation and progression. Although much progress has been made in terms of developing and analysing mathematical models, far less pr... | Quantifying the underlying parameters that drive the expansion of melanoma cell colonies such as the cell diffusivity, cell proliferation rate and cell-to-cell adhesion strength can improve our understanding of melanoma biology and its response to treatment. We combine a simulation-based model of collective cell spread... | Skin cancer consists of two groups: melanoma and non-melanoma. Melanoma is the least common, approximately 5% of all skin cancer occurrences, but it is responsible for most skin cancer deaths [1]. It is estimated that 132,000 new cases of melanoma are reported worldwide each year, with more than 12,500 of these cases r... |
10.1371/journal.pcbi.1006232 | Transmission of temporally correlated spike trains through synapses with short-term depression | Short-term synaptic depression, caused by depletion of releasable neurotransmitter, modulates the strength of neuronal connections in a history-dependent manner. Quantifying the statistics of synaptic transmission requires stochastic models that link probabilistic neurotransmitter release with presynaptic spike-train s... | Synapses between neurons transmit signals with strengths that vary with the history of their activity, over scales from milliseconds to decades. Short-term changes in synaptic strength modulate and sculpt ongoing neuronal activity, whereas long-term changes underpin memory formation. Here we focus on changes of strengt... | Variability in synaptic function arises from stochasticity in processes ranging in scale from the transitory opening and closing of ion channels to probabilistic neurotransmitter release and vesicle restock [1–4]. The transmission of signals between neurons is therefore inherently stochastic and, moreover, will interac... |
10.1371/journal.pntd.0003833 | Risk Factors Associated with Ebola and Marburg Viruses Seroprevalence in Blood Donors in the Republic of Congo | Ebola and Marburg viruses (family Filoviridae, genera Ebolavirus and Marburgvirus) cause haemorrhagic fevers in humans, often associated with high mortality rates. The presence of antibodies to Ebola virus (EBOV) and Marburg virus (MARV) has been reported in some African countries in individuals without a history of ha... | Ebola and Marburg viruses cause haemorrhagic fevers often fatal to humans. Here, we looked for antibodies to Ebola and Marburg viruses (i.e., markers of previous contact with these viruses) in Congolese blood donors with no previous history of haemorrhagic fever. We found serologic evidence for contact with Marburg and... | Marburg and Ebola viruses (family Filoviridae, genera Marburgvirus and Ebolavirus) cause severe Viral Haemorrhagic Fever (VHF) in humans, with a high fatality rate in symptomatic cases [1,2,3]. They appear to infect and persist in some species of fruit bats, that may serve as natural reservoirs for these viruses [4,5,6... |
10.1371/journal.pcbi.1003068 | Inference of Gene Regulatory Networks with Sparse Structural Equation Models Exploiting Genetic Perturbations | Integrating genetic perturbations with gene expression data not only improves accuracy of regulatory network topology inference, but also enables learning of causal regulatory relations between genes. Although a number of methods have been developed to integrate both types of data, the desiderata of efficient and power... | Deciphering the structure of gene regulatory networks is crucial for understanding gene functions and cellular dynamics, as well as system-level modeling of individual genes and cellular functions. Computational methods exploiting gene expression and other types of data generated from high-throughput experiments provid... | Genes in living organisms do not function in isolation, but may interact with each other and act together forming intricate networks [1]. Deciphering the structure of gene regulatory networks is crucial for understanding gene functions and cellular dynamics, as well as for system-level modeling of individual genes and ... |
10.1371/journal.ppat.1000563 | Nuclear Entry of Hepatitis B Virus Capsids Involves Disintegration to Protein Dimers followed by Nuclear Reassociation to Capsids | Assembly and disassembly of viral capsids are essential steps in the viral life cycle. Studies on their kinetics are mostly performed in vitro, allowing application of biochemical, biophysical and visualizing techniques. In vivo kinetics are poorly understood and the transferability of the in vitro models to the cellul... | Viral capsids facilitate protection of the enclosed viral genome and participate in the intracellular transport of the genome. At the site of replication capsids have to release the genome, but after replication new capsids have to be assembled for encapsidation of the progeny genomes. Detailed data on stability of cap... | Viral capsids facilitate multiple functions in the viral life cycle. Outside the cell, they protect the enclosed viral genome against nucleases, and in case of non-enveloped viruses they mediate attachment and entry. For both enveloped and non-enveloped viruses, they carry the viral genome to the site of replication wh... |
10.1371/journal.pcbi.1002268 | Dominant Glint Based Prey Localization in Horseshoe Bats: A Possible Strategy for Noise Rejection | Rhinolophidae or Horseshoe bats emit long and narrowband calls. Fluttering insect prey generates echoes in which amplitude and frequency shifts are present, i.e. glints. These glints are reliable cues about the presence of prey and also encode certain properties of the prey. In this paper, we propose that these glints,... | Rhinolophidae are echolocating bats that hunt among vegetation. The foliage returns clutter echoes that potentially mask the echoes of insect prey. However, prey introduces frequency and amplitude shifts, called glints, into the echo to which these bats are highly sensitive. Therefore, these glints are used by Rhinolop... | Rhinolophidae or Horseshoe bats, a family of echolocating bats, hunt for fluttering insects amongst vegetation [1], [2]. This implies that, with each call, they receive a large number of echoes most of which originate from foliage. They have evolved an echolocation system that allows detecting prey under these difficul... |
10.1371/journal.pntd.0001743 | Safety of the Recombinant Cholera Toxin B Subunit, Killed Whole-Cell (rBS-WC) Oral Cholera Vaccine in Pregnancy | Mass vaccinations are a main strategy in the deployment of oral cholera vaccines. Campaigns avoid giving vaccine to pregnant women because of the absence of safety data of the killed whole-cell oral cholera (rBS-WC) vaccine. Balancing this concern is the known higher risk of cholera and of complications of pregnancy sh... | Pregnant women are more vulnerable to complications of cholera than other people. It would be helpful to include pregnant women in vaccination campaigns against cholera but pregnant women and their unborn children are highly vulnerable to the potential adverse effects of biological products such as vaccines. The safety... | The recombinant cholera toxin B subunit, killed whole-cell oral cholera (rBS-WC, Dukoral) vaccine, has been found to be safe and protective in a range of settings over the last 30 years [1], [2], [3]. This vaccine is mainly used by tourists visiting endemic areas [4] where the control of cholera has traditionally been ... |
10.1371/journal.ppat.1005147 | Flavodoxin-Like Proteins Protect Candida albicans from Oxidative Stress and Promote Virulence | The fungal pathogen Candida albicans causes lethal systemic infections in humans. To better define how pathogens resist oxidative attack by the immune system, we examined a family of four Flavodoxin-Like Proteins (FLPs) in C. albicans. In agreement with previous studies showing that FLPs in bacteria and plants act as N... | Oxidative damage is a fundamental problem for cells and a particular challenge for microbial pathogens, which require special mechanisms to resist the oxidative attack by the host immune system. We identified four proteins in the human fungal pathogen Candida albicans that belong to a large family of enzymes in bacteri... | Oxidative stress poses a great threat to cells. Unchecked oxidative damage to DNA, proteins, and lipids causes disruption of physiological processes, harmful mutations, and cell death [1]. To prevent these destructive effects, cells utilize a variety of mechanisms to protect against oxidation. These antioxidant mechani... |
10.1371/journal.pbio.0050114 | From Parasite to Mutualist: Rapid Evolution of Wolbachia in Natural Populations of Drosophila | Wolbachia are maternally inherited bacteria that commonly spread through host populations by causing cytoplasmic incompatibility, often expressed as reduced egg hatch when uninfected females mate with infected males. Infected females are frequently less fecund as a consequence of Wolbachia infection. However, theory pr... | Wolbachia are endosymbiotic bacteria that live inside the cells of their invertebrate hosts. They are transmitted directly from mother to offspring, and spread through populations by manipulating the reproduction of their hosts. The most common reproductive manipulation responsible for the spread of these bacteria, cal... | When microbes that live within animal cells are transmitted only maternally, their reproductive success is directly tied to that of the matrilines they inhabit. Both intuition and mathematics suggest that such endosymbionts will be selected towards mutualism, if possible, increasing the fecundity of their female hosts ... |
10.1371/journal.pcbi.1006605 | Binding of the general anesthetic sevoflurane to ion channels | The direct-site hypothesis assumes general anesthetics bind ion channels to impact protein equilibrium and function, inducing anesthesia. Despite advancements in the field, a first principle all-atom demonstration of this structure-function premise is still missing. We focus on the clinically used sevoflurane interacti... | General anesthetics are central to modern medicine, yet their microscopic mechanism of action is still unknown. Here, we demonstrate that a clinically used anesthetic, sevoflurane, binds the mammalian voltage-gated potassium channel Kv1.2 effecting a shift in its open probability, even at low concentrations. The result... | Volatile and injected general anesthetics encompass a diverse array of small and uncharged chemotypes including haloalkanes, haloethers and alkylphenols. Despite efforts reaching back over a century, clarification of their microscopic mechanism in general anesthesia has proven difficult and wanting. A favored hypothesi... |
10.1371/journal.pgen.1005849 | Accounting for Population Structure in Gene-by-Environment Interactions in Genome-Wide Association Studies Using Mixed Models | Although genome-wide association studies (GWASs) have discovered numerous novel genetic variants associated with many complex traits and diseases, those genetic variants typically explain only a small fraction of phenotypic variance. Factors that account for phenotypic variance include environmental factors and gene-by... | Although genome-wide association studies (GWASs) have discovered numerous novel genetic variants associated with many complex traits and diseases, those genetic variants typically explain only a small fraction of phenotypic variance. Factors that account for phenotypic variance include environmental factors and gene-by... | Over the past decade, genome-wide association studies (GWASs) have been a predominant approach to identify genetic variants involved in many complex traits and diseases.[1–3] While GWASs have discovered associations of many genetic variants, a large proportion of phenotypic variance for most traits is not explained by ... |
10.1371/journal.pgen.1001296 | Parallel Evolution of a Type IV Secretion System in Radiating Lineages of the Host-Restricted Bacterial Pathogen Bartonella | Adaptive radiation is the rapid origination of multiple species from a single ancestor as the result of concurrent adaptation to disparate environments. This fundamental evolutionary process is considered to be responsible for the genesis of a great portion of the diversity of life. Bacteria have evolved enormous biolo... | Adaptive radiation is the rapid origination of an array of species by the divergent colonization of disparate ecological niches. In the case of pathogenic bacteria, radiations can lead to the emergence of novel human pathogens. Being divergently adapted to a range of different mammalian hosts, including humans as reser... | Adaptation to different ecological niches can lead to rapid diversification of a single ancestor into an array of distinct species or ecotypes. This process, called adaptive radiation, typically occurs after the arrival of a founding population in a novel environment with unoccupied ecological niches (‘ecological oppor... |
10.1371/journal.pgen.1006593 | Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer’s disease | Nrf2, a transcriptional activator of cell protection genes, is an attractive therapeutic target for the prevention of neurodegenerative diseases, including Alzheimer’s disease (AD). Current Nrf2 activators, however, may exert toxicity and pathway over-activation can induce detrimental effects. An understanding of the m... | As our population ages the incidence of neurodegenerative diseases, including Alzheimer’s disease (AD), is predicted to increase dramatically. Despite providing important symptomatic relief, existing treatments for such conditions do not slow-down disease progression, and this will cause an overwhelming future burden o... | The transcription factor Nrf2 (nuclear factor E2-related factor 2) targets cellular defence genes containing antioxidant response elements (ARE), which include antioxidant enzymes (glutamate cysteine ligase; GCL), drug metabolising enzymes (cytochrome P450s, glutathione S-transferases; GSTs), molecular chaperones, DNA ... |
10.1371/journal.pntd.0001330 | The Long Term Effect of Current and New Interventions on the New Case Detection of Leprosy: A Modeling Study | Although the number of newly detected leprosy cases has decreased globally, a quarter of a million new cases are detected annually and eradication remains far away. Current options for leprosy prevention are contact tracing and BCG vaccination of infants. Future options may include chemoprophylaxis and early diagnosis ... | Leprosy is a contagious disease that will remain prevalent, despite the declining number of patients worldwide over the last century. With approximately 250,000 new cases detected annually, leprosy is far from being eradicated. Leprosy can be treated with drugs after disease detection.
Some cases can be prevented with ... | The global new case detection rate of leprosy has dropped considerably during last century, but with approximately 250,000 new cases detected annually, leprosy is far from being eradicated [1]. Currently, the primary strategy for controlling leprosy is case detection and treatment with multidrug therapy (MDT). Although... |
10.1371/journal.pbio.2006810 | Sex-specific dominance reversal of genetic variation for fitness | The maintenance of genetic variance in fitness represents one of the most longstanding enigmas in evolutionary biology. Sexually antagonistic (SA) selection may contribute substantially to maintaining genetic variance in fitness by maintaining alternative alleles with opposite fitness effects in the two sexes. This is ... | Evolution requires genetic variation, but selection will tend to fix whichever alleles confer the highest fitness, depleting the genetic variation upon which it acts. Sexually antagonistic (SA) genetic variation—in which alternative alleles have opposite fitness effects in the sexes—can generate balancing selection tha... | One of the most longstanding challenges for evolutionary biologists has been to explain the maintenance of genetic variance in fitness [1–7]. Selection should erode genetic variation as it eliminates deleterious alleles and fixes beneficial ones. Yet natural populations harbor abundant heritable variation for fitness a... |
10.1371/journal.pgen.1002329 | Transcriptome-Wide Binding Sites for Components of the Saccharomyces cerevisiae Non-Poly(A) Termination Pathway: Nrd1, Nab3, and Sen1 | RNA polymerase II synthesizes a diverse set of transcripts including both protein-coding and non-coding RNAs. One major difference between these two classes of transcripts is the mechanism of termination. Messenger RNA transcripts terminate downstream of the coding region in a process that is coupled to cleavage and po... | Transcription in eukaryotes is widespread including both protein-coding transcripts and an increasing number of non-coding RNAs. Here we present the results of transcriptome-wide mapping of a set of yeast RNA–binding proteins that control expression of some protein-coding genes and a number of novel non-coding RNAs. Th... | Early in each transcription cycle RNA polymerase II (Pol II) can follow one of two paths; terminate early through the Nrd1-Nab3-Sen1 pathway or continue on to form longer, potentially coding transcripts [1], [2]. Yeast Nrd1, Nab3 and Sen1 are part of a complex [3] that interacts both with the phosphorylated Pol II C-te... |
10.1371/journal.pntd.0006465 | Prevalence and risk factors for Taenia solium cysticercosis in school-aged children: A school based study in western Sichuan, People’s Republic of China | Taenia solium cysticercosis affects millions of impoverished people worldwide and can cause neurocysticercosis, an infection of the central nervous system which is potentially fatal. Children may represent an especially vulnerable population to neurocysticercosis, due to the risk of cognitive impairment during formativ... | The zoonotic tapeworm, Taenia solium, affects millions of impoverished people worldwide and can cause neurocysticercosis (NCC), an infection of the central nervous system which is potentially fatal. Hypothetically, children may be a vulnerable population to infection as neurological problems and cognitive impairment ca... | Infection with the zoonotic tapeworm Taenia solium affects millions of people living in poverty throughout Asia, Africa, and Latin America [1]. Considered a neglected tropical disease, infection is linked to inadequate sanitation and hygiene, presence of free roaming pigs, and poverty [2]. Infection in humans has two m... |
10.1371/journal.pgen.1000336 | Pervasive Hitchhiking at Coding and Regulatory Sites in Humans | Much effort and interest have focused on assessing the importance of natural selection, particularly positive natural selection, in shaping the human genome. Although scans for positive selection have identified candidate loci that may be associated with positive selection in humans, such scans do not indicate whether ... | There is much reported evidence for positive selection at specific loci in the human genome. Additional papers based on comparisons between the genomes of humans and chimpanzees have also suggested that adaptive evolution may be quite common. At the same time, it has been surprisingly hard to find unambiguous evidence ... | The neutral theory of molecular evolution [1] postulates that adaptive substitutions occur so rarely that they can be safely ignored in most studies in population genetics or molecular evolution. This view has dominated the field of molecular evolution for the past 40 years. However, the past 4–6 years have seen a stro... |
10.1371/journal.pgen.1005967 | Competition between Jagged-Notch and Endothelin1 Signaling Selectively Restricts Cartilage Formation in the Zebrafish Upper Face | The intricate shaping of the facial skeleton is essential for function of the vertebrate jaw and middle ear. While much has been learned about the signaling pathways and transcription factors that control facial patterning, the downstream cellular mechanisms dictating skeletal shapes have remained unclear. Here we pres... | The exquisite functions of the vertebrate face require the precise formation of its underlying bones. Remarkably, many of the genes required to shape the facial skeleton are the same from fish to man. In this study, we use the powerful zebrafish system to understand how the skeletal components of the face acquire diffe... | Morphogenesis of the facial skeleton in zebrafish is tightly linked with the early differentiation of pharyngeal arch neural crest-derived cells (NCCs) into cartilage. Shortly after migration into the pharyngeal arches, NCCs form a series of pre-cartilage condensations that prefigure the distinct shapes of the later ca... |
10.1371/journal.pntd.0003581 | Beriberi (Thiamine Deficiency) and High Infant Mortality in Northern Laos | Infantile beriberi (thiamine deficiency) occurs mainly in infants breastfed by mothers with inadequate intake of thiamine, typically among vulnerable populations. We describe possible and probable cases of infantile thiamine deficiency in northern Laos.
Three surveys were conducted in Luang Namtha Province. First, we p... | Infantile thiamine deficiency (beriberi), is rarely seen today after decades of strong public health attention. Infantile beriberi occurs mainly in infants breastfed by mothers with inadequate intake of thiamine. There is evidence of the persistence of infantile thiamine deficiency in Vientiane, the capital of Laos, bu... | Thiamine (vitamin B1) acts as an important cofactor in metabolism and energy production. It is required for the biosynthesis of neurotransmitters and the production of substances used in defence against oxidant stress [1]. Thiamine deficiency occurs predominantly in populations, in which the diet consists mainly of ver... |
10.1371/journal.ppat.1000923 | Analysis of Virion Structural Components Reveals Vestiges of the Ancestral Ichnovirus Genome | Many thousands of endoparasitic wasp species are known to inject polydnavirus (PDV) particles into their caterpillar host during oviposition, causing immune and developmental dysfunctions that benefit the wasp larva. PDVs associated with braconid and ichneumonid wasps, bracoviruses and ichnoviruses respectively, both d... | The polydnaviruses (PDVs) are a unique virus type used by an organism (a parasitic wasp) to manipulate the physiology of another organism (a lepidopteran host) in order to ensure successful parasitism. The evolutionary origin of these unusual viruses, found in ∼17,500 braconid wasps (Bracoviruses) and ∼15,000 ichneumon... | Polydnaviruses (PDVs) are unique viruses symbiotically associated with endoparasitic wasps belonging to the families Braconidae and Ichneumonidae. Virus particles produced in the ovaries [1] are injected into lepidopteran hosts during wasp oviposition. The PDV genomes packaged in the particles are composed of circular ... |
10.1371/journal.ppat.1000080 | Varicellovirus UL49.5 Proteins Differentially Affect the Function of the Transporter Associated with Antigen Processing, TAP | Cytotoxic T-lymphocytes play an important role in the protection against viral infections, which they detect through the recognition of virus-derived peptides, presented in the context of MHC class I molecules at the surface of the infected cell. The transporter associated with antigen processing (TAP) plays an essenti... | Herpesviruses have the conspicuous property that they persist for life in the infected host. This is also the case for varicelloviruses, a large subfamily of herpesviruses with representatives in humans (varicella zoster virus or VZV), cattle (bovine herpesvirus 1 or BHV-1), pigs (pseudorabies virus or PRV), and horses... | Evolving under the selective pressure of the host immune system, herpesviruses have developed countermeasures to prevent recognition of infected cells by cytotoxic CD8+ T lymphocytes (CTLs). CTLs recognize viral antigens presented as peptides bound to major histocompatibility complex (MHC) class I molecules at the surf... |
10.1371/journal.pcbi.1006530 | Host contact dynamics shapes richness and dominance of pathogen strains | The interaction among multiple microbial strains affects the spread of infectious diseases and the efficacy of interventions. Genomic tools have made it increasingly easy to observe pathogenic strains diversity, but the best interpretation of such diversity has remained difficult because of relationships with host and ... | Pathogens are structured in multiple strains that interact and co-circulate on the same host population. This ecological diversity affects, in many cases, the spread dynamics and the efficacy of vaccination and antibiotic treatment. Thus understanding its biological and host-behavioral drivers is crucial for outbreak a... | Interactions between strains of the same pathogen play a central role in how they spread in host populations. [1–7]. In Streptococcus pneumoniae and Staphylococcus aureus, for instance, several dozen strains can be characterized for which differences in transmissibility, virulence and duration of colonization have been... |
10.1371/journal.ppat.1003893 | Glutamate Utilization Couples Oxidative Stress Defense and the Tricarboxylic Acid Cycle in Francisella Phagosomal Escape | Intracellular bacterial pathogens have developed a variety of strategies to avoid degradation by the host innate immune defense mechanisms triggered upon phagocytocis. Upon infection of mammalian host cells, the intracellular pathogen Francisella replicates exclusively in the cytosolic compartment. Hence, its ability t... | Intracellular bacterial pathogens have developed a variety of strategies to avoid degradation by the host innate immune defense mechanisms triggered upon phagocytocis. We show here for the first time that glutamate acquisition is essential for phagosomal escape and virulence of an intracellular pathogen. Remarkably, in... | Francisella tularensis is a Gram-negative bacterium causing the disease tularemia in a large number of animal species. This highly infectious bacterial pathogen can be transmitted to humans in numerous ways [1], including direct contact with sick animals, inhalation, ingestion of contaminated water or food, or by bites... |
10.1371/journal.pgen.1005828 | Rab6 Is Required for Multiple Apical Transport Pathways but Not the Basolateral Transport Pathway in Drosophila Photoreceptors | Polarized membrane trafficking is essential for the construction and maintenance of multiple plasma membrane domains of cells. Highly polarized Drosophila photoreceptors are an excellent model for studying polarized transport. A single cross-section of Drosophila retina contains many photoreceptors with 3 clearly diffe... | Cells in animal bodies have multiple plasma membrane domains; this polarized characteristic of cells is essential for their specific functions. Selective membrane transport pathways play key roles in the construction and maintenance of polarized structures. Drosophila photoreceptors with multiple plasma membrane domain... | Many cells that make up animal bodies have multiple plasma membrane domains, which are the basis of their specific functions. Polarized vesicle transport is essential for establishing and maintaining these domains. However, the underlying mechanisms are not well elucidated. The Drosophila retina is a good genetics-base... |
10.1371/journal.pcbi.1001011 | Reconstructing the Three-Dimensional GABAergic Microcircuit of the Striatum | A system's wiring constrains its dynamics, yet modelling of neural structures often overlooks the specific networks formed by their neurons. We developed an approach for constructing anatomically realistic networks and reconstructed the GABAergic microcircuit formed by the medium spiny neurons (MSNs) and fast-spiking i... | The brain has an immensely complex wiring diagram, but few computational models of brain regions attempt accurate renditions of the wiring between neurons. Consequently, these models' dynamics may not accurately reflect those of the region. Key barriers here are the difficulty of reconstructing such networks and the pa... | The mammalian brain is a vastly complex structure at every level of description. Faced with the sheer breadth of neuron and receptor types, many researchers are abandoning attempts to intuit the ‘essential elements’ of a neural circuit, instead building large-scale models of neural circuits, modelling neuron-for-neuron... |
10.1371/journal.pcbi.1000096 | Model-Based Hypothesis Testing of Key Mechanisms in Initial Phase of Insulin Signaling | Type 2 diabetes is characterized by insulin resistance of target organs, which is due to impaired insulin signal transduction. The skeleton of signaling mediators that provide for normal insulin action has been established. However, the detailed kinetics, and their mechanistic generation, remain incompletely understood... | Insulin is a central player in maintaining energy balance in our bodies and in type 2 diabetes, where the effect of insulin on its target tissues is diminished. Insulin acts on cells by binding to specific insulin receptors (IRs) at the cell surface. This triggers a series of events, including attachment of phosphate t... | Insulin is the primary hormone in control of whole body energy metabolism in human beings. The hormone is secreted to the blood circulation by the β-cells, located in the islands of Langerhans in the pancreas. The adipose tissue and the adipocytes are important targets for insulin control of energy metabolism. Failure ... |
10.1371/journal.pgen.1007273 | Ethylene induced plant stress tolerance by Enterobacter sp. SA187 is mediated by 2‐keto‐4‐methylthiobutyric acid production | Several plant species require microbial associations for survival under different biotic and abiotic stresses. In this study, we show that Enterobacter sp. SA187, a desert plant endophytic bacterium, enhances yield of the crop plant alfalfa under field conditions as well as growth of the model plant Arabidopsis thalian... | Plants as sessile organisms are facing multiple stresses during their lifetime. Among them, abiotic stresses, such as salt stress, can cause severe crop yield reduction, leading to food security issues in many regions of the world. In order to respond to growing food demands, especially in the context of the global cli... | Abiotic stresses like salinity, drought or heat negatively affect plant growth and yield and belong to the most limiting factors of agriculture worldwide [1,2]. For example, salinity, known to affect almost one fourth of arable land globally, is a two-phase stress composed of a rapid osmotic and a slower toxic stress, ... |
10.1371/journal.pbio.1000414 | The Role of Nucleosome Positioning in the Evolution of Gene Regulation | Chromatin organization plays a major role in gene regulation and can affect the function and evolution of new transcriptional programs. However, it can be difficult to decipher the basis of changes in chromatin organization and their functional effect on gene expression. Here, we present a large-scale comparative genom... | Divergence in gene regulation plays a major role in organismal evolution. Evidence suggests that changes in the packaging of eukaryotic genomes into chromatin can underlie the evolution of divergent gene expression patterns. Here, we explore the role of chromatin structure in regulatory evolution by whole-genome measur... | Regulatory differences affecting gene expression can play a major role in species evolution [1] and can help elucidate the functional mechanisms that control gene regulation [2],[3]. Although specific examples of regulatory divergence are known in bacteria [4], fungi [5],, flies [9], and mammals [10], a general underst... |
10.1371/journal.ppat.1000169 | Molecular Mechanisms Involved in Vascular Interactions of the Lyme Disease Pathogen in a Living Host | Hematogenous dissemination is important for infection by many bacterial pathogens, but is poorly understood because of the inability to directly observe this process in living hosts at the single cell level. All disseminating pathogens must tether to the host endothelium despite significant shear forces caused by blood... | Many bacterial pathogens can cause systemic illness by disseminating through the blood to distant target sites. However, hematogenous dissemination is still poorly understood, in part because of an inability to directly observe this process in living hosts in real time and at the level of individual pathogens. We recen... | Hematogenous dissemination of pathogenic organisms is an important feature of disease progression. However, dissemination is poorly understood, in large part because of the difficulty in studying this process directly in living organisms under the shear stress conditions that characterize the host vasculature. One such... |
10.1371/journal.pbio.3000091 | Non-proteolytic ubiquitin modification of PPARγ by Smurf1 protects the liver from steatosis | Nonalcoholic fatty liver disease (NAFLD) is characterized by abnormal accumulation of triglycerides (TG) in the liver and other metabolic syndrome symptoms, but its molecular genetic causes are not completely understood. Here, we show that mice deficient for ubiquitin ligase (E3) Smad ubiquitin regulatory factor 1 (Smu... | Nonalcoholic fatty liver disease (NAFLD) is a disease associated with abnormal fat accumulation in the liver and other metabolic symptoms. Among its many social–behavioral and genetic causes, dysregulation of peroxisome proliferator-activated receptor γ (PPARγ) is an investigative focal point for therapeutic interventi... | Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition associated with obesity, non–insulin-dependent diabetes, and hyperglyceridemia [1]. Although presenting few clinical symptoms at early stages, a subset of patients with NAFLD will progress to nonalcoholic steatohepatitis (NASH) consisting of hepatic ... |
10.1371/journal.pcbi.1003174 | Conditional Cooperativity of Toxin - Antitoxin Regulation Can Mediate Bistability between Growth and Dormancy | Many toxin-antitoxin operons are regulated by the toxin/antitoxin ratio by mechanisms collectively coined “conditional cooperativity”. Toxin and antitoxin form heteromers with different stoichiometric ratios, and the complex with the intermediate ratio works best as a transcription repressor. This allows transcription ... | The effectiveness of antibiotics on many pathogenic bacteria is compromised by multidrug tolerance. This is caused by a small sub-population of bacteria that happen to be in a dormant, non-dividing state when antibiotics are applied and thus are protected from being killed. These bacteria are called persisters. Unravel... | Many bacteria and archaea have multiple Toxin-Antitoxin (TA) loci [1], where the toxin normally inhibits cell growth, while the antitoxin neutralizes the activity of the toxin by forming a tight TA complex. One of the known functions of TA loci is to respond to nutritional stress [2], namely, toxins are activated upon ... |
10.1371/journal.ppat.1005954 | SIRT1-PGC1α-NFκB Pathway of Oxidative and Inflammatory Stress during Trypanosoma cruzi Infection: Benefits of SIRT1-Targeted Therapy in Improving Heart Function in Chagas Disease | Chronic chagasic cardiomyopathy (CCM) is presented by increased oxidative/inflammatory stress and decreased mitochondrial bioenergetics. SIRT1 senses the redox changes and integrates mitochondrial metabolism and inflammation; and SIRT1 deficiency may be a major determinant in CCM. To test this, C57BL/6 mice were infect... | In this study, we determined whether enhancing the activity of sirtuin 1 (SIRT1) would be beneficial in maintaining heart health in Chagas disease. SIRT1 senses the redox shifts and integrates mitochondrial metabolism and inflammation. We found that treatment with SIRT1 agonists, given in a therapeutic window of time a... | Trypanosoma cruzi (T. cruzi or Tc) is the etiological agent of Chagas disease that is endemic in Latin America [1]. After an exposure to parasite, infected individuals develop mild-to-no overt clinical symptoms. However, several decades later, ~30% of the infected individuals progress to heart failure associated with c... |
10.1371/journal.pcbi.1000944 | Experimental and Computational Analysis of Polyglutamine-Mediated Cytotoxicity | Expanded polyglutamine (polyQ) proteins are known to be the causative agents of a number of human neurodegenerative diseases but the molecular basis of their cytoxicity is still poorly understood. PolyQ tracts may impede the activity of the proteasome, and evidence from single cell imaging suggests that the sequestrati... | Neurodegenerative diseases feature concentration of misfolded or damaged proteins into inclusion bodies. There is controversy over whether these entities are protective, detrimental, or relatively benign. The formation of inclusion bodies may be accelerated by inefficient protein degradation and may promote activation ... | A hallmark feature of human neurodegenerative diseases is the accumulation of misfolded or otherwise abnormal proteins which become concentrated into large aggregates. Inclusion bodies are large nuclear or cytoplasmic protein aggregates whose predominant constituents may be characteristic of particular diseases. In man... |
10.1371/journal.pntd.0003447 | Review on Dog Rabies Vaccination Coverage in Africa: A Question of Dog Accessibility or Cost Recovery? | Rabies still poses a significant human health problem throughout most of Africa, where the majority of the human cases results from dog bites. Mass dog vaccination is considered to be the most effective method to prevent rabies in humans. Our objective was to systematically review research articles on dog rabies parent... | Rabies is one of the most fatal diseases in both humans and animals. A bite by a rabid dog is the main cause of human rabies in Africa. Parenteral mass dog vaccination is the most cost-effective tool to prevent rabies in humans. Our main objective was to review research articles on the parenteral dog rabies vaccination... | Rabies is one of the infectious diseases with the highest human case fatality rate (almost 100%)[1]. Globally, rabies is responsible for more than 60,000 human deaths, while approximately 15 million people receive rabies post exposure prophylaxis (PEP) annually. More than 95% of the global deaths occur in Asia and Afri... |
10.1371/journal.pgen.1004815 | The Complex I Subunit NDUFA10 Selectively Rescues Drosophila pink1 Mutants through a Mechanism Independent of Mitophagy | Mutations in PINK1, a mitochondrially targeted serine/threonine kinase, cause autosomal recessive Parkinson's disease (PD). Substantial evidence indicates that PINK1 acts with another PD gene, parkin, to regulate mitochondrial morphology and mitophagy. However, loss of PINK1 also causes complex I (CI) deficiency, and h... | Two genes linked to heritable forms of the neurodegenerative movement disorder Parkinson's disease (PD), PINK1 and parkin, play important roles in mitochondrial homeostasis through mechanisms which include the degradation of dysfunctional mitochondria, termed mitophagy, and the maintenance of complex I (CI) activity. H... | Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, the etiology of which remains unknown. Mitochondrial dysfunction, including complex I (CI) deficiency, are frequently observed in pathologic specimens. To elucidate the underlying molecular events, intensive research has focused on identi... |
10.1371/journal.ppat.1001183 | The Gag Cleavage Product, p12, is a Functional Constituent of the Murine Leukemia Virus Pre-Integration Complex | The p12 protein is a cleavage product of the Gag precursor of the murine leukemia virus (MLV). Specific mutations in p12 have been described that affect early stages of infection, rendering the virus replication-defective. Such mutants showed normal generation of genomic DNA but no formation of circular forms, which ar... | All retroviruses reverse transcribe their RNA genome to a DNA copy in the cytoplasm of the infected cell. To be expressed, the viral genomic DNA has to travel to the cell nucleus and to integrate into the cellular chromosomes. This trafficking is governed by cellular and viral proteins that associate with the viral gen... | Reverse transcription and integration are the hallmarks of the retroviral life cycle. These steps include reverse transcription of the genomic RNA into a linear double-stranded DNA and the subsequent integration of this DNA into the genome of the infected cell. These events are part of the ‘early’ stages of the retrovi... |
10.1371/journal.pcbi.1004033 | Computer Simulations Suggest a Key Role of Membranous Nanodomains in Biliary Lipid Secretion | The bile fluid contains various lipids that are secreted at the canalicular membrane of hepatocytes. As the secretion mechanism is still a matter of debate and a direct experimental observation of the secretion process is not possible so far, we used a mathematical model to simulate the extraction of the major bile lip... | Formation of the bile is one of the central functions of the liver. The bile fluid aids in the digestion of edible fats and removal of drugs and toxins from the body. The bile fluid is mainly composed of bile salts (BS), phosphatidylcholine (PC) and cholesterol (CH) in a fairly fixed proportion that prevents liver impa... | One central function of the liver is the production of the bile which is indispensable for the efficient digestion of dietary lipids, elimination of hydrophobic xenobiotics and removal of cholesterol from the body. The bile is formed in the biliary canaliculi, i.e. the extracellular space that faces the canalicular mem... |
10.1371/journal.ppat.1003648 | Absence of Siglec-H in MCMV Infection Elevates Interferon Alpha Production but Does Not Enhance Viral Clearance | Plasmacytoid dendritic cells (pDCs) express the I-type lectin receptor Siglec-H and produce interferon α (IFNα), a critical anti-viral cytokine during the acute phase of murine cytomegalovirus (MCMV) infection. The ligands and biological functions of Siglec-H still remain incompletely defined in vivo. Thus, we generate... | Plasmacytoid dendritic cells (pDCs) represent a minor but functionally important subset of dendritic cells. Siglec-H, a surface receptor expressed on these cells, was shown to modulate IFNα production, which in turn could influence anti-viral functions in vivo. A potential role for Siglec-H as a pathogen uptake recepto... | Dendritic cells (DCs) are a diverse population of professional antigen-presenting cells that exhibit differences in both their developmental origins and their functional properties. They are distributed in different anatomical compartments such as the skin, intestine, lung and lymphoid organs [1], [2] where pathogen ac... |
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