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10.1371/journal.pntd.0007592 | The evolutionary dynamics of DENV 4 genotype I over a 60-year period | Dengue virus serotype 4 (DENV 4) has had a relatively low prevalence worldwide for decades; however, likely due to data paucity, no study has investigated the epidemiology and evolutionary dynamics of DENV 4 genotype I (DENV 4-I). This study aims to understand the diversity, epidemiology and dynamics of DENV 4-I. We co... | Dengue virus (DENV) can be classified into four serotypes, DENV 1, 2, 3 and 4. Although DENV 4 is the first dengue serotype to diverge in phylogenetic analyses of the genus Flavivirus, this serotype occurs at a low prevalence worldwide and spreads the least rapidly. Similar to other serotypes, DENV 4 can also cause sev... | Dengue is a mosquito-borne viral infectious disease. Although the geographical origin of dengue is still under some debate, the recent global expansion has been attributed to environmental changes, unprecedented population growth, uncontrolled urbanization, spread of the mosquito vectors, and host population movements ... |
10.1371/journal.pntd.0006021 | Schistosoma japonicum transmission risk maps at present and under climate change in mainland China | The South-to-North Water Diversion (SNWD) project is designed to channel fresh water from the Yangtze River north to more industrialized parts of China. An important question is whether future climate change and dispersal via the SNWD may synergistically favor a northward expansion of species involved in hosting and tr... | The South-to-North Water Diversion (SNWD) project is designed to channel fresh water from the Yangtze River north to more industrialized parts of China. An important question is whether future climate change and dispersal via the SNWD may synergistically favor northward expansion of schistosomiasis in China. Our models... | Schistosomiasis is a neglected tropical disease that is known to have affected people in China for more than 2100 years, with presently ~800,000 infected and ~65 million people at risk of infection [1]. The challenge of combatting this disease lies in the wide distribution of its snail hosts and the broad range of dome... |
10.1371/journal.pgen.1000719 | Gene Dosage, Expression, and Ontology Analysis Identifies Driver Genes in the Carcinogenesis and Chemoradioresistance of Cervical Cancer | Integrative analysis of gene dosage, expression, and ontology (GO) data was performed to discover driver genes in the carcinogenesis and chemoradioresistance of cervical cancers. Gene dosage and expression profiles of 102 locally advanced cervical cancers were generated by microarray techniques. Fifty-two of these pati... | Genetic gains and losses, i.e. changes in gene dosages, are common abnormalities of human cancers. Discovering these defects and understanding the biological meaning can lead to improved therapeutic opportunities. This paper reports a large scale screening of gene dosage alterations in cervical cancer and gives a broad... | Cervical cancer is one of the most common malignancies affecting women worldwide and a major cause of cancer death for women globally [1]. Radiotherapy combined with cisplatin is the treatment of choice at the locally advanced stages [2]. Improved therapy is needed, since more than 30% of the patients show progressive ... |
10.1371/journal.pgen.1007299 | Cell polarity protein Spa2 coordinates Chs2 incorporation at the division site in budding yeast | Deposition of additional plasma membrane and cargoes during cytokinesis in eukaryotic cells must be coordinated with actomyosin ring contraction, plasma membrane ingression and extracellular matrix remodelling. The process by which the secretory pathway promotes specific incorporation of key factors into the cytokineti... | Eukaryotic cells require division of all their cellular components before finally giving rise to two independent cells in a process named cytokinesis. Eukaryotic cells must build a physical barrier of plasma membrane, which is coupled with the remodelling of the extracellular matrix between the dividing cells. Plasma m... | Before the end of mitosis, eukaryotic cells need to redirect the secretory machinery towards the site of division to ensure cells deposit additional plasma membrane between the two daughter cells. In addition, secretory vesicles transport key factors to enable cells to perform cytokinesis successfully [1–3]. Although t... |
10.1371/journal.pgen.1006275 | Reverse Chemical Genetics: Comprehensive Fitness Profiling Reveals the Spectrum of Drug Target Interactions | The emergence and prevalence of drug resistance demands streamlined strategies to identify drug resistant variants in a fast, systematic and cost-effective way. Methods commonly used to understand and predict drug resistance rely on limited clinical studies from patients who are refractory to drugs or on laborious evol... | One of the most profound outcomes of fast, reliable genome sequencing is the ability to tailor drug therapy to an individual’s genotype. This ‘personalized’ or ‘precision medicine’ is the realization of a decades-long effort to maximize drug effect and limit unwanted side effects. An undesirable consequence of such tar... | Drug resistance is a worldwide health concern that affects all drug classes, including anti-infectives and anti-cancer agents [1–3]. Recent reports illustrate that first-line antibiotic treatment failure rates have increased 12% from 1991–2012 [4]. Cancer drug resistance has increased, in part due to the use of highly ... |
10.1371/journal.ppat.1007836 | A broadly neutralizing germline-like human monoclonal antibody against dengue virus envelope domain III | Dengue is the most widespread vector-borne viral disease caused by dengue virus (DENV) for which there are no safe, effective drugs approved for clinical use. Here, by using sequential antigen panning of a yeast antibody library derived from healthy donors against the DENV envelop protein domain III (DIII) combined wit... | Dengue virus infects 50–100 million people each year. Infection is initiated by entry of the virus into cells mediated by the viral envelope glycoproteins. There are four closely related DENV serotypes, but they all are antigenically distinct, with each comprising several genotypes that exhibit differences in their inf... | Dengue virus (DENV) causes the most prevalent mosquito-borne viral disease. Over 2.5 billion people are at risk for infection in over 100 countries, 50–100 million are infected with symptoms, and up to 50,000 die from dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) each year [1,2]. No specific antiviral ... |
10.1371/journal.pgen.1004432 | Genetic Background Drives Transcriptional Variation in Human Induced Pluripotent Stem Cells | Human iPS cells have been generated using a diverse range of tissues from a variety of donors using different reprogramming vectors. However, these cell lines are heterogeneous, which presents a limitation for their use in disease modeling and personalized medicine. To explore the basis of this heterogeneity we generat... | Human induced pluripotent stem (hiPS) cells are a potentially powerful model system for studying human disease and development, and a resource for personalized medicine. However, it has been reported that hiPS cells exhibit substantial heterogeneity which could limit their use as model systems. Clearly, knowledge of th... | Induced pluripotent stem cells (iPSCs) are the subject of tremendous interest as model systems for studying human disease and development [1], [2]. However, cellular reprogramming to iPSCs is an inefficient process in which stochastic events during clonal selection may fix a variety of alternative epigenetic and transc... |
10.1371/journal.pntd.0002991 | Risk Factors and Spatial Distribution of Schistosoma mansoni Infection among Primary School Children in Mbita District, Western Kenya | An increasing risk of Schistosoma mansoni infection has been observed around Lake Victoria, western Kenya since the 1970s. Understanding local transmission dynamics of schistosomiasis is crucial in curtailing increased risk of infection.
We carried out a cross sectional study on a population of 310 children from eight ... | It is estimated that more than ten percent of the world's population is at risk of schistosome transmission, with over 90% of infections occurring in sub-Saharan Africa. In Kenya, schistosomiasis remains a major public health concern particularly around Lake Victoria. The objective of this study was to identify the ris... | Schistosomiasis is a parasitic disease affecting 249 million people worldwide. It is endemic in 78 countries with over 90% of cases occurring in sub-Saharan Africa [1]. About 779 million people, more than 10% of the world's population, were estimated to have been at risk of schistosome infection in mid-2003 [2]–[5]. In... |
10.1371/journal.pbio.1001474 | Strigolactone Can Promote or Inhibit Shoot Branching by Triggering Rapid Depletion of the Auxin Efflux Protein PIN1 from the Plasma Membrane | Plants continuously extend their root and shoot systems through the action of meristems at their growing tips. By regulating which meristems are active, plants adjust their body plans to suit local environmental conditions. The transport network of the phytohormone auxin has been proposed to mediate this systemic growt... | Plants can adapt their form to suit the environment in which they are growing. For example, genetically identical plants can develop as a single unbranched stem or as a highly ramified bush. This broad developmental potential is possible because the shoot system is produced continuously by growing tips, known as shoot ... | Plants can alter their body plan to adapt to the environment in which they are growing (reviewed in Leyser 2009 [1]). This is possible because plant development is continuous, with postembryonic development being dependent on the activity of meristems. For example, the primary shoot apical meristem is laid down during ... |
10.1371/journal.pntd.0001459 | Murine Dendritic Cells Transcriptional Modulation upon Paracoccidioides brasiliensis Infection | Limited information is available regarding the modulation of genes involved in the innate host response to Paracoccidioides brasiliensis, the etiologic agent of paracoccidioidomycosis. Therefore, we sought to characterize, for the first time, the transcriptional profile of murine bone marrow-derived dendritic cells (DC... | Paracoccidioidomycosis is a systemic disease that has an important mortality and morbidity impact in Latin America, mainly affecting rural workers of Argentina, Colombia, Venezuela and Brazil. Upon host infection, one of the most important aspects contributing to disease outcome is the initial encounter of the Paracocc... | The thermodimorphic fungus Paracoccidioides brasiliensis is the causative agent of paracoccidioidomycosis (PCM), a systemic human disease that is geographically confined to Latin America. PCM is mainly endemic in Argentina, Colombia, Venezuela and especially in Brazil, where it is the most prevalent cause of death amon... |
10.1371/journal.ppat.1000840 | Suppression of mRNAs Encoding Tegument Tetraspanins from Schistosoma mansoni Results in Impaired Tegument Turnover | Schistosomes express a family of integral membrane proteins, called tetraspanins (TSPs), in the outer surface membranes of the tegument. Two of these tetraspanins, Sm-TSP-1 and Sm-TSP-2, confer protection as vaccines in mice, and individuals who are naturally resistant to S. mansoni infection mount a strong IgG respons... | Schistosomes, or blood flukes, reside in the blood vessels surrounding the liver and bowel of their human hosts. They infect 200 million people and kill many thousands each year in developing countries. The parasites cover themselves in a unique series of cell membranes called the tegument. Molecules in the tegument me... | Schistosomes are parasitic trematodes that cause chronic infection in over 207 million people in 76 developing tropical countries. Schistosomiasis is generally associated with poverty, poor water supply and inadequate sanitation [1]. Infection rates and intensities are high in early childhood, peak around 8 to 15 years... |
10.1371/journal.pbio.3000136 | A mutagenesis screen for essential plastid biogenesis genes in human malaria parasites | Endosymbiosis has driven major molecular and cellular innovations. Plasmodium spp. parasites that cause malaria contain an essential, non-photosynthetic plastid—the apicoplast—which originated from a secondary (eukaryote–eukaryote) endosymbiosis. To discover organellar pathways with evolutionary and biomedical signific... | Plasmodium parasites, which cause malaria, and related apicomplexan parasites evolved from photosynthetic algae that acquired their chloroplast through two successive endosymbioses. Although no longer photosynthetic, the apicomplexan plastid—or apicoplast—was retained in these pathogens and provides critical metabolite... | Plasmodium spp., which cause malaria, and related apicomplexan parasites are important human and veterinary pathogens. These disease-causing protozoa are highly divergent from well-studied model organisms that are the textbook examples of eukaryotic biology, such that parasite biology often reveals striking eukaryotic ... |
10.1371/journal.ppat.1004500 | Silencing by H-NS Potentiated the Evolution of Salmonella | The bacterial H-NS protein silences expression from sequences with higher AT-content than the host genome and is believed to buffer the fitness consequences associated with foreign gene acquisition. Loss of H-NS results in severe growth defects in Salmonella, but the underlying reasons were unclear. An experimental evo... | H-NS is an abundant DNA-binding protein found in enteric bacteria including the important pathogens Escherichia, Salmonella, Vibrio, and Yersinia, that plays a primary role in defending the bacterial genome by silencing AT-rich foreign genes. H-NS has been hypothesized to facilitate the evolution of bacterial species b... | Horizontal gene transfer (HGT) has profoundly shaped the course of bacterial speciation and diversification. The uptake of ‘pre-assembled’ genetic loci involved in antibiotic resistance, virulence, phage resistance or novel modes of metabolism can instantly confer beneficial phenotypes to the recipient cell. HGT events... |
10.1371/journal.pntd.0005710 | 2b-RAD genotyping for population genomic studies of Chagas disease vectors: Rhodnius ecuadoriensis in Ecuador | Rhodnius ecuadoriensis is the main triatomine vector of Chagas disease, American trypanosomiasis, in Southern Ecuador and Northern Peru. Genomic approaches and next generation sequencing technologies have become powerful tools for investigating population diversity and structure which is a key consideration for vector ... | Understanding Chagas disease vector (triatomine) population dispersal is key for the design of control measures tailored for the epidemiological situation of a particular region. In Ecuador, Rhodnius ecuadoriensis is a cause of concern for Chagas disease transmission, since it is widely distributed from the central coa... | Vector control has been the mainstay of Chagas disease control strategies in Latin America. Several Latin American countries implemented nation-wide insecticide-spraying programs to eradicate Chagas disease vector populations in human dwellings over the last 30 years. These campaigns resulted in a dramatic reduction in... |
10.1371/journal.pntd.0001626 | In Vitro and In Vivo Activity of a Palladacycle Complex on Leishmania (Leishmania) amazonensis | Antitumor cyclopalladated complexes with low toxicity to laboratory animals have shown leishmanicidal effect. These findings stimulated us to test the leishmanicidal property of one palladacycle compound called DPPE 1.2 on Leishmania (Leishmania) amazonensis, an agent of simple and diffuse forms of cutaneous leishmania... | Leishmaniasis is an important public health problem with an estimated annual incidence of 1.5 million of new human cases of cutaneous leishmaniasis and 500,000 of visceral leishmaniasis. Treatment of the diseases is limited by toxicity and parasite resistance to the drugs currently in use, validating the need to develo... | Protozoan parasites of the Leishmania genus induce cutaneous, mucocutaneous and visceral diseases in man and animals. According to the World Health Organization, about 1.5 million of new human cases of cutaneous leishmaniasis and 500,000 of visceral leishmaniasis are registered annually [1]. Leishmania (Leishmania) ama... |
10.1371/journal.pbio.1000465 | IL-6 and IL-10 Anti-Inflammatory Activity Links Exercise to Hypothalamic Insulin and Leptin Sensitivity through IKKβ and ER Stress Inhibition | Overnutrition caused by overeating is associated with insulin and leptin resistance through IKKβ activation and endoplasmic reticulum (ER) stress in the hypothalamus. Here we show that physical exercise suppresses hyperphagia and associated hypothalamic IKKβ/NF-κB activation by a mechanism dependent upon the pro-inflam... | The hypothalamus is a brain region that gathers information on the body's nutritional status and governs the release of multiple metabolic signaling molecules such as insulin and leptin to maintain homeostasis. Overeating and obesity are associated with insulin and leptin resistance in the hypothalamus, and recent stud... | Overnutrition and sedentary lifestyle are among the most important factors that lead to an unprecedented increase in the prevalence of obesity. In mammals, food intake and energy expenditure are tightly regulated by specific neurons localized in the hypothalamus. The hypothalamus can gather information on the body's nu... |
10.1371/journal.pcbi.1000007 | Robustness of Learning That Is Based on Covariance-Driven Synaptic Plasticity | It is widely believed that learning is due, at least in part, to long-lasting modifications of the strengths of synapses in the brain. Theoretical studies have shown that a family of synaptic plasticity rules, in which synaptic changes are driven by covariance, is particularly useful for many forms of learning, includi... | It is widely believed that learning is due, at least in part, to modifications of synapses in the brain. The ability of a synapse to change its strength is called “synaptic plasticity,” and the rules governing these changes are a subject of intense research. Theoretical studies have shown that a particular family of sy... | Synaptic plasticity that is driven by covariance is the basis of numerous models in computational neuroscience. It is the cornerstone of models of associative memory [1],[2],[3], is used in models of gradient estimation in reinforcement learning [4],[5],[6],[7],[8],[9],[10] and has been suggested to be the basis of ope... |
10.1371/journal.pcbi.1004396 | Manifold Based Optimization for Single-Cell 3D Genome Reconstruction | The three-dimensional (3D) structure of the genome is important for orchestration of gene expression and cell differentiation. While mapping genomes in 3D has for a long time been elusive, recent adaptations of high-throughput sequencing to chromosome conformation capture (3C) techniques, allows for genome-wide structu... | Understanding how the genome is folded in three-dimensional (3D) space is crucial for unravelling the complex regulatory mechanisms underlying the differentiation and proliferation of cells. With recent high-throughput adaptations of chromosome conformation capture in techniques such as single-cell Hi-C, it is now poss... | Understanding genomes in three dimensions (3D) is a fundamental problem in biology. Recently, the combination of chromosome conformation capture (3C) methods with next-generation sequencing, such as 5C [1], Hi-C [2], TCC [3], and GCC [4], has enabled the study of contact frequencies across large genomic regions or enti... |
10.1371/journal.ppat.1005450 | Resistance to Bacillus thuringiensis Mediated by an ABC Transporter Mutation Increases Susceptibility to Toxins from Other Bacteria in an Invasive Insect | Evolution of pest resistance reduces the efficacy of insecticidal proteins from the gram-positive bacterium Bacillus thuringiensis (Bt) used widely in sprays and transgenic crops. Recent efforts to delay pest adaptation to Bt crops focus primarily on combinations of two or more Bt toxins that kill the same pest, but th... | The soil bacterium Bacillus thuringiensis (Bt) produces proteins that kill insect pests but do not harm most other organisms including people. Extensive use of Bt proteins in sprays and genetically engineered crops selects for rapid evolution of resistance in pests, reducing economic and environmental advantages of thi... | Insecticidal proteins from the bacterium Bacillus thuringiensis (Bt) are used widely in sprays and transgenic plants to control insects that attack crops and vector diseases [1,2]. These Bt proteins are especially valuable because they kill some devastating pests, but are not toxic to humans and most other organisms [1... |
10.1371/journal.pntd.0002761 | The Effect of Multiple Rounds of Mass Drug Administration on the Association between Ocular Chlamydia trachomatis Infection and Follicular Trachoma in Preschool-Aged Children | To examine the relationship between ocular Chlamydia trachomatis infection and follicular trachoma (TF) in children prior to and following multiple rounds of annual mass drug administration (MDA) with azithromycin.
Thirty-two communities with endemic trachoma in Kongwa District, Tanzania, were offered annual MDA as par... | Trachoma, which is caused by infection by the bacterium Chlamydia trachomatis, is the leading preventable cause of blindness worldwide. Annual mass drug administration with azithromycin is recommended for trachoma control; however, monitoring the impact of azithromycin, which targets C. trachomatis, relies on the clini... | Trachoma, the most common preventable cause of blindness in the world [1], [2], is caused by repeated and/or prolonged episodes of ocular infection by the bacterium Chlamydia trachomatis. The disease disproportionately affects individuals living in rural and resource-poor settings, and children are the primary carriers... |
10.1371/journal.pcbi.1000937 | Semantic Similarity for Automatic Classification of Chemical Compounds | With the increasing amount of data made available in the chemical field, there is a strong need for systems capable of comparing and classifying chemical compounds in an efficient and effective way. The best approaches existing today are based on the structure-activity relationship premise, which states that biological... | Among the existing systems capable of computationally comparing chemical compounds, the majority use only structural and physicochemical properties. However, with the emergence of ChEBI and other chemical compound databases, it has become feasible to create a system that can use the relevance of compounds in a biologic... | The recent publication of large-scale chemical information, made available by PubChem, ChEMBL and ChEBI, for instance, increased the focus of the scientific community on the problem of chemical comparison. With the amount of chemical data being published and produced today, it has become increasingly necessary to devis... |
10.1371/journal.ppat.1006779 | A parapoxviral virion protein targets the retinoblastoma protein to inhibit NF-κB signaling | Poxviruses have evolved multiple strategies to subvert signaling by Nuclear Factor κB (NF-κB), a crucial regulator of host innate immune responses. Here, we describe an orf virus (ORFV) virion-associated protein, ORFV119, which inhibits NF-κB signaling very early in infection (≤ 30 min post infection). ORFV119 NF-κB in... | Poxviruses have evolved multiple strategies to subvert signaling by NF-κB, a crucial regulator of host innate immune responses. Viruses often encode multiple inhibitory proteins, which largely target cytoplasmic activation events of NF-κB signaling. The retinoblastoma protein (pRb), a multifunctional protein best known... | Orf virus (ORFV), the type member of the genus Parapoxvirus of the Poxviridae, is the causative agent of orf or contagious ecthyma, a ubiquitous disease of sheep and goats characterized by proliferative lesions affecting muco-cutaneous tissues of the mouth and muzzle [1,2]. Orf is a zoonotic disease affecting humans in... |
10.1371/journal.pgen.1001314 | The Evolution of Host Specialization in the Vertebrate Gut Symbiont Lactobacillus reuteri | Recent research has provided mechanistic insight into the important contributions of the gut microbiota to vertebrate biology, but questions remain about the evolutionary processes that have shaped this symbiosis. In the present study, we showed in experiments with gnotobiotic mice that the evolution of Lactobacillus r... | The gastrointestinal microbiota of vertebrates is important for nutrient utilization, resistance against pathogens, and immune maturation of its host, but little is known about the evolutionary relationships between vertebrates and individual bacterial members of these communities. Here we provide robust evidence that ... | Vertebrates are associated with trillions of microbes, the majority of which inhabit the digestive tract [1]. Research has led to an appreciation of the importance of these microbial communities, revealing substantial roles in development and performance of the host [2], [3]. As vertebrates evolved, they did so in asso... |
10.1371/journal.pbio.1000343 | Binding Site Turnover Produces Pervasive Quantitative Changes in Transcription Factor Binding between Closely Related Drosophila Species | Changes in gene expression play an important role in evolution, yet the molecular mechanisms underlying regulatory evolution are poorly understood. Here we compare genome-wide binding of the six transcription factors that initiate segmentation along the anterior-posterior axis in embryos of two closely related species:... | The differentiation of cells, tissues, and organs during animal development is established by a process in which genes that control cell identity and behavior are turned on and off at specific times and places. This process is choreographed, to a large extent, by a collection of proteins known as transcription factors ... | Despite four decades of interest in the evolution of transcriptional regulation, we still have a poor understanding of the molecular bases for regulatory divergence and the constraints under which cis-regulatory sequences evolve. Most regulatory sequences appear to be under strong selection to maintain their transcript... |
10.1371/journal.pbio.1001299 | ROP GTPase-Dependent Actin Microfilaments Promote PIN1 Polarization by Localized Inhibition of Clathrin-Dependent Endocytosis | Cell polarization via asymmetrical distribution of structures or molecules is essential for diverse cellular functions and development of organisms, but how polarity is developmentally controlled has been poorly understood. In plants, the asymmetrical distribution of the PIN-FORMED (PIN) proteins involved in the cellul... | Formation of cell polarity is a process of distributing cellular structures or molecules in an asymmetric manner. This process plays an important role in the generation of diverse cell forms and types. In plants, the quintessential hormone auxin is important for diverse physiological functions, including growth and dev... | Cell polarity is a conserved cellular property that is necessary for the generation of diverse forms and types of cells in both uni- and multicellular organisms [1],[2]. The general design principles that govern the formation of polarity and how they are used to generate diverse forms of polarity is a fundamental issue... |
10.1371/journal.pgen.1000076 | ATM Promotes the Obligate XY Crossover and both Crossover Control and Chromosome Axis Integrity on Autosomes | During meiosis in most sexually reproducing organisms, recombination forms crossovers between homologous maternal and paternal chromosomes and thereby promotes proper chromosome segregation at the first meiotic division. The number and distribution of crossovers are tightly controlled, but the factors that contribute t... | Meiosis is the specialized cell division that gives rise to reproductive cells such as sperm and eggs. During meiosis in most organisms, genetic information is exchanged between homologous maternal and paternal chromosomes through the process of homologous recombination. This recombination forms connections between hom... | Crossing-over between homologous chromosomes in conjunction with sister chromatid cohesion provides physical connections necessary for accurate chromosome segregation during the first meiotic division [1]. Due to their central role in meiosis, crossovers are tightly controlled in most organisms such that each chromosom... |
10.1371/journal.ppat.1002374 | CD11b+, Ly6G+ Cells Produce Type I Interferon and Exhibit Tissue Protective Properties Following Peripheral Virus Infection | The goal of the innate immune system is containment of a pathogen at the site of infection prior to the initiation of an effective adaptive immune response. However, effector mechanisms must be kept in check to combat the pathogen while simultaneously limiting undesirable destruction of tissue resulting from these acti... | During a natural virus infection, small doses of infectious virus are deposited at a peripheral infection site, and then a “race” ensues, in which the replicating virus attempts to “outpace” the responding immune system of the host. In the early phases of infection, the innate immune system must contain the infection p... | Typically, the acute innate immune response to a peripheral challenge involves rapid infiltration of Ly6C+Ly6G+ neutrophils, followed by Ly6C+Ly6G- monocytes, in a process that involves chemoattraction mediated by arachidonic acid metabolites, cytokines, and chemokines [1]. Both neutrophils and monocytes mediate inflam... |
10.1371/journal.pcbi.1002228 | Comparative Microbial Modules Resource: Generation and Visualization of Multi-species Biclusters | The increasing abundance of large-scale, high-throughput datasets for many closely related organisms provides opportunities for comparative analysis via the simultaneous biclustering of datasets from multiple species. These analyses require a reformulation of how to organize multi-species datasets and visualize compara... | Advancing high-throughput experimental technologies are providing access to genome-wide measurements for multiple related species on multiple information levels (e.g. mRNA, protein, interactions, functional assays, etc.). We present a biclustering algorithm and an associated visualization system for generating and expl... | It is now routine to have genomics data for multiple organisms of interest. For example, data may be available for both an organism of primary relevance to a specific study, as well as data for related species. Tools and algorithms for comparative analysis of multi-species datasets are therefore in high demand. Compara... |
10.1371/journal.pcbi.1003016 | Synthetic Lethality between Gene Defects Affecting a Single Non-essential Molecular Pathway with Reversible Steps | Systematic analysis of synthetic lethality (SL) constitutes a critical tool for systems biology to decipher molecular pathways. The most accepted mechanistic explanation of SL is that the two genes function in parallel, mutually compensatory pathways, known as between-pathway SL. However, recent genome-wide analyses in... | Organizing gene functions into molecular pathways is a major challenge in biology. The observation that two viable gene mutations become lethal when combined as a double mutant has been developed into a major genetic tool called synthetic lethality. The classic interpretation of synthetic lethality stipulates that the ... | Synthetic interactions between two mutations in different genes were first revealed in Drosophila by Dobzhansky in the 1940s [1]. Synthetic lethality (SL) describes that two viable single gene mutations lead to lethality (synthetic-lethal) or severely impair growth (synthetic-sick) when combined as a double mutant. Thi... |
10.1371/journal.pntd.0000874 | Cost-Effectiveness of a Chemoprophylactic Intervention with Single Dose Rifampicin in Contacts of New Leprosy Patients | With 249,007 new leprosy patients detected globally in 2008, it remains necessary to develop new and effective interventions to interrupt the transmission of M. leprae. We assessed the economic benefits of single dose rifampicin (SDR) for contacts as chemoprophylactic intervention in the control of leprosy.
We conducte... | In 2008, 249,007 new leprosy patients were detected in the world. It therefore remains necessary to develop new and effective interventions to interrupt the transmission of M. leprae. We assessed the economic benefits of single dose rifampicin (SDR) for contacts as chemoprophylactic intervention in the control of lepro... | Leprosy is a chronic infectious disease, caused by the bacillus Mycobacterium leprae, which affects the skin and peripheral nerves leading to skin lesions, loss of sensation, and nerve damage. This in turn can lead to secondary impairments or deformities of the eyes, hands and feet. For treatment purposes, leprosy is c... |
10.1371/journal.pntd.0001209 | Evidence of Gene Conversion in Genes Encoding the Gal/GalNac Lectin Complex of Entamoeba | The human gut parasite Entamoeba histolytica, uses a lectin complex on its cell surface to bind to mucin and to ligands on the intestinal epithelia. Binding to mucin is necessary for colonisation and binding to intestinal epithelia for invasion, therefore blocking this binding may protect against amoebiasis. Acquired p... | Gene conversion is a process of recombination that can generate diversity among genes. Gene conversion occurs in some pathogenic species of protozoa to generate diversity among gene families encoding important antigens. The process may contribute to immune evasion by the parasites. Gene conversion, or indeed recombinat... | Entamoeba histolytica causes a significant amount of death and disease, an annual estimate made in the 1980s indicated that 40,000–110,000 people died and 34–50 million people developed severe amoebiasis (dysentery or liver abscess) in 1981 [1]. Infection commonly results from the consumption of contaminated food and w... |
10.1371/journal.pntd.0007290 | Molecular detection of P. vivax and P. ovale foci of infection in asymptomatic and symptomatic children in Northern Namibia | Knowledge of the foci of Plasmodium species infections is critical for a country with an elimination agenda. Namibia is targeting malaria elimination by 2020. To support decision making regarding targeted intervention, we examined for the first time, the foci of Plasmodium species infections and regional prevalence in ... | Namibia is a member of the SADC elimination 8 (E8) group with a target to eliminate malaria by 2020. This target stems from years of aggressive interventional strategies that has led to significant reductions in morbidity and mortality. The focus of this strategy is mainly on Plasmodium falciparum as the primary parasi... | Progress in malaria elimination efforts have intensified across the Southern African Development Community (SADC) with the aim of elimination by 2030 for most countries [1], [2], [3], [4]. This means a knowledge of current levels of transmission as part of the malariogenic potential is required. The burden of malaria i... |
10.1371/journal.pcbi.1000793 | Game Theory of Social Distancing in Response to an Epidemic | Social distancing practices are changes in behavior that prevent disease transmission by reducing contact rates between susceptible individuals and infected individuals who may transmit the disease. Social distancing practices can reduce the severity of an epidemic, but the benefits of social distancing depend on the e... | One of the easiest ways for people to lower their risk of infection during an epidemic is for them to reduce their rate of contact with infectious individuals. However, the value of such actions depends on how the epidemic progresses. Few analyses of behavior change to date have accounted for how changes in behavior ch... | Epidemics of infectious diseases are a continuing threat to the health of human communities, and one brought to prominence in the public mind by the 2009 pandemic of H1N1 influenza [1]. One of the key questions of public health epidemiology is how individual and community actions can help mitigate and manage the costs ... |
10.1371/journal.pbio.2003864 | Endoplasmic reticulum-plasma membrane contact sites integrate sterol and phospholipid regulation | Tether proteins attach the endoplasmic reticulum (ER) to other cellular membranes, thereby creating contact sites that are proposed to form platforms for regulating lipid homeostasis and facilitating non-vesicular lipid exchange. Sterols are synthesized in the ER and transported by non-vesicular mechanisms to the plasm... | Almost half of the inner surface area of the yeast plasma membrane (PM) is covered with closely associated cortical endoplasmic reticulum (ER). In yeast and human cells, it has been proposed that ER-anchored tether proteins staple the ER to the PM, creating membrane contact sites at which lipid transport between the ER... | Most lipids are synthesized in the endoplasmic reticulum (ER) and distributed to other membranes by non-vesicular mechanisms. These mechanisms act in conjunction with lipid metabolic networks to maintain the unique lipid profile of the plasma membrane (PM) and subcellular organelles, and enable rapid membrane lipid rem... |
10.1371/journal.pcbi.1006292 | Gain control with A-type potassium current: IA as a switch between divisive and subtractive inhibition | Neurons process and convey information by transforming barrages of synaptic inputs into spiking activity. Synaptic inhibition typically suppresses the output firing activity of a neuron, and is commonly classified as having a subtractive or divisive effect on a neuron’s output firing activity. Subtractive inhibition ca... | Neurons process information by generating spikes in response to two types of synaptic inputs. Excitatory inputs increase spike rates and inhibitory inputs decrease spike rates (typically). The interaction between these two input types and the transformation of these inputs into spike outputs is not, however, a simple m... | The activity of a neuron is driven by barrages of synaptic inputs. Synaptic inputs are classified as either excitatory (those that promote spike generation) and inhibitory (those that impede spike generation). The interplay between these two “opposing” inputs influences how neurons process and transmit information in t... |
10.1371/journal.ppat.1000971 | Genome-Wide Mutagenesis Reveals That ORF7 Is a Novel VZV Skin-Tropic Factor | The Varicella Zoster Virus (VZV) is a ubiquitous human alpha-herpesvirus that is the causative agent of chicken pox and shingles. Although an attenuated VZV vaccine (v-Oka) has been widely used in children in the United States, chicken pox outbreaks are still seen, and the shingles vaccine only reduces the risk of shin... | The Varicella Zoster Virus (VZV) is the causative agent of chicken pox and shingles. The long-term efficacy of the current chickenpox vaccine is yet to be determined, and the current shingles vaccine fails to provide protective immunity for a substantial number of individuals. Shingles can also lead to post-herpetic ne... | Human varicella-zoster virus (VZV) is a widespread human alpha-herpesvirus, and the majority of the US population has been previously exposed [1]. VZV is the causative agent of chicken pox and shingles, the latter of which is associated with a significant incidence of post-herpetic neuralgia [2], [3]. A universal chick... |
10.1371/journal.pbio.1002435 | How Many Parameters Does It Take to Describe Disease Tolerance? | The study of infectious disease has been aided by model organisms, which have helped to elucidate molecular mechanisms and contributed to the development of new treatments; however, the lack of a conceptual framework for unifying findings across models, combined with host variability, has impeded progress and translati... | It is an intuitive assumption that the severity of symptoms suffered during an infection must be linked to pathogen loads. However, the dose–response relationship explaining how health varies with respect to pathogen load is non-linear and can be described as a “disease tolerance curve;” this relationship can vary in r... | The clinical goal of treating infectious diseases is to reduce the levels of sickness experienced by infected hosts. One approach to studying this problem is to quantitate illness by correlating the dose response of pathology to pathogen load; graphs like these are called “disease tolerance curves” [1–6]. We argue that... |
10.1371/journal.pbio.1001771 | Def1 Promotes the Degradation of Pol3 for Polymerase Exchange to Occur During DNA-Damage–Induced Mutagenesis in Saccharomyces cerevisiae | DNA damages hinder the advance of replication forks because of the inability of the replicative polymerases to synthesize across most DNA lesions. Because stalled replication forks are prone to undergo DNA breakage and recombination that can lead to chromosomal rearrangements and cell death, cells possess different mec... | DNA damages can lead to the stalling of the cellular replication machinery if not repaired on time, inducing DNA strand breaks, recombination that can result in gross chromosomal rearrangements, even cell death. In order to guard against this outcome, cells have evolved several precautionary mechanisms. One of these in... | The stalling of the replication machinery that occurs as a consequence of encountering unrepaired DNA damages is a challenging problem for cells. Stalled replication forks can undergo DNA breakage and recombination that can lead to chromosomal rearrangements and cell death. To ensure survival, cells have evolved differ... |
10.1371/journal.ppat.1003047 | Neutrophil-derived IL-1β Is Sufficient for Abscess Formation in Immunity against Staphylococcus aureus in Mice | Neutrophil abscess formation is critical in innate immunity against many pathogens. Here, the mechanism of neutrophil abscess formation was investigated using a mouse model of Staphylococcus aureus cutaneous infection. Gene expression analysis and in vivo multispectral noninvasive imaging during the S. aureus infection... | Invasive infections caused by the human pathogen Staphylococcus aureus result in more deaths annually than infections caused by any other single infectious agent in the United States. Although neutrophil recruitment and abscess formation is crucial for effective host defense against this pathogen, how neutrophils sense... | Neutrophil abscess formation represents an important component of the innate immune response, which helps control the spread of an invading pathogen into deeper tissues and systemically [1]. At the site of infection, neutrophils primarily function through the phagocytosis of microorganisms and utilize a variety of anti... |
10.1371/journal.pcbi.1003741 | Structure-Based Druggability Assessment of the Mammalian Structural Proteome with Inclusion of Light Protein Flexibility | Advances reported over the last few years and the increasing availability of protein crystal structure data have greatly improved structure-based druggability approaches. However, in practice, nearly all druggability estimation methods are applied to protein crystal structures as rigid proteins, with protein flexibilit... | Advances reported over the last few years and the increasing availability of protein crystal structure data have greatly improved structure-based druggability approaches. These algorithms predict our ability to discover small molecule drugs for protein targets and can help in identifying promising new biological target... | The majority of small molecule drug discovery efforts towards new, unprecedented biological targets do not progress past high-throughput screening or hit-to-lead optimization due to lack of pursuable chemical matter [1], [2]. To counter this, drug discovery groups increasingly use druggability analysis methods to estim... |
10.1371/journal.pntd.0004261 | Time-Dependent Transcriptional Changes in Axenic Giardia duodenalis Trophozoites | Giardia duodenalis is the most common gastrointestinal protozoan parasite of humans and a significant contributor to the global burden of both diarrheal disease and post-infectious chronic disorders. Although G. duodenalis can be cultured axenically, significant gaps exist in our understanding of the molecular biology ... | Giardia is the most common gastrointestinal protozoan parasite of humans. This parasite causes diarrheal disease and is correlated with post-infectious conditions such as irritable bowel syndrome. In the absence of a vaccine, treatment is limited to drugs such as metronidazole, against which clinical resistance is repo... | Giardia duodenalis (syn. G. lamblia or G. intestinalis) is a gastrointestinal protozoan parasite, and a major cause of chronic infectious diarrhoea in the developed and developing world. G. duodenalis infects approximately one billion people world-wide, causing 200–300 million reported clinical cases each year [1]. G. ... |
10.1371/journal.pgen.1005617 | DCA1 Acts as a Transcriptional Co-activator of DST and Contributes to Drought and Salt Tolerance in Rice | Natural disasters, including drought and salt stress, seriously threaten food security. In previous work we cloned a key zinc finger transcription factor gene, Drought and Salt Tolerance (DST), a negative regulator of drought and salt tolerance that controls stomatal aperture in rice. However, the exact mechanism by wh... | Drought and salt are two of the most serious threats to food production worldwide, and research on stress tolerance in crops is important for future food security. In this study we identified DCA1, a transcriptional co-activator of DST that is conserved in the world’s three major crops. DCA1 participates in stress tole... | How to feed a growing population that is expected to reach roughly 9 billion by the middle of this century is among the major challenges of our time [1]. Modern agriculture has greatly improved food production [2], but progress towards avoiding the negative effects of climate change and diminishing soil conditions has ... |
10.1371/journal.pgen.1000902 | GTPase Activity Plays a Key Role in the Pathobiology of LRRK2 | Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are associated with late-onset, autosomal-dominant, familial Parkinson's disease (PD) and also contribute to sporadic disease. The LRRK2 gene encodes a large protein with multiple domains, including functional Roc GTPase and protein kinase domains. Mutations in... | Parkinson's disease (PD) is the second most common neurodegenerative disorder. PD is considered to be caused by a combination of risk factors including environmental exposure, age, and a positive family history for disease. Several genes have been unambiguously implicated in PD. However, our knowledge is still limited ... | Parkinson's disease (PD (OMIM #168600)) is a common neurodegenerative movement disorder that is characterized by muscular rigidity, bradykinesia, resting tremor and postural instability [1],[2]. Although typically a sporadic disease, mutations in the leucine-rich repeat kinase 2 (LRRK2, PARK8, OMIM #607060, GenBank #AY... |
10.1371/journal.pcbi.1004499 | The Elementary Operations of Human Vision Are Not Reducible to Template-Matching | It is generally acknowledged that biological vision presents nonlinear characteristics, yet linear filtering accounts of visual processing are ubiquitous. The template-matching operation implemented by the linear-nonlinear cascade (linear filter followed by static nonlinearity) is the most widely adopted computational ... | Any attempt to model human vision must first ask: can it be approximated by a process that linearly matches the visual stimulus with an internal template? We often take this approximation for granted without properly checking its validity. Even if we assume that the approximation is valid under specific conditions, doe... | Animals constantly submit environmental signals to neural operations designed to extract useful information for guiding behaviour. Whether their sensory apparatus is considered in its entirety as a behavioural machine or in relation to hardware components like individual nerve cells, it can be described as an input-out... |
10.1371/journal.ppat.0040028 | Methamphetamine Inhibits Antigen Processing, Presentation, and Phagocytosis | Methamphetamine (Meth) is abused by over 35 million people worldwide. Chronic Meth abuse may be particularly devastating in individuals who engage in unprotected sex with multiple partners because it is associated with a 2-fold higher risk for obtaining HIV and associated secondary infections. We report the first speci... | There is a new population of HIV+ men who are developing AIDS over months instead of years as typical. It has recently become popular among gay and bisexual men to consume very high levels of Meth. Unsafe sex together with Meth abuse has been suspected to lead to rapid disease progression. While studies show exacerbate... | Chronic methamphetamine (Meth) abuse has reached epidemic proportion throughout the United States, where a 2003 survey indicated that approximately 5% of the population over 12 years of age has tried Meth and the rate of treatment admissions for primary Meth abuse increased over 3-fold (The DASIS Report, http://www.oas... |
10.1371/journal.pntd.0000808 | A Simple Colorimetric Assay for Specific Detection of Glutathione-S Transferase Activity Associated with DDT Resistance in Mosquitoes | Insecticide-based methods represent the most effective means of blocking the transmission of vector borne diseases. However, insecticide resistance poses a serious threat and there is a need for tools, such as diagnostic tests for resistance detection, that will improve the sustainability of control interventions. The ... | Aedes mosquitoes transmit many human viral pathogens including dengue, yellow fever and chikungunya. Most of these pathogens have no specific treatment or vaccine and hence their control is reliant on controlling the mosquito vectors, which usually involves the use of insecticides. In order to prevent the alarming pros... | Prevention of mosquito-borne diseases depends in large part on vector control and usually involves the use of insecticides. Insecticide-based methods include insecticide-impregnated bed nets, indoor or aerial sprays and water treatments. Pyrethroids and the organochlorinated insecticide DDT (1,1,1-dichloro-2,2-bis(p-ch... |
10.1371/journal.pgen.1002502 | Computational Prediction and Molecular Characterization of an Oomycete Effector and the Cognate Arabidopsis Resistance Gene | Hyaloperonospora arabidopsidis (Hpa) is an obligate biotroph oomycete pathogen of the model plant Arabidopsis thaliana and contains a large set of effector proteins that are translocated to the host to exert virulence functions or trigger immune responses. These effectors are characterized by conserved amino-terminal t... | Oomycete plant pathogens are among the most devastating agricultural pests and employ arsenals of effector proteins to manipulate their plant hosts. Some of these effectors, however, are recognized in the plant and trigger an immune response. Hyaloperonospora arabidopsidis (Hpa) causes downy mildew on the model plant A... | Oomycetes comprise a number of agriculturally important plant pathogens, including Phytophthora infestans (potato and tomato late blight), P. ramorum (sudden oak death) and P. sojae (soybean root rot). Hyaloperonospora arabidopsidis (Hpa, downy mildew, formerly known as Peronospora parasitica) is a naturally occurring ... |
10.1371/journal.pcbi.1004016 | A Systematic Computational Analysis of Biosynthetic Gene Cluster Evolution: Lessons for Engineering Biosynthesis | Bacterial secondary metabolites are widely used as antibiotics, anticancer drugs, insecticides and food additives. Attempts to engineer their biosynthetic gene clusters (BGCs) to produce unnatural metabolites with improved properties are often frustrated by the unpredictability and complexity of the enzymes that synthe... | Bacterial secondary metabolites mediate a broad range of microbe-microbe and microbe-host interactions, and are widely used in human medicine, agriculture and manufacturing. Despite recent advances in synthetic biology, efforts to engineer their biosynthetic genes for the production of unnatural variants are frustrated... | Bacterial secondary metabolites are widely used as pharmaceutical, agricultural, and dietary agents. They consist of many classes of compounds including polyketides (PKs), nonribosomal peptides (NRPs), ribosomally synthesized and post-translationally modified peptides (RiPPs), terpenoids, saccharides, and a plethora of... |
10.1371/journal.pgen.1001366 | Genome Analysis Reveals Interplay between 5′UTR Introns and Nuclear mRNA Export for Secretory and Mitochondrial Genes | In higher eukaryotes, messenger RNAs (mRNAs) are exported from the nucleus to the cytoplasm via factors deposited near the 5′ end of the transcript during splicing. The signal sequence coding region (SSCR) can support an alternative mRNA export (ALREX) pathway that does not require splicing. However, most SSCR–containi... | The function and evolution of introns have been topics of great interest since introns were discovered in the 1970s. Introns that interrupt protein-coding regions have the most obvious potential to affect coding sequences and their evolution, and they have therefore been studied most intensively. However, about one thi... | In humans, ∼35% of all genes have introns in their 5′ untranslated regions (UTRs) [1]–[3]. These introns differ from those in coding regions, for example, in typical length and nucleotide composition [1]–[3]. Previously, 5′UTR introns (5UIs) were suggested to be evolving under a neutral model of random insertion and de... |
10.1371/journal.pcbi.1003921 | Linking Macroscopic with Microscopic Neuroanatomy Using Synthetic Neuronal Populations | Dendritic morphology has been shown to have a dramatic impact on neuronal function. However, population features such as the inherent variability in dendritic morphology between cells belonging to the same neuronal type are often overlooked when studying computation in neural networks. While detailed models for morphol... | Computational models of neurons and neural networks provide a valuable avenue to test our understanding of brain regions and to make predictions to guide future experimentation. Each neuron has a unique dendritic tree, features of which can vary depending on the location of the neuron within the particular brain region... | Growing evidence for the importance of dendritic structure on neuronal function has inspired the construction of morphologically realistic computational models of single neurons. Dendritic morphology has been shown to have a significant impact on neuronal firing properties, both between neurons of different classes [1]... |
10.1371/journal.pbio.2001323 | What makes a reach movement effortful? Physical effort discounting supports common minimization principles in decision making and motor control | When deciding between alternative options, a rational agent chooses on the basis of the desirability of each outcome, including associated costs. As different options typically result in different actions, the effort associated with each action is an essential cost parameter. How do humans discount physical effort when... | Economic choice in humans and animals can be understood as a weighing of benefits (e.g., reward) against costs (e.g., effort, delay, risk), leading to a preference for the behavioral option with highest expected utility. The costs of the action associated with a choice can thereby affect its utility: for equivalent ben... | Should I rather bring the groceries from the car trunk to the kitchen in 1 trip or in 2 trips? Even in a seemingly simple decision like this, multiple decision parameters are at odds. When doing a single trip, this bothersome task will certainly be finished more quickly but will require an intense physical effort. This... |
10.1371/journal.pgen.1006698 | VAMP3/Syb and YKT6 are required for the fusion of constitutive secretory carriers with the plasma membrane | The cellular machinery required for the fusion of constitutive secretory vesicles with the plasma membrane in metazoans remains poorly defined. To address this problem we have developed a powerful, quantitative assay for measuring secretion and used it in combination with combinatorial gene depletion studies in Drosoph... | The constitutive secretory pathway delivers newly synthesised proteins and lipids to the cell surface and is essential for cell growth and viability. This pathway is required for the secretion of molecules such as antibodies, cytokines and extracellular matrix components so has both significant physiological and commer... | Constitutive secretion delivers newly synthesised proteins and lipids to the cell surface and is essential for cell growth and viability. This pathway is required for the exocytosis of molecules such as antibodies, cytokines and extracellular matrix components so has both significant physiological and commercial import... |
10.1371/journal.pntd.0001980 | Distinct Transcriptional Signatures of Bone Marrow-Derived C57BL/6 and DBA/2 Dendritic Leucocytes Hosting Live Leishmania amazonensis Amastigotes | The inoculation of a low number (104) of L. amazonensis metacyclic promastigotes into the dermis of C57BL/6 and DBA/2 mouse ear pinna results in distinct outcome as assessed by the parasite load values and ear pinna macroscopic features monitored from days 4 to 22-phase 1 and from days 22 to 80/100-phase 2. While in C5... | The rapid and long term establishment of parasites such as L. amazonensis, otherwise known to strictly rely on subversion of macrophage and dendritic leucocyte (DL) lineages, is expected to reflect stepwise processes taking place in both the skin dermis where the infective form of the parasite and the skin-draining lym... | Leishmania (L.) amazonensis perpetuates in South and Central America, its main location being the wet forests of the Amazon basin. The perpetuation of this Leishmania species relies successively on two hosts which cohabit more or less transiently within this ecosystem: blood-feeding sand flies and mammals, including wi... |
10.1371/journal.pntd.0006076 | Virulence, pathology, and pathogenesis of Pteropine orthoreovirus (PRV) in BALB/c mice: Development of an animal infection model for PRV | Cases of acute respiratory tract infection caused by Pteropine orthoreovirus (PRV) of the genus Orthoreovirus (family: Reoviridae) have been reported in Southeast Asia, where it was isolated from humans and bats. It is possible that PRV-associated respiratory infections might be prevalent in Southeast Asia. The clinica... | It is assumed that Pteropine orthoreovirus (PRV) is a causative agent of acute respiratory tract infection (RTI) in humans. PRV was isolated from patients and fruit bats in Southeast Asia. Furthermore, the genome of PRV was detected in patients with respiratory symptoms, suggesting that PRV causes RTI in humans. There ... | Pteropine orthoreovirus (PRV), a member of genus Orthoreovirus in the family Reoviridae, was originally isolated from the heart blood of a grey-headed flying fox (Pteropus poliocephalus) in Australia in 1968 [1].
PRV was isolated from a patient with respiratory tract infection (RTI) as a causative agent in Malaysia in... |
10.1371/journal.pcbi.1001002 | Environments that Induce Synthetic Microbial Ecosystems | Interactions between microbial species are sometimes mediated by the exchange of small molecules, secreted by one species and metabolized by another. Both one-way (commensal) and two-way (mutualistic) interactions may contribute to complex networks of interdependencies. Understanding these interactions constitutes an o... | Microbial metabolism affects biogeochemical cycles and human health. In most natural environments, multiple microbial species interact with each other, forming complex ecosystems whose properties are poorly understood. In an effort to understand inter-microbial interactions, and to explore new metabolic engineering ave... | While several aspects of microbial metabolism can be fruitfully addressed by studying individual microbial species, many contemporary challenges, including environmental remediation and infectious diseases, require a massive effort towards understanding how microbes interact with each other. In fact, in nature, most mi... |
10.1371/journal.pcbi.1002742 | Modeling Protective Anti-Tumor Immunity via Preventative Cancer Vaccines Using a Hybrid Agent-based and Delay Differential Equation Approach | A next generation approach to cancer envisions developing preventative vaccinations to stimulate a person's immune cells, particularly cytotoxic T lymphocytes (CTLs), to eliminate incipient tumors before clinical detection. The purpose of our study is to quantitatively assess whether such an approach would be feasible,... | An innovative approach to treating cancer envisions developing preventative anti-cancer vaccines to train a person's immune cells to eliminate early-stage tumors close to genesis. The design of such a treatment strategy requires an understanding of the tumor and immune interactions leading to a successful anti-cancer i... | The most effective way to treat a disease is to prevent its development in the first place. Consequently, a next generation approach to cancer treatment envisions developing preventative cancer vaccines that would train a person's immune response to eliminate tumors near inception by stimulating a person's immune syste... |
10.1371/journal.pcbi.1004653 | MiR-192-Mediated Positive Feedback Loop Controls the Robustness of Stress-Induced p53 Oscillations in Breast Cancer Cells | The p53 tumor suppressor protein plays a critical role in cellular stress and cancer prevention. A number of post-transcriptional regulators, termed microRNAs, are closely connected with the p53-mediated cellular networks. While the molecular interactions among p53 and microRNAs have emerged, a systems-level understand... | DNA damage triggered activities of the tumor suppressor protein p53 could be significantly dynamical. The functional role of p53 oscillations in cellular decision making during cancer development has been appreciated. A set of recent studies have revealed extensive crosstalk between the p53 network and microRNAs, but t... | Cells depend on complex intracellular signaling to process and react to external stimuli. One prominent type of dynamic response is the periodic accumulation of key transcription factors in the nucleus, where they elicit temporally controlled gene activation [1–4]. The tumor suppressor protein p53, a pivotal player inv... |
10.1371/journal.ppat.1000185 | Immunity to HIV-1 Is Influenced by Continued Natural Exposure to Exogenous Virus | Unprotected sexual intercourse between individuals who are both infected with HIV-1 can lead to exposure to their partner's virus, and potentially to super-infection. However, the immunological consequences of continued exposure to HIV-1 by individuals already infected, has to our knowledge never been reported. We meas... | Serosorting, the practice of seeking to engage in unprotected sexual activities only with partners who are of the same HIV-1 status, is a growing trend. Unprotected sexual intercourse between two HIV-1 infected individuals can lead to consequences such as HIV-1 super-infection. However, continued exposure to HIV-1 may ... | Immune responses seen during chronic viral infections are thought to be driven only by ‘endogenous’ virus. However, continued exposure to ‘exogenous’ virus could boost anti-viral immunity. HIV-1 infection provides a model to test this hypothesis. Continued sexual intercourse between two HIV-1 infected individuals leads... |
10.1371/journal.pcbi.1005894 | Modeling visual-based pitch, lift and speed control strategies in hoverflies | To avoid crashing onto the floor, a free falling fly needs to trigger its wingbeats quickly and control the orientation of its thrust accurately and swiftly to stabilize its pitch and hence its speed. Behavioural data have suggested that the vertical optic flow produced by the fall and crossing the visual field plays a... | On the basis of vision-based feedback control of optic flow occurring during insects’ flight, we developed a dynamic model that accounts for the pitch orientation and speed in plummeting flies. We compared the hoverflies’ responses with our model and showed that an optic-flow based control strategy can be used to corre... | Flying insects are subjected to a broad range of disturbances, for which fast, robust sensorimotor reflexes compensate. The flight stabilization performance of flies are even more impressive in view of the intrinsic aerodynamic instability of their flapping flight [1–4]. Compensating for this passive instability requir... |
10.1371/journal.pcbi.1005929 | Representability of algebraic topology for biomolecules in machine learning based scoring and virtual screening | This work introduces a number of algebraic topology approaches, including multi-component persistent homology, multi-level persistent homology, and electrostatic persistence for the representation, characterization, and description of small molecules and biomolecular complexes. In contrast to the conventional persisten... | Conventional persistent homology neglects chemical and biological information during the topological abstraction and thus has limited representational power for complex chemical and biological systems. In terms of methodological development, we introduce advanced persistent homology approaches for the characterization ... | Arguably, machine learning has become one of the most important developments in data science and artificial intelligence. With its ability to extract features of various levels hierarchically, deep convolutional neural networks (CNNs) have made breakthroughs in image processing, video, audio, and computer vision [1, 2]... |
10.1371/journal.pbio.1002217 | Sustained Pax6 Expression Generates Primate-like Basal Radial Glia in Developing Mouse Neocortex | The evolutionary expansion of the neocortex in mammals has been linked to enlargement of the subventricular zone (SVZ) and increased proliferative capacity of basal progenitors (BPs), notably basal radial glia (bRG). The transcription factor Pax6 is known to be highly expressed in primate, but not mouse, BPs. Here, we ... | During development, neural progenitors generate all cells that make up the mammalian brain. Differences in brain size among the various mammalian species are attributed to differences in the abundance and proliferative capacity of a specific class of neural progenitors called basal progenitors. Among these, a specific ... | The evolutionary expansion of the mammalian neocortex is thought to be primarily the consequence of the increasing proliferative capacity of cortical stem and progenitor cells during development [1–9]. Recent studies have progressively focused on differences between species regarding the type, abundance, and modes of d... |
10.1371/journal.pgen.1003228 | Hepatocyte Growth Factor, a Determinant of Airspace Homeostasis in the Murine Lung | The alveolar compartment, the fundamental gas exchange unit in the lung, is critical for tissue oxygenation and viability. We explored hepatocyte growth factor (HGF), a pleiotrophic cytokine that promotes epithelial proliferation, morphogenesis, migration, and resistance to apoptosis, as a candidate mediator of alveola... | The airspace compartment of the mammalian lung, comprised of spherical sacs termed alveoli, harbors the architecture, cellular composition, and molecular armamentarium to perform the critical function of gas exchange or oxygen uptake. Despite the necessity of this alveolar compartment for organismal viability, the mech... | One approach to identifying mediators of alveolar formation and regeneration in the mammalian lung is to delineate the elemental events that attend airspace formation and then systematically investigate candidate proteins that harbor a compatible signaling repertoire in animal or cellular model systems. From a developm... |
10.1371/journal.ppat.0040043 | Structure–Function Aspects of PstS in Multi-Drug–Resistant Pseudomonas aeruginosa | The increasing prevalence of multi-drug–resistant (MDR) strains of Pseudomonas aeruginosa among critically ill humans is of significant concern. In the current study, we show that MDR clinical isolates of P. aeruginosa representing three distinct genotypes that display high virulence against intestinal epithelial cells... | The resistance of bacteria to multiple antibiotics is a major problem in critically ill patients who often become colonized by highly lethal pathogens such as Pseudomonas aeruginosa. During the course of critical illness, as many as 50% of patients' intestinal tracts become colonized with P. aeruginosa, with as many as... | Infection due to P. aeruginosa continues to be a major cause of mortality among critically ill and immuno-compromised patients despite the development of newer and more powerful antibiotics. Both the immunoevasive nature of P. aeruginosa as well as its acquisition of multi-drug resistance makes elimination of this orga... |
10.1371/journal.pgen.1002358 | A Novel Protein LZTFL1 Regulates Ciliary Trafficking of the BBSome and Smoothened | Many signaling proteins including G protein-coupled receptors localize to primary cilia, regulating cellular processes including differentiation, proliferation, organogenesis, and tumorigenesis. Bardet-Biedl Syndrome (BBS) proteins are involved in maintaining ciliary function by mediating protein trafficking to the cil... | Primary cilia are considered to be a signaling hub coordinating multiple signaling pathways. Impairment of ciliary function results in developmental defects in vertebrates and also underlies many human disorders including obesity, polycystic kidney disease, and retinopathy. BBS is a prototypical human genetic disorder ... | Primary cilia are microtubule-based subcellular organelles projecting from the surface of cells. Studies during the last decade have shown that primary cilia play essential roles in regulating cell cycle, embryonic development, and tissue homeostasis by acting as a cellular antenna transducing extracellular signals int... |
10.1371/journal.pcbi.1005152 | Interrogating Emergent Transport Properties for Molecular Motor Ensembles: A Semi-analytical Approach | Intracellular transport is an essential function in eucaryotic cells, facilitated by motor proteins—proteins converting chemical energy into kinetic energy. It is understood that motor proteins work in teams enabling unidirectional and bidirectional transport of intracellular cargo over long distances. Disruptions of t... | Molecular motors such as kinesin and dynein facilitate directed transport of intracellular cargo over tracks called microtubules. Inside cells, multiple motor proteins are known to bind and move cargoes. These teams of motors enable the transport of cargoes over longer distances, extending beyond the processive runleng... | Motor proteins- kinesin, dynein and myosins- are nanoscale machines that are the main effectors of intracellular transport. They play a critical role in the growth and sustenance of healthy cells by enabling a transport of intracellular cargo over networks of microtubules [1]. Disruption of the functions performed by t... |
10.1371/journal.pcbi.1000409 | Spatio-Temporal Dynamics of Yeast Mitochondrial Biogenesis:
Transcriptional and Post-Transcriptional mRNA Oscillatory Modules | Examples of metabolic rhythms have recently emerged from studies of budding
yeast. High density microarray analyses have produced a remarkably detailed
picture of cycling gene expression that could be clustered according to
metabolic functions. We developed a ... | In bacterial and eukaryotic cells, gene expression is regulated at both the
transcriptional and translational levels. In eukaryotes these two processes
cannot be directly coupled because the nuclear membrane separates the
chromosomes from the ribosomes. Althou... | Cell construction requires the tight linking of various molecular processes, from
nuclear transcription to the site-specific production of proteins. The control of
the orchestration of these processes remains poorly understood. In classical
experimental conditions, coordi... |
10.1371/journal.ppat.1002016 | Human Cytomegalovirus IE1 Protein Elicits a Type II Interferon-Like
Host Cell Response That Depends on Activated STAT1 but Not
Interferon-γ | Human cytomegalovirus (hCMV) is a highly prevalent pathogen that, upon primary
infection, establishes life-long persistence in all infected individuals. Acute
hCMV infections cause a variety of diseases in humans with developmental or
acquired immune deficits.... | Human cytomegalovirus (hCMV) is a leading cause of birth defects and severe
disease in people with compromised immunity. Disease caused by hCMV is
frequently linked to inflammation, and the virus has been shown to induce
numerous host genes many of which encod... | Human cytomegalovirus (hCMV), the prototypical β-herpesvirus, is an extremely
widespread pathogen (reviewed in [1]). Primary hCMV infection is invariably followed by
life-long viral persistence in all infected individuals. The groups most evidently
affected by hCMV diseas... |
10.1371/journal.pcbi.1007205 | Bayesian hypothesis testing and experimental design for two-photon imaging data | Variability, stochastic or otherwise, is a central feature of neural activity. Yet the means by which estimates of variation and uncertainty are derived from noisy observations of neural activity is often heuristic, with more weight given to numerical convenience than statistical rigour. For two-photon imaging data, co... | There are many sources of noise in recordings of neural activity, and the first challenge in neural data analysis is to separate this noise from experimentally relevant variation. This is particularly problematic for two-photon imaging data. Two-photon imaging uses fluorescent indicators to measure changes in the conce... | Over the last two decades, two-photon (2P) imaging has become one of the premier tools for studying coding in neural systems from the population level down to individual neural compartments [1]. The resulting data is highly variable due to the inherent variability of neurons and technical sources of noise in the imagin... |
10.1371/journal.ppat.1003889 | Detection of Host-Derived Sphingosine by Pseudomonas aeruginosa Is Important for Survival in the Murine Lung | Pseudomonas aeruginosa is a common environmental bacterium that is also a significant opportunistic pathogen, particularly of the human lung. We must understand how P. aeruginosa responds to the lung environment in order to identify the regulatory changes that bacteria use to establish and maintain infections. The P. a... | Many opportunistic pathogens transition from an environmental niche into the host. To establish an infection, these bacteria must rapidly adapt their transcriptional profile to the conditions at the site of infection. We used the response of Pseudomonas aeruginosa to lung surfactant as a model to discover genes importa... | Pseudomonas aeruginosa is a common, Gram negative, environmental bacterium that can cause significant disease as an opportunistic pathogen, particularly in the lung. P. aeruginosa lung infections are prevalent in people with cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), as well as individuals u... |
10.1371/journal.pgen.1004006 | Multi-tissue Analysis of Co-expression Networks by Higher-Order Generalized Singular Value Decomposition Identifies Functionally Coherent Transcriptional Modules | Recent high-throughput efforts such as ENCODE have generated a large body of genome-scale transcriptional data in multiple conditions (e.g., cell-types and disease states). Leveraging these data is especially important for network-based approaches to human disease, for instance to identify coherent transcriptional modu... | Complex biological interactions and processes can be modelled as networks, for instance metabolic pathways or protein-protein interactions. The growing availability of large high-throughput data in several experimental conditions now permits the full-scale analysis of biological interactions and processes. However, no ... | The increasingly cheaper and rapid accumulation of large -omics datasets across several experimental conditions has prompted generation of a wealth of data on biological networks. This growth of network data now permits their large scale applications to biomedical research, including analysis of gene function, metaboli... |
10.1371/journal.ppat.1006696 | Natural killer cell-intrinsic type I IFN signaling controls Klebsiella pneumoniae growth during lung infection | Klebsiella pneumoniae is a significant cause of nosocomial pneumonia and an alarming pathogen owing to the recent isolation of multidrug resistant strains. Understanding of immune responses orchestrating K. pneumoniae clearance by the host is of utmost importance. Here we show that type I interferon (IFN) signaling pro... | The isolation of multidrug-resistant Klebsiella pneumoniae strains has significantly narrowed, or in some settings completely removed, the therapeutic options for the treatment of Klebsiella infections. Therapies targeting the immune system rather than the pathogen represent important alternatives. Despite the clinical... | Klebsiella pneumoniae is a capsulated Gram negative pathogen which causes a wide range of infectious diseases, from urinary tract infections to pneumonia, the latter being particularly devastating among immunocompromised patients [1]. Of particular concern is the increasing isolation of multidrug resistant strains that... |
10.1371/journal.pgen.1007822 | De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders | Congenital diaphragmatic hernia (CDH) is a severe birth defect that is often accompanied by other congenital anomalies. Previous exome sequencing studies for CDH have supported a role of de novo damaging variants but did not identify any recurrently mutated genes. To investigate further the genetics of CDH, we analyzed... | Congenital diaphragmatic hernia (CDH) is a life-threatening condition affecting about 1 every 3000 newborns. Although the role of genetics in the pathogenesis of CDH has been well established, only a handful of disease genes have been identified so far. We and other have previously shown that de novo variants, those ca... | Congenital diaphragmatic hernia (CDH) is a severe developmental disorder affecting 1 in 3000 live births [1, 2]. It is characterized by defects in diaphragm that allow the abdominal viscera to move into the thoracic cavity and is associated with pulmonary hypoplasia and in some cases pulmonary hypertension. CDH can be ... |
10.1371/journal.pcbi.1000855 | Organization of Cellular Receptors into a Nanoscale Junction during HIV-1 Adhesion | The fusion of the human immunodeficiency virus type 1 (HIV-1) with its host cell is the target for new antiretroviral therapies. Viral particles interact with the flexible plasma membrane via viral surface protein gp120 which binds its primary cellular receptor CD4 and subsequently the coreceptor CCR5. However, whether... | The entry of human immunodeficiency virus (HIV) into cells is the target for new therapies preventing HIV infection. While intermediate steps of viral entry have been characterized, the progression between these steps and how they result in productive infection are not well understood. By using stochastic modeling, we ... | Strategies for antiretroviral therapy have recently focused on inhibiting human immunodeficiency virus (HIV) adhesion, fusion, and entry. The biochemical properties of the dynamic binding interactions between host cell and viral receptors have been well characterized [1], [2]. However, how these interactions may work t... |
10.1371/journal.pntd.0001012 | Collagenolytic Activities of the Major Secreted Cathepsin L Peptidases Involved in the Virulence of the Helminth Pathogen, Fasciola hepatica | The temporal expression and secretion of distinct members of a family of virulence-associated cathepsin L cysteine peptidases (FhCL) correlates with the entry and migration of the helminth pathogen Fasciola hepatica in the host. Thus, infective larvae traversing the gut wall secrete cathepsin L3 (FhCL3), liver migratin... | Fasciola hepatica is a helminth parasite that causes liver fluke disease (fasciolosis) in domestic animals (sheep and cattle) and humans worldwide. In order to infect their mammalian hosts, F. hepatica larvae must penetrate and traverse the intestinal wall of the duodenum, move through the peritoneum and penetrate the ... | Papain-like cysteine peptidases, including cathepsins B and L, are ubiquitously secreted extracorporeally by helminth parasites of human and veterinary importance where they perform many important roles that are critical to the development and survival of the parasite within the mammalian host [1]. These roles include ... |
10.1371/journal.pntd.0005624 | Radiological evolution of porcine neurocysticercosis after combined antiparasitic treatment with praziquantel and albendazole | The onset of anthelmintic treatment of neurocysticercosis (NCC) provokes an acute immune response of the host, which in human cases is associated with exacerbation of neurological symptoms. This inflammation can occur at the first days of therapy. So, changes in the brain cysts appearance may be detected by medical ima... | Neurocysticercosis (NCC) is a frequent parasitic infection of the human brain and the most common cause of adult onset epilepsy in developing countries. Acute inflammatory response in NCC plays an important role in the pathogenesis of symptoms by anthelminitic therapies. The anthelmintic recommended therapy for NCC has... | Neurocysticercosis (NCC) is a neurological parasitic disease caused by the infection of the brain by the larval stage of Taenia solium [1]. NCC represents a serious and persisting public health problem because it is the most frequent cause of late-onset seizures in developing countries [1, 2].
Treatment with anthelmin... |
10.1371/journal.ppat.1006738 | RIG-I-like receptor activation by dengue virus drives follicular T helper cell formation and antibody production | Follicular T helper cells (TFH) are fundamental in orchestrating effective antibody-mediated responses critical for immunity against viral infections and effective vaccines. However, it is unclear how virus infection leads to TFH induction. We here show that dengue virus (DENV) infection of human dendritic cells (DCs) ... | Strong antibody production is critical for effective immune responses against viral infections and is a primary factor in the development of successful vaccines. However, it is unclear how virus infection leads to effective antibody responses. Dengue virus (DENV) is known to induce potent antibody production, although ... | Dengue virus is a global mosquito-transmitted pathogen that infects 400 mln people annually [1]. The majority of patients experience only mild fever, but the disease can progress to life-threatening dengue shock syndrome and dengue hemorrhagic fever. With no specific antivirals or effective vaccine available there is u... |
10.1371/journal.pcbi.1006633 | Deep image reconstruction from human brain activity | The mental contents of perception and imagery are thought to be encoded in hierarchical representations in the brain, but previous attempts to visualize perceptual contents have failed to capitalize on multiple levels of the hierarchy, leaving it challenging to reconstruct internal imagery. Recent work showed that visu... | Machine learning-based analysis of human functional magnetic resonance imaging (fMRI) patterns has enabled the visualization of perceptual content. However, prior work visualizing perceptual contents from brain activity has failed to combine visual information of multiple hierarchical levels. Here, we present a method ... | While the externalization of states of the mind is a long-standing theme in science fiction, it is only recently that the advent of machine learning-based analysis of functional magnetic resonance imaging (fMRI) data has expanded its potential in the real world. Although sophisticated decoding and encoding models have ... |
10.1371/journal.pgen.1007693 | Non-proteolytic activity of 19S proteasome subunit RPT-6 regulates GATA transcription during response to infection | GATA transcription factors play a crucial role in the regulation of immune functions across metazoans. In Caenorhabditis elegans, the GATA transcription factor ELT-2 is involved in the control of not only infections but also recovery after an infection. We identified RPT-6, part of the 19S proteasome subunit, as an ELT... | The conserved GATA transcription factor ELT-2 plays an important role in the control of genes required for both defense and recovery from infection. We show that RPT-6, a component of the 19S subunit, physically interacts with ELT-2 in vivo, controlling the expression of ELT-2-dependent genes and the response of the ne... | The regulation of gene transcription plays crucial roles in the control of an array of critical biological processes, including immune responses against microbial infections [1,2]. At the heart of immune activation are transcription factors, which directly bind to specific DNA motifs in promoter regions to control gene... |
10.1371/journal.pntd.0000287 | Landscape Composition and Spatial Prediction of Alveolar Echinococcosis in Southern Ningxia, China | Alveolar echinococcosis (AE) presents a serious public health challenge within China. Mass screening ultrasound surveys can detect pre-symptomatic AE, but targeting areas identified from hospital records is inefficient regarding AE. Prediction of undetected or emerging hotspots would increase detection rates. Voles and... | In humans, larvae of the fox tapeworm Echinococcus multilocularis typically infect the liver where metastasis, calcification and necrosis cause the zoonotic disease alveolar echinococcosis (AE). Treatment is difficult. Early detection greatly increases patient life expectancy but under-detection is a problem. Understan... | Biological mechanisms known to affect space-time dynamics of infectious diseases include: habitat changes affecting vector breeding sites or reservoir host distributions; niche invasion; biodiversity change including keystone predator loss and rapid magnitudinal increases in reservoir host populations; genetic change i... |
10.1371/journal.ppat.1003051 | GABAergic Signaling Is Linked to a Hypermigratory Phenotype in Dendritic Cells Infected by Toxoplasma gondii | During acute infection in human and animal hosts, the obligate intracellular protozoan Toxoplasma gondii infects a variety of cell types, including leukocytes. Poised to respond to invading pathogens, dendritic cells (DC) may also be exploited by T. gondii for spread in the infected host. Here, we report that human and... | Toxoplasma gondii is an obligate intracellular protozoan parasite and an important food- and water-borne human and veterinary pathogen. Toxoplasmosis is normally self-limiting but severe manifestations occur upon congenital transmission to the developing fetus or during infection in immune-compromised individuals. Toxo... | Toxoplasma gondii is an obligate intracellular parasite that infects warm-blooded vertebrates. It infects approximately 25% of the global human population [1]. Initial infection occurs orally or congenitally, whereby the formed tachyzoite stages disseminate widely in the organism. Although principally asymptomatic in h... |
10.1371/journal.ppat.1002365 | Single Molecule Analysis of Replicated DNA Reveals the Usage of Multiple KSHV Genome Regions for Latent Replication | Kaposi's sarcoma associated herpesvirus (KSHV), an etiologic agent of Kaposi's sarcoma, Body Cavity Based Lymphoma and Multicentric Castleman's Disease, establishes lifelong latency in infected cells. The KSHV genome tethers to the host chromosome with the help of a latency associated nuclear antigen (LANA). Additional... | Kaposi's sarcoma associated herpesvirus (KSHV) establishes lifelong infection in the infected host and induces lymphoproliferative diseases, body cavity based lymphomas and sarcomas in immune compromised individuals. Herpesviruses including KSHV uses host cellular replication machinery for the replication of their geno... | Kaposi's sarcoma associated herpesvirus, also referred to as human herpesvirus 8 (HHV8), belongs to the gammaherpesvirus family and is associated with multiple lymphoproliferative diseases including Body Cavity Based Lymphomas (BCBLs) and Multicentric Castleman's Disease (MCDs) [1], [2], [3]. KSHV, like other herpesvir... |
10.1371/journal.ppat.1000633 | The HIV Envelope but Not VSV Glycoprotein Is Capable of Mediating HIV Latent Infection of Resting CD4 T Cells | HIV fusion and entry into CD4 T cells are mediated by two receptors, CD4 and CXCR4. This receptor requirement can be abrogated by pseudotyping the virion with the vesicular stomatitis virus glycoprotein (VSV-G) that mediates viral entry through endocytosis. The VSV-G-pseudotyped HIV is highly infectious for transformed... | While receptor-mediated viral endocytosis or fusion with the cell membrane can be achieved through multiple surface molecules, the repetitious selection of two chemokine receptors, CCR5 or CXCR4, as the main HIV entry coreceptor implies an urgent viral need to exploit the chemotactic process in the immune system. Cytos... | Binding of the HIV envelope to its receptors, CD4 and the chemokine coreceptor, CCR5 or CXCR4, triggers sequential fusion and entry events [1],[2],[3],[4]. Fusion is believed to occur directly at the plasma membrane [5],[6],[7],[8],[9], but fusion in endosomes has also been proposed recently [10]. It has been known tha... |
10.1371/journal.pmed.1002305 | Impact evaluation of different cash-based intervention modalities on child and maternal nutritional status in Sindh Province, Pakistan, at 6 mo and at 1 y: A cluster randomised controlled trial | Cash-based interventions (CBIs), offer an interesting opportunity to prevent increases in wasting in humanitarian aid settings. However, questions remain as to the impact of CBIs on nutritional status and, therefore, how to incorporate them into emergency programmes to maximise their success in terms of improved nutrit... | Cash-based interventions (CBIs) are being increasingly used during humanitarian emergencies as an alternative to food-based interventions to prevent wasting.
However, due to the lack of evidence available on the impact of CBIs in these settings, it is unclear what are the best ways to implement them.
There is a lack of... | The current global estimate of wasting prevalence is 7.4%, affecting approximately 50 million children under the age of 5 y annually [1]. The World Health Assembly (WHA) 2025 target to reduce and maintain childhood wasting at 5% is unlikely to be met [1]. Globally, attention to child and maternal undernutrition is very... |
10.1371/journal.ppat.1003408 | The Systemic Immune State of Super-shedder Mice Is Characterized by a Unique Neutrophil-dependent Blunting of TH1 Responses | Host-to-host transmission of a pathogen ensures its successful propagation and maintenance within a host population. A striking feature of disease transmission is the heterogeneity in host infectiousness. It has been proposed that within a host population, 20% of the infected hosts, termed super-shedders, are responsib... | Bacteria belonging to the genus Salmonella are capable of causing long-term chronic systemic infections in specific hosts where they are shed in the feces. These persistently infected individuals include typhoid carriers and they serve as a reservoir for disease transmission. Despite the importance of Salmonella as a h... | Host-adapted pathogens depend on their host for transmission and dissemination within a population. Recent epidemiological studies have uncovered heterogeneities in infection wherein a minority of the infected individuals (20%) are responsible for the majority of the infections (80%), described as the 80/20 rule [1]. I... |
10.1371/journal.pntd.0001355 | Life Quality Impairment Caused by Hookworm-Related Cutaneous Larva Migrans in Resource-Poor Communities in Manaus, Brazil | Hookworm-related cutaneous larva migrans (CLM) is a common but neglected tropical skin disease caused by the migration of animal hookworm larvae in the epidermis. The disease causes intense pruritus and is associated with important morbidity. The extent to which CLM impairs skin disease-associated life quality has neve... | Hookworm-related cutaneous larva migrans (CLM) is a parasitic skin disease common in developing countries with hot climates. In resource-poor settings, CLM is associated with considerable morbidity. The disease is caused by animal hookworm larvae that penetrate the skin and migrate aimlessly in the epidermis as they ca... | Hookworm-related cutaneous larva migrans (CLM) is a parasitic skin disease caused by the migration of animal hookworm larvae such as Ancylostoma braziliense, A. caninum or Uncinaria stenocephala in the epidermis. The infection occurs when third-stage larvae come into contact with human skin and penetrate into the epide... |
10.1371/journal.pntd.0004963 | Live Attenuated Leishmania donovani Centrin Knock Out Parasites Generate Non-inferior Protective Immune Response in Aged Mice against Visceral Leishmaniasis | Visceral leishmaniasis (VL) caused by the protozoan parasite Leishmania donovani causes severe disease. Age appears to be critical in determining the clinical outcome of VL and at present there is no effective vaccine available against VL for any age group. Previously, we showed that genetically modified live attenuate... | Visceral leishmaniasis (VL) is caused by the protozoan parasite Leishmania donovani. There is no effective vaccine available against VL for any age group and importantly, there are no previous studies regarding immune responses against experimental Leishmania vaccines tested in aged animals. We have reported earlier th... | Visceral leishmaniasis caused by the protozoan parasite, Leishmania donovani, is fatal when left untreated. Epidemiological studies show that more than 90% of VL infections are concentrated in five countries viz, India, Brazil, Bangladesh, Nepal, and Sudan [1]. According to the World Health Organization report, Leishma... |
10.1371/journal.pgen.1006155 | Complex Ancestries of Lager-Brewing Hybrids Were Shaped by Standing Variation in the Wild Yeast Saccharomyces eubayanus | Lager-style beers constitute the vast majority of the beer market, and yet, the genetic origin of the yeast strains that brew them has been shrouded in mystery and controversy. Unlike ale-style beers, which are generally brewed with Saccharomyces cerevisiae, lagers are brewed at colder temperatures with allopolyploid h... | Yeasts are key industrial microbes, most notably Saccharomyces cerevisiae, which is used to make a variety of products, including bread, wine, and ale-style beers. However, lager-style beers are brewed with interspecies hybrids of S. cerevisiae x Saccharomyces eubayanus. After its discovery in South America in 2011, ra... | Humans changed from living in hunter-gatherer societies to agricultural societies in part through the domestication of animals and plants [1,2]. At the same time, humans began unwittingly domesticating microorganisms for the production of fermented beverages and foods, but the underlying source populations and genetic ... |
10.1371/journal.ppat.1003490 | CD40 Activation Rescues Antiviral CD8+ T Cells from PD-1-Mediated Exhaustion | The intrahepatic immune environment is normally biased towards tolerance. Nonetheless, effective antiviral immune responses can be induced against hepatotropic pathogens. To examine the immunological basis of this paradox we studied the ability of hepatocellularly expressed hepatitis B virus (HBV) to activate immunolog... | Hepatitis B virus (HBV) infection is responsible for more than 500,000 deaths annually as a result of the immune-mediated chronic liver damage it induces. The HBV specific CD8+ T cell response contributes to the pathogenesis of liver disease and viral clearance, and the failure to induce and/or sustain a vigorous CD8+ ... | Rapid clonal expansion of CD8+ T cells in response to antigenic challenge is a hallmark of adaptive immunity and a crucial element of host defense. Activation and differentiation of T cells are largely determined by their initial encounter with antigen-presenting cells (APCs), and the resultant responses range from ful... |
10.1371/journal.pmed.1002811 | Retention and viral suppression in a cohort of HIV patients on antiretroviral therapy in Zambia: Regionally representative estimates using a multistage-sampling-based approach | Although the success of HIV treatment programs depends on retention and viral suppression, routine program monitoring of these outcomes may be incomplete. We used data from the national electronic medical record (EMR) system in Zambia to enumerate a large and regionally representative cohort of patients on treatment. W... | Retention and HIV RNA suppression in HIV treatment programs represent critical metrics of success, but regionally representative estimates in longitudinal cohorts remain uncommon.
Most treatment programs, whether at the national or sub-national level, lack data systems able to capture patient movement across facilities... | Assessments of retention and HIV RNA suppression levels after HIV treatment initiation in routine program settings represent the backbone of data-driven public health efforts to bring the epidemic under control. As HIV treatment reaches more patients in the era of test-and-treat, the remaining gaps in the cascade are l... |
10.1371/journal.ppat.1000766 | IFN-α-Induced Upregulation of CCR5 Leads to Expanded HIV Tropism In Vivo | Chronic immune activation and inflammation (e.g., as manifest by production of type I interferons) are major determinants of disease progression in primate lentivirus infections. To investigate the impact of such activation on intrathymic T-cell production, we studied infection of the human thymus implants of SCID-hu T... | Human immunodeficiency virus (HIV), a lentivirus, is the causative agent of AIDS. Chronic immune activation and inflammation are major determinants of disease progression in primate lentivirus infections and are associated with the production of type I interferon. To investigate the impact of type I interferon on HIV i... | HIV disease progression is marked by chronic immune activation associated with accelerated destruction of T cells in the periphery and diminished production of new T cells from progenitors in the thymus and elsewhere [1],[2]. Although the detection of X4 HIV as the predominant viral species in peripheral blood is clear... |
10.1371/journal.pntd.0003080 | Cytokine Responses to Schistosoma mansoni and Schistosoma haematobium in Relation to Infection in a Co-endemic Focus in Northern Senegal | In Africa, many areas are co-endemic for the two major Schistosoma species, S. mansoni and S. haematobium. Epidemiological studies have suggested that host immunological factors may play an important role in co-endemic areas. As yet, little is known about differences in host immune responses and possible immunological ... | In the developing world, over 207 million people are infected with blood-dwelling parasitic Schistosoma worms. Schistosoma haematobium and S. mansoni are the most widespread species. In Africa, they often occur together in the same area, with many people carrying both species. Yet, little is known about the differences... | Schistosomiasis is a parasitic disease of major public health importance. Schistosoma mansoni and S. haematobium are the main human species. Both species are endemic in Africa, where their distributions show a great overlap [1]. Schistosomes are known to down-regulate host immune responses and to induce so-called modif... |
10.1371/journal.pgen.1003841 | Whole Genome Sequencing Identifies a Deletion in Protein Phosphatase 2A That Affects Its Stability and Localization in Chlamydomonas reinhardtii | Whole genome sequencing is a powerful tool in the discovery of single nucleotide polymorphisms (SNPs) and small insertions/deletions (indels) among mutant strains, which simplifies forward genetics approaches. However, identification of the causative mutation among a large number of non-causative SNPs in a mutant strai... | Whole genome sequencing is a powerful tool to detect changes in genomic DNA. However, how to identify a causative mutation from over 20,000 changes remains a big challenge. For the unicellular green alga Chlamydomonas, we built a library that consists of over 2 million changes from 16 strains. A comparison of changes f... | Forward genetics allows the identification of mutants with phenotypes of interest and the mechanistic understanding of biological processes [1], [2]. While gene lesions generated by insertional mutagenesis can be identified by Southern blot analysis [3]–[6] or PCR-based approaches [7]–[9], identification of mutations i... |
10.1371/journal.pntd.0002001 | Field Cage Studies and Progressive Evaluation of Genetically-Engineered Mosquitoes | A genetically-engineered strain of the dengue mosquito vector Aedes aegypti, designated OX3604C, was evaluated in large outdoor cage trials for its potential to improve dengue prevention efforts by inducing population suppression. OX3604C is engineered with a repressible genetic construct that causes a female-specific ... | The absence of a commercially-available dengue vaccine or anti-viral drug makes control of Aedes aegypti, the principal dengue mosquito vector, the only available method to prevent this disease. Sustained, effective application of vector control, however, has been difficult and this led to the call for innovative strat... | The recent worldwide increase in dengue [1], [2] has made urgent the development and assessment of new tools for controlling the disease [3]. Because no vaccines or drugs are commercially available [4], [5], mosquito vector control by insecticides, insect growth regulators and larval development site elimination (sourc... |
10.1371/journal.pbio.0060178 | Proteomics Reveals Novel Drosophila Seminal Fluid Proteins Transferred at Mating | Across diverse taxa, seminal fluid proteins (Sfps) transferred at mating affect the reproductive success of both sexes. Such reproductive proteins often evolve under positive selection between species; because of this rapid divergence, Sfps are hypothesized to play a role in speciation by contributing to reproductive i... | Across many species, males transfer both sperm and seminal proteins to their mates. These proteins increase male reproductive success by improving sperm competitive ability and modifying female behavior. In Drosophila, seminal proteins increase female rates of egg-laying and sperm storage and reduce a female's willingn... | In addition to sperm, males of many internally fertilizing species transfer seminal fluid proteins (Sfps) to their mates during copulation. These proteins function in a variety of reproductive processes, including sperm capacitation, sperm storage and competition, and fertilization, and in some cases they affect female... |
10.1371/journal.pntd.0000127 | Quantitative High-Throughput Screen Identifies Inhibitors of the Schistosoma mansoni Redox Cascade | Schistosomiasis is a tropical disease associated with high morbidity and mortality, currently affecting over 200 million people worldwide. Praziquantel is the only drug used to treat the disease, and with its increased use the probability of developing drug resistance has grown significantly. The Schistosoma parasites ... | Schistosomiasis, also known as bilharzia, is a tropical disease associated with high morbidity and mortality, currently affecting over 200 million people worldwide. Praziquantel is the only drug used to treat the disease, and with its increased use the probability of developing resistance has grown significantly. The S... | Schistosomiasis, also known as bilharzia, a debilitating disease resulting from the infection by the trematode parasite Schistosoma ssp. (S. mansoni, S. mekongi, S. japonicum, S. haematobium, and S. intercalatum) currently affects over 200 million people worldwide, mostly in developing countries [1]. A large percentage... |
10.1371/journal.pmed.1002316 | Risk of hospitalization with neurodegenerative disease after moderate-to-severe traumatic brain injury in the working-age population: A retrospective cohort study using the Finnish national health registries | Previous epidemiological studies suggest that working-aged persons with a history of moderate-to-severe traumatic brain injury (TBI) may have an increased risk for developing neurodegenerative disease (NDD) while persons with a history of mild TBI do not. In this comprehensive nationwide study in Finland, we assessed t... | Traumatic brain injury is a leading cause of death and disability worldwide, especially among young adults.
Previous studies on the association between traumatic brain injury and neurodegenerative diseases have controversial findings. Furthermore, association studies with a long follow-up time are scarce.
We conducted ... | Traumatic brain injury (TBI) is a globally increasing healthcare problem, affecting persons of all ages [1]. Following the early phases of TBI, patients face a significant risk of long-term disability and neurological morbidity [2]. Previous epidemiological studies have found an association between history of TBI and r... |
10.1371/journal.pntd.0005420 | Single locus genotyping to track Leishmania donovani in the Indian subcontinent: Application in Nepal | We designed a straightforward method for discriminating circulating Leishmania populations in the Indian subcontinent (ISC). Research on transmission dynamics of visceral leishmaniasis (VL, or Kala-azar) was recently identified as one of the key research priorities for elimination of the disease in the ISC. VL in Bangl... | Visceral Leishmaniasis (VL) or Kala-azar is a life-threatening neglected tropical disease that annually affects half a million people worldwide. In the Indian subcontinent (India, Nepal, Bangladesh), the disease is caused by infection with the protozoan parasite Leishmania donovani, which is transmitted by female sand ... | Visceral Leishmaniasis (VL) is a neglected tropical disease caused by parasites of the Leishmania donovani species complex, which are transmitted by the bite of phlebotomine sand flies. WHO estimates that annually, 300 million people worldwide are at risk of VL [1]. In the Indian subcontinent (ISC), including Banglades... |
10.1371/journal.ppat.1000855 | A Timescale for Evolution, Population Expansion, and Spatial Spread of an Emerging Clone of Methicillin-Resistant Staphylococcus aureus | Due to the lack of fossil evidence, the timescales of bacterial evolution are largely unknown. The speed with which genetic change accumulates in populations of pathogenic bacteria, however, is a key parameter that is crucial for understanding the emergence of traits such as increased virulence or antibiotic resistance... | Because fossils of bacteria do not exist or are morphologically indeterminate, the timescales of bacterial evolution are widely unknown. We have investigated the short-term evolution of a particular strain of methicillin-resistant Staphylococcus aureus (MRSA), a notorious cause of hospital-associated infections. By com... | Clinical microbiologists have frequently been astonished by the impressive capability of pathogenic bacteria to acquire novel traits such as antimicrobial resistance. However, the actual speed at which nucleotide substitutions, entire genes, or complex mobile genetic elements are gained and lost in bacterial population... |
10.1371/journal.pntd.0001909 | Application of PCR in Serum Samples for Diagnosis of Paracoccidioidomycosis in the Southern Bahia-Brazil | Paracoccidioidomycosis (PCM) cannot always be diagnosed by conventional means such as direct examination of histopathology or clinical samples, and serological methods, used as an alternative, still have many cases of cross-reactivity. In this scenario, molecular techniques seem to arise as a rapid approach, specific a... | Paracoccidioidomycosis (PCM) has been included in such diseases neglected since this impact on public health have not been measured. Except in the South and Southeast of Brazil, there are no government programs for this mycosis. After 100 years of discovery of the disease there is the need to deploy an effective and co... | Paracoccidioidomycosis (PCM) is a deep mycosis caused by the thermo-dimorphic fungus Paracoccidioides brasiliensis, endemic in some countries of Latin America, mainly in Brazil [1]. In this disease, the fungus can remain confined in the lungs, the primary focus of infection, or spread to other organs and tissues, resul... |
10.1371/journal.pbio.1001493 | Mechanistic Insights Revealed by the Crystal Structure of a Histidine Kinase with Signal Transducer and Sensor Domains | Two-component systems (TCSs) are important for the adaptation and survival of bacteria and fungi under stress conditions. A TCS is often composed of a membrane-bound sensor histidine kinase (SK) and a response regulator (RR), which are relayed through sequential phosphorylation steps. However, the mechanism for how an ... | Two-component signal transduction systems (TCSs) are promising targets for new antimicrobial research because they help bacteria and fungi adapt and survive. One of the main components of TCSs is a sensor histidine kinase (SK), which relays extracellular signals to intracellular pathways. Despite intensive research, a ... | Protein phosphorylation is an essential signal carrier. Bacteria respond to transient living environments through transmembrane-integrated sensor histidine kinases (SKs), which act in concert with their intracellular cognate response regulators (RRs) to elicit necessary adaptive responses that are critical for their su... |
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