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10.1371/journal.pcbi.1000921 | Is Protein Folding Sub-Diffusive? | Protein folding dynamics is often described as diffusion on a free energy surface considered as a function of one or few reaction coordinates. However, a growing number of experiments and models show that, when projected onto a reaction coordinate, protein dynamics is sub-diffusive. This raises the question as to wheth... | To understand dynamics of complex systems with many degrees of freedom, one often projects it onto one or several collective variables. Protein folding, the complex, concerted motion of a protein chain towards a unique three-dimensional structure, is one example of where such reduction of complexity is useful. It is us... | A free energy surface (FES) projected onto one or a small number of coordinates is often used to describe the equilibrium and kinetic properties of complex systems with a very large number (100 to 1,000 or more) of degrees of freedom. Studies of protein folding are an important case where this type of projected surface... |
10.1371/journal.pgen.1003168 | Approaching the Functional Annotation of Fungal Virulence Factors Using Cross-Species Genetic Interaction Profiling | In many human fungal pathogens, genes required for disease remain largely unannotated, limiting the impact of virulence gene discovery efforts. We tested the utility of a cross-species genetic interaction profiling approach to obtain clues to the molecular function of unannotated pathogenicity factors in the human path... | HIV/AIDS patients, cancer chemotherapy patients, and organ transplant recipients are highly susceptible to infection by opportunistic fungal pathogens, organisms common in the environment that are harmless to normal individuals. Understanding how these pathogens cause disease requires the identification of genes requir... | Diseases produced by fungal infections are challenging to diagnose and treat, making these infections a major cause of morbidity and mortality worldwide [1], [2]. Genetics and genomics have led to the identification of numerous pathogen genes required for replication in the mammalian host [3]–[7]. Unfortunately, many, ... |
10.1371/journal.pbio.2004644 | Effective polyploidy causes phenotypic delay and influences bacterial evolvability | Whether mutations in bacteria exhibit a noticeable delay before expressing their corresponding mutant phenotype was discussed intensively in the 1940s to 1950s, but the discussion eventually waned for lack of supportive evidence and perceived incompatibility with observed mutant distributions in fluctuation tests. Phen... | What is the time delay between the occurrence of a genetic mutation in a bacterial cell and manifestation of its phenotypic effect? We show that antibiotic resistance mutations in Escherichia coli show a remarkably long phenotypic delay of three to four bacterial generations. The primary underlying mechanism of this de... | As genetic mutations appear on the DNA, their effects must first transcend the RNA and protein levels before resulting in an altered phenotype. This so-called “phenotypic delay” in the expression of new mutations could have major implications for evolutionary adaptation, particularly if selection pressures change on a ... |
10.1371/journal.pbio.0060191 | TSCOT + Thymic Epithelial Cell-Mediated Sensitive CD4 Tolerance by Direct Presentation | Although much effort has been directed at dissecting the mechanisms of central tolerance, the role of thymic stromal cells remains elusive. In order to further characterize this event, we developed a mouse model restricting LacZ to thymic stromal cotransporter (TSCOT)-expressing thymic stromal cells (TDLacZ). The thymu... | T cells play critical roles in the immune response. While developing in the thymus (from whence T cells and their precursors, thymocytes, derive their name), thymocytes are selected for the ability to recognize harmful antigen (positive selection), while those that respond to antigens present in their own body are elim... | T cell tolerance is established mainly in the thymus where the T cell population develops and learns by a process called negative selection to avoid harmful reactivity against self-antigens expressed in that thymus (reviewed in [1,2]). In the periphery, organ-specific tolerance can be established by various other mecha... |
10.1371/journal.pbio.1000072 | Mammalian Kinesin-3 Motors Are Dimeric In Vivo and Move by Processive Motility upon Release of Autoinhibition | Kinesin-3 motors drive the transport of synaptic vesicles and other membrane-bound organelles in neuronal cells. In the absence of cargo, kinesin motors are kept inactive to prevent motility and ATP hydrolysis. Current models state that the Kinesin-3 motor KIF1A is monomeric in the inactive state and that activation re... | Molecular motors transport a wide variety of cellular cargoes that are important for diverse cellular phenomena such as mitosis, polarity, motility, and secretion. Motor activity must be tightly regulated to ensure that ATP hydrolysis and processive motility occur only upon coupling to the correct cargo. In neuronal ce... | Kinesin motors drive the long-distance transport of membrane-bound cargoes along microtubules. Long-distance transport is particularly important in neuronal cells whose length and polarity require robust sorting and transport of cargoes to pre- and postsynaptic destinations. Transport of synaptic vesicle precursors to ... |
10.1371/journal.pntd.0007724 | Effect of insecticide-treated bed nets on visceral leishmaniasis incidence in Bangladesh. A retrospective cohort analysis | Visceral leishmaniasis (VL) is a parasitic disease, transmitted by the sand fly species Phlebotomus argentipes in the Indian sub-continent. Effective vector control is highly desirable to reduce vector density and human and vector contact in the endemic communities with the aim to curtail disease transmission. We evalu... | Visceral leishmaniasis (VL) is a deadly parasitic disease, transmitted by the sand fly species Phlebotomus argentipes in the Indian sub-continent. Humans are the only proven reservoir of the parasite, Leishmania donovani. Effective vector control is highly desirable to reduce vector density and human and vector contact... | Visceral leishmaniasis (VL)—also known as kala-azar (KA) in the Indian sub-continent—is a deadly parasitic disease transmitted by the female Phlebotomus argentipes sand fly. In the South-East Asia Region, humans are the only proven reservoir of the parasite, Leishmania donovani. Kala-azar has been present in the Bengal... |
10.1371/journal.ppat.1002413 | Norovirus Regulation of the Innate Immune Response and Apoptosis Occurs via the Product of the Alternative Open Reading Frame 4 | Small RNA viruses have evolved many mechanisms to increase the capacity of their short genomes. Here we describe the identification and characterization of a novel open reading frame (ORF4) encoded by the murine norovirus (MNV) subgenomic RNA, in an alternative reading frame overlapping the VP1 coding region. ORF4 is t... | This report describes the identification and characterization of a novel protein of unknown function encoded by a mouse virus genetically similar to human noroviruses. This gene is unique to the mouse virus and occupies the same part of the genome that codes for the major capsid protein. The protein that we have descri... | Collectively, the innate and adaptive immune systems result in a strong evolutionary pressure on pathogens to develop countermeasures to allow their continued existence. Therefore pathogens, including viruses, have evolved a multitude of mechanisms for evading the host response to infection, often by the expression of ... |
10.1371/journal.pgen.1006808 | Impact of mutations in Toll-like receptor pathway genes on esophageal carcinogenesis | Esophageal adenocarcinoma (EAC) develops in an inflammatory microenvironment with reduced microbial diversity, but mechanisms for these influences remain poorly characterized. We hypothesized that mutations targeting the Toll-like receptor (TLR) pathway could disrupt innate immune signaling and promote a microenvironme... | Esophageal adenocarcinoma (EAC) is a deadly human cancer that develops in the lower esophagus, which is exposed to reflux of acidic stomach contents and has reduced microbial diversity. Next generation sequencing studies have shown that accumulation of somatic mutations occurs along the metaplasia–dysplasia–carcinoma s... | Esophageal adenocarcinoma (EAC) is increasing in incidence and has poor survival outcomes. The main risk factor for EAC is Barrett’s esophagus, a pre-malignant glandular epithelium that develops in the setting of gastro-esophageal reflux disease. Over time exposure to refluxed acid and bile in the lower esophagus leads... |
10.1371/journal.pcbi.1000901 | Similar Impact of CD8+ T Cell Responses on Early Virus Dynamics during SIV Infections of Rhesus Macaques and Sooty Mangabeys | Despite comparable levels of virus replication, simian immunodeficiency viruses (SIV) infection is non-pathogenic in natural hosts, such as sooty mangabeys (SM), whereas it is pathogenic in non-natural hosts, such as rhesus macaques (RM). Comparative studies of pathogenic and non-pathogenic SIV infection can thus shed ... | Simian immunodeficiency viruses (SIV) are typically non-pathogenic in their natural hosts. However, if the same virus infects a non-natural host it often leads to AIDS-like symptoms. Therefore, comparing SIV infections in these two types of host might help explain the pathogenesis of SIV in non-natural hosts and thereb... | The simian immunodeficiency virus (SIV) occurs as a natural infection in several Old-world monkey species, such as sooty mangabeys (SM) or African green monkeys [1], [2]. In striking contrast to HIV infection of humans, SIV infection does not cause disease in natural hosts. The levels of virus replication, however, are... |
10.1371/journal.pntd.0007216 | Determinants for progression from asymptomatic infection to symptomatic visceral leishmaniasis: A cohort study | Asymptomatic Leishmania donovani infections outnumber clinical presentations, however the predictors for development of active disease are not well known. We aimed to identify serological, immunological and genetic markers for progression from L. donovani infection to clinical Visceral Leishmaniasis (VL).
We enrolled a... | Visceral Leishmaniasis (VL) or Kala-azar is a vector born disease, deadly if not treated. On the Indian subcontinent VL is caused by the protozoan parasite Leismania donovani, transmitted by an insect vector, sand fly of the Phlebotomus argentipes species, and considered an anthroponotic disease. Not every L.donovani i... | Visceral leishmaniasis (VL) or kala-azar is the severest form of leishmaniasis and fatal if left untreated. More than 90% of global VL cases occur in just six countries: India, Bangladesh, Sudan, South Sudan, Brazil and Ethiopia [1]. India accounts for approximately 50% of the global burden of VL and is a signatory to ... |
10.1371/journal.pbio.0050207 | Proboscidean Mitogenomics: Chronology and Mode of Elephant Evolution Using Mastodon as Outgroup | We have sequenced the complete mitochondrial genome of the extinct American mastodon (Mammut americanum) from an Alaskan fossil that is between 50,000 and 130,000 y old, extending the age range of genomic analyses by almost a complete glacial cycle. The sequence we obtained is substantially different from previously re... | We determined the complete mitochondrial genome of the mastodon (Mammut americanum), a recently extinct relative of the living elephants that diverged about 26 million years ago. We obtained the sequence from a tooth dated to 50,000–130,000 years ago, increasing the specimen age for which such palaeogenomic analyses ha... | An accurate and well-supported phylogeny is the basis for understanding the evolution of species. With the appropriate and adequate amount of data, it is possible not only to determine relationships among species, but also to date divergence events between lineages. In turn, divergence events can be correlated to envir... |
10.1371/journal.pcbi.1006626 | Coevolving residues inform protein dynamics profiles and disease susceptibility of nSNVs | The conformational dynamics of proteins is rarely used in methodologies used to predict the impact of genetic mutations due to the paucity of three-dimensional protein structures as compared to the vast number of available sequences. Until now a three-dimensional (3D) structure has been required to predict the conforma... | Proteins are dynamic machines that undergo atomic fluctuations, side chain rotations, and collective domain movements that are required for biological function. There is, therefore, a need for quantitative metrics that capture the dynamic fluctuations per position to understand the critical role of protein dynamics in ... | A 3D structure is still required to computationally obtain protein dynamics, drastically limiting the extent to which conformational dynamics can be incorporated into genomic analysis. The reason for this is that there are exponentially more sequences than experimental structures. Currently, UniProtKB contains more tha... |
10.1371/journal.pntd.0001158 | Protection against Diarrhea Associated with Giardia intestinalis Is Lost with Multi-Nutrient Supplementation: A Study in Tanzanian Children | Asymptomatic carriage of Giardia intestinalis is highly prevalent among children in developing countries, and evidence regarding its role as a diarrhea-causing agent in these settings is controversial. Impaired linear growth and cognition have been associated with giardiasis, presumably mediated by malabsorption of nut... | Giardia intestinalis is a well-known cause of diarrhea in industrialized countries. In children in developing countries, asymptomatic infections are common and their role as cause of diarrhea has been questioned. In a cohort of rural Tanzanian pre-school children, we assessed the association between the presence of Gia... | In developed countries, Giardia intestinalis (syn. G. duodenalis, G. lamblia) causes diarrhea while the prevalence of infections in the general population usually does not exceed 5% [1]. In developing countries, however, asymptomatic infections are much more common, with prevalence values in pediatric populations typic... |
10.1371/journal.pgen.1005023 | Co-chaperone p23 Regulates C. elegans Lifespan in Response to Temperature | Temperature potently modulates various physiologic processes including organismal motility, growth rate, reproduction, and ageing. In ectotherms, longevity varies inversely with temperature, with animals living shorter at higher temperatures. Thermal effects on lifespan and other processes are ascribed to passive chang... | Temperature is a critical environmental factor that affects ageing in both cold-blooded and warm-blooded species. In invertebrate animals, lifespan varies inversely with temperature, with higher temperature resulting in faster development but shorter lifespan. This phenomenon has been usually attributed to passive chan... | Temperature dramatically impacts the lifespan of ectotherms, with lower temperatures typically extending and higher temperatures shortening life [1–3]. The conventional view is that temperature passively affects the rate of chemical reactions and metabolism, thereby influencing species longevity. An emerging body of ev... |
10.1371/journal.pbio.1001326 | Novel Role of NOX in Supporting Aerobic Glycolysis in Cancer Cells with Mitochondrial Dysfunction and as a Potential Target for Cancer Therapy | Elevated aerobic glycolysis in cancer cells (the Warburg effect) may be attributed to respiration injury or mitochondrial dysfunction, but the underlying mechanisms and therapeutic significance remain elusive. Here we report that induction of mitochondrial respiratory defect by tetracycline-controlled expression of a d... | Glycolysis is a cytoplasmic metabolic process that produces energy from glucose. In normal cells, the rate of glycolysis is low, and glycolysis products are further processed in the mitochondria via oxidative phosphorylation, a very efficient energy-producing process. Cancer cells, however, display higher levels of gly... | Development of selective anticancer agents based on the biological differences between normal and cancer cells is essential to improve therapeutic selectivity. Increased aerobic glycolysis and elevated oxidative stress are two prominent biochemical features frequently observed in cancer cells. A metabolic shift from ox... |
10.1371/journal.pgen.1004590 | Differential Responses to Wnt and PCP Disruption Predict Expression and Developmental Function of Conserved and Novel Genes in a Cnidarian | We have used Digital Gene Expression analysis to identify, without bilaterian bias, regulators of cnidarian embryonic patterning. Transcriptome comparison between un-manipulated Clytia early gastrula embryos and ones in which the key polarity regulator Wnt3 was inhibited using morpholino antisense oligonucleotides (Wnt... | The recent wave of genome sequencing from many species has revealed that most of the gene families known to regulate animal development are shared not only between humans and laboratory favorites such as mice, flies and worms, but also by evolutionarily more distant animals such as jellyfish and sponges. It is often as... | A major challenge in biology is to understand how the current extraordinary diversity of animal forms has been generated during evolution. Specific goals are to determine which genes were employed to regulate developmental processes in the earliest multi-cellular animals, and how this set of regulators was expanded dur... |
10.1371/journal.pgen.1007912 | Temporal and spatial regulation of protein cross-linking by the pre-assembled substrates of a Bacillus subtilis spore coat transglutaminase | In many cases protein assemblies are stabilized by covalent bonds, one example of which is the formation of intra- or intermolecular ε-(γ-glutamyl)lysil cross-links catalyzed by transglutaminases (TGases). Because of the potential for unwanted cross-linking reactions, the activities of many TGases have been shown to be... | The orderly recruitment of proteins during the assembly of complex macromolecular structures poses challenges throughout cell biology. During endospore development in the bacterium Bacillus subtilis at least 80 proteins synthesized in the mother cell are assembled around the developing spore to form a protective coat. ... | Protein function is often restricted to specific cellular locations, in both eukaryotes or prokaryotes, and knowledge of the pathways governing protein localization is essential to understand protein function (reviewed by [1]). The formation of supramolecular protein assemblies, for instance, requires targeting pathway... |
10.1371/journal.ppat.1003303 | Identification of Targets of CD8+ T Cell Responses to Malaria Liver Stages by Genome-wide Epitope Profiling | CD8+ T cells mediate immunity against Plasmodium liver stages. However, the paucity of parasite-specific epitopes of CD8+ T cells has limited our current understanding of the mechanisms influencing the generation, maintenance and efficiency of these responses. To identify antigenic epitopes in a stringent murine malari... | Vaccination against malaria is feasible, as demonstrated with radiation-attenuated sporozoite vaccine, which protects experimental animals and humans by targeting the clinically silent liver stages. Potent protection largely depends on CD8+ T cells, a type of white blood cell that is tailor-made to kill obligate intrac... | Malaria is responsible for an estimated 250 million episodes of clinical disease and 600,00 to 1.2 million deaths each year [1], [2]. Notwithstanding recent reductions in the burden of malaria in some endemic areas, sustained control, elimination or eradication of the disease will require a highly efficacious vaccine t... |
10.1371/journal.pntd.0001439 | Dengue Virus Type 4 Phylogenetics in Brazil 2011: Looking beyond the Veil | Dengue Fever and Dengue Hemorrhagic Fever are diseases affecting approximately 100 million people/year and are a major concern in developing countries. In the present study, the phylogenetic relationship of six strains of the first autochthonous cases of DENV-4 infection occurred in Sao Paulo State, Parana State and Ri... | Dengue virus infections are a major concern in developing countries, affecting approximately 100 million people/year. The virus has four immunologically related serotypes (DENV-1, DENV-2, DENV-3 and DENV-4) associated with human disease. The virus is widespread in tropical and Sub-Tropical areas of Asia, Africa and Ame... | Dengue virus (DENV) is a single stranded RNA virus, with four immunologically related serotypes (DENV-1, DENV-2, DENV-3 and DENV-4) associated with Dengue Fever (DF) and Dengue Hemorrhagic Fever (DHF) [1].
The virus is widespread in tropical and Sub-Tropical areas of Asia, Africa and Americas. The virus is trans... |
10.1371/journal.pcbi.1002700 | Multistationary and Oscillatory Modes of Free Radicals Generation by the Mitochondrial Respiratory Chain Revealed by a Bifurcation Analysis | The mitochondrial electron transport chain transforms energy satisfying cellular demand and generates reactive oxygen species (ROS) that act as metabolic signals or destructive factors. Therefore, knowledge of the possible modes and bifurcations of electron transport that affect ROS signaling provides insight into the ... | The mitochondrial respiratory chain shows a variety of modes of behavior. In living cells, flashes of ROS production and oscillations accompanied by a decrease of transmembrane potential can be registered. The mechanisms of such complex behavior are difficult to rationalize without a mathematical formalization of mitoc... | The electron transport chain links the central carbohydrate energy metabolism with ATP synthesis (see Fig. 1). It transforms the free energy released by the oxidation of NADH and succinate into a form of transmembrane electrochemical potential (ΔΨ), which is used for ATP synthesis [1]. Reactive oxygen species (ROS) are... |
10.1371/journal.pntd.0000881 | High Affinity Human Antibody Fragments to Dengue Virus Non-Structural Protein 3 | The enzyme activities catalysed by flavivirus non-structural protein 3 (NS3) are essential for virus replication. They are distributed between the N-terminal protease domain in the first one-third and the C-terminal ATPase/helicase and nucleoside 5′ triphosphatase domain which forms the remainder of the 618-aa long pro... | Dengue virus is the most prevalent mosquito transmitted infectious disease in humans and is responsible for febrile disease such as dengue fever, dengue hemorrhagic fever and dengue shock syndrome. Dengue non-structural protein 3 (NS3) is an essential, multifunctional, viral enzyme with two distinct domains; a protease... | Dengue virus belongs to the Flaviviridae family and is the etiological agent of dengue fever, dengue hemorrhagic fever and dengue shock syndrome. It is the most prevalent arthropod transmitted infectious disease in humans and has four antigenically distinct viral serotypes (DENV 1–4) [1]. The genome of dengue viruses c... |
10.1371/journal.pcbi.1000610 | Alu and B1 Repeats Have Been Selectively Retained in the Upstream and Intronic Regions of Genes of Specific Functional Classes | Alu and B1 repeats are mobile elements that originated in an initial duplication of the 7SL RNA gene prior to the primate-rodent split about 80 million years ago and currently account for a substantial fraction of the human and mouse genome, respectively. Following the primate-rodent split, Alu and B1 elements spread i... | Despite their fundamental role in cell regulation, genes account for less than 1% of the human genome. Recent studies have shown that non-genic regions of our DNA may also play an important functional role in human cells. In this paper, we study Alu and B elements, a specific class of such non-genic elements that accou... | Identifiable repeat elements cover a very large fraction of the human and mouse genomes, and even though they are quite diverse at the sequence level, they can be assigned to a fairly small number of families [1]. Alu and B elements belong to the Short Interspersed Nuclear Element (SINE) family, members of which exist ... |
10.1371/journal.ppat.1003182 | Genome-wide Prediction and Functional Validation of Promoter Motifs Regulating Gene Expression in Spore and Infection Stages of Phytophthora infestans | Most eukaryotic pathogens have complex life cycles in which gene expression networks orchestrate the formation of cells specialized for dissemination or host colonization. In the oomycete Phytophthora infestans, the potato late blight pathogen, major shifts in mRNA profiles during developmental transitions were identif... | The genus Phytophthora includes over one hundred species of plant pathogens that have devastating effects worldwide in agriculture and natural environments. Its most notorious member is P. infestans, which causes the late blight diseases of potato and tomato. Their success as pathogens is dependent on the formation of ... | Eukaryotic pathogens typically employ specialized structures for dissemination and infection. Most filamentous fungi and oomycetes, for example, proliferate in their hosts as vegetative hyphae, which generate spores that are used to reach new infection sites [1]. The spores of many plant pathogens, especially those wit... |
10.1371/journal.pgen.1005089 | Mutation in MRPS34 Compromises Protein Synthesis and Causes Mitochondrial Dysfunction | The evolutionary divergence of mitochondrial ribosomes from their bacterial and cytoplasmic ancestors has resulted in reduced RNA content and the acquisition of mitochondria-specific proteins. The mitochondrial ribosomal protein of the small subunit 34 (MRPS34) is a mitochondria-specific ribosomal protein found only in... | Mitochondria make most of the energy required by eukaryotic cells and therefore they are essential for their normal function and survival. Mitochondrial function is regulated by both the mitochondrial and nuclear genome. Mutations in nuclear genes encoding mitochondrial proteins lead to mitochondrial dysfunction and co... | Mitochondria are composed of proteins encoded by the nuclear and mitochondrial genomes. Most of the mitochondrial proteins including the ribosomal proteins and translation factors that are responsible for the expression of the mitochondrial genome are synthesized on cytoplasmic ribosomes and imported into mitochondria ... |
10.1371/journal.pcbi.1005837 | A cyber-linked undergraduate research experience in computational biomolecular structure prediction and design | Computational biology is an interdisciplinary field, and many computational biology research projects involve distributed teams of scientists. To accomplish their work, these teams must overcome both disciplinary and geographic barriers. Introducing new training paradigms is one way to facilitate research progress in c... | Computational biology research is frequently conducted by virtual teams: groups of scientists in different locations that use shared resources and online communication tools to collaborate on a problem. It is imperative that the next generation of computational biologists can easily work in these interdisciplinary, dis... | Computational biology is an interdisciplinary field, and many computational biology research projects are performed by distributed international teams of scientists. In the coming decade, it will be imperative for computational biologists to collaborate within these virtual communities [1,2]. However, few undergraduate... |
10.1371/journal.pntd.0000574 | Prevalence and Spatial Distribution of Entamoeba histolytica/dispar and Giardia lamblia among Schoolchildren in Agboville Area (Côte d'Ivoire) | New efforts are being made to improve understanding of the epidemiology of the helminths and intensifying the control efforts against these parasites. In contrast, relatively few studies are being carried out in this direction for the intestinal protozoa. To contribute to a better comprehension of the epidemiology of t... | According to WHO, intestinal amoebiasis caused by Entamoeba histolytica is the third principal parasitic disease responsible for mortality in the world. This protozoal parasite infects approximately 180 million individuals throughout the world, among whom 40 to 110 thousand die from it each year. Giardiasis, caused by ... | Although intestinal parasites seem to raise much less interest than do AIDS and tuberculosis, they are a major public health problem in tropical regions [1]. In 2002, WHO estimated the number of people infected by digestive tract parasites at 3.5 billion and the number of people made ill by them at 450 million [2]. Whe... |
10.1371/journal.pgen.1007144 | Brassinosteroids regulate root growth by controlling reactive oxygen species homeostasis and dual effect on ethylene synthesis in Arabidopsis | The brassinosteroids (BRs) represent a class of phytohormones, which regulate numerous aspects of growth and development. Here, a det2-9 mutant defective in BR synthesis was identified from an EMS mutant screening for defects in root length, and was used to investigate the role of BR in root development in Arabidopsis.... | Both brassinosteroids (BRs) and ethylene have been known to control root growth and development. ROS have been also reported to play an important role in root development. However, the relationship between BRs and ethylene or ROS in root growth and development was not addressed before. In this study, a det2-9 mutant de... | Roots are important plant ground organs, which absorb water and nutrients to control plant growth and development. In higher plants, root growth is maintained by coordinating cell proliferation and differentiation [1–3]. Plant hormones have been known to play a crucial role in the regulation of root growth [4]. Recent ... |
10.1371/journal.pcbi.1005206 | Extending Integrate-and-Fire Model Neurons to Account for the Effects of Weak Electric Fields and Input Filtering Mediated by the Dendrite | Transcranial brain stimulation and evidence of ephaptic coupling have recently sparked strong interests in understanding the effects of weak electric fields on the dynamics of brain networks and of coupled populations of neurons. The collective dynamics of large neuronal populations can be efficiently studied using sin... | How extracellular electric fields—as generated endogenously or through transcranial brain stimulation—affect the dynamics of neuronal populations is of great interest but not well understood. To study neuronal activity at the network level single-compartment neuron models have been proven very successful, because of th... | Extracellular electric fields in the brain and their impact on neural activity have gained a considerable amount of attention in neuroscience over the past decade. These electric fields can be generated endogenously [1–3] or through transcranial (alternating) current stimulation [4–6], and can modify the activity of ne... |
10.1371/journal.pbio.2000225 | Phylosymbiosis: Relationships and Functional Effects of Microbial Communities across Host Evolutionary History | Phylosymbiosis was recently proposed to describe the eco-evolutionary pattern, whereby the ecological relatedness of host-associated microbial communities parallels the phylogeny of related host species. Here, we test the prevalence of phylosymbiosis and its functional significance under highly controlled conditions by... | Studies on the assembly and function of host-microbiota symbioses are inherently complicated by the diverse effects of diet, age, sex, host genetics, and endosymbionts. Central to unraveling one effect from the other is an experimental framework that reduces confounders. Using common rearing conditions across four anim... | A large body of literature has documented genetic and environmental influences on the composition of host-associated microbial communities [1–10]. Although environmental factors are considered to play a much larger role than host genetics and evolutionary history [11], host influences and their functional consequences ... |
10.1371/journal.pgen.1000942 | Bulk Segregant Analysis by High-Throughput Sequencing Reveals a Novel Xylose Utilization Gene from Saccharomyces cerevisiae | Fermentation of xylose is a fundamental requirement for the efficient production of ethanol from lignocellulosic biomass sources. Although they aggressively ferment hexoses, it has long been thought that native Saccharomyces cerevisiae strains cannot grow fermentatively or non-fermentatively on xylose. Population surve... | Ethanol made from fermentation of lignocellulosic biomass by baker's yeast can be considered “carbon neutral” and is one alternative to fossil fuels for powering vehicles. One of the recognized requirements for cost-effective and energy-efficient cellulosic ethanol production is the need to convert the sugar xylose—a m... | It is clear that society has a responsibility to address the anthropogenic causes of climate change. Current estimates indicate that about 95% of the world's energy comes from burning fossil fuels [1], which is the leading contributor of carbon dioxide emissions. Combustion of liquid fossil fuels for transportation is ... |
10.1371/journal.pcbi.1002310 | Translating Clinical Findings into Knowledge in Drug Safety Evaluation - Drug Induced Liver Injury Prediction System (DILIps) | Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models f... | Translational research involves utilization of clinical data to address challenges in drug discovery and development. The rationale behind this study is that the side effects observed in clinical trial and post-marketing surveillance can be translated into a screening system for use in drug discovery. As a proof-of-con... | Drug-induced liver injury (DILI) poses a significant challenge to medical and pharmaceutical professionals as well as regulatory agencies. It is the leading cause of acute liver failure, which has a high mortality rate (30%) as treatment is limited due to the availability of livers for transplantation [1]. Although man... |
10.1371/journal.pntd.0006608 | Vitamin D status contributes to the antimicrobial activity of macrophages against Mycobacterium leprae | The immune system depends on effector pathways to eliminate invading pathogens from the host in vivo. Macrophages (MΦ) of the innate immune system are armed with vitamin D-dependent antimicrobial responses to kill intracellular microbes. However, how the physiological levels of vitamin D during MΦ differentiation affec... | A key function of MΦ is to recognize, phagocytose and mount an antimicrobial response against microbial pathogens to defend the host. In humans, monocytes are recruited to the site of infection and differentiate into MΦ upon the onset of microbial infection. The MΦ phenotype and function are determined by the cytokine ... | The MΦ is a sentinel of the innate immune system that serves as the first line of defense to recognize and destroy invading microbes. In human MΦ, activation by a toll-like receptor 2/1 (TLR2/1) ligand or interferon-γ (IFN-γ) triggers a direct antimicrobial response that depends upon the level of available vitamin D [1... |
10.1371/journal.ppat.1004173 | The Cytoplasmic Domain of Varicella-Zoster Virus Glycoprotein H Regulates Syncytia Formation and Skin Pathogenesis | The conserved herpesvirus fusion complex consists of glycoproteins gB, gH, and gL which is critical for virion envelope fusion with the cell membrane during entry. For Varicella Zoster Virus (VZV), the complex is necessary for cell-cell fusion and presumed to mediate entry. VZV causes syncytia formation via cell-cell f... | Varicella zoster virus (VZV) infects the human population globally, causing chickenpox in children and shingles in adults. While those afflicted with shingles experience severe pain that might last from weeks to months, the cause is not known. Biopsies of VZV infected skin and specimens of nerve ganglia collected at au... | Varicella Zoster Virus (VZV) is a ubiquitous human pathogen that causes varicella (chickenpox) in children and zoster (shingles) in adults [1]. Primary infection with VZV initiates at the mucosal epithelium following contact with respiratory droplets or skin vesicle fluid from infected individuals [2]. Viral disseminat... |
10.1371/journal.pmed.1002033 | Inter-pregnancy Weight Change and Risks of Severe Birth-Asphyxia-Related Outcomes in Singleton Infants Born at Term: A Nationwide Swedish Cohort Study | Maternal overweight and obesity are associated with increased risks of birth-asphyxia-related outcomes, but the mechanisms are unclear. If a change of exposure (i.e., maternal body mass index [BMI]) over time influences risks, this would be consistent with a causal relationship between maternal BMI and offspring risks.... | The increasing prevalence of overweight and obesity has epidemic proportions, also among pregnant women.
Maternal overweight and obesity increase the risks of pregnancy complications and adverse neonatal outcomes, including severe birth asphyxia disorders.
An independent association between maternal body mass index (BM... | Maternal overweight and obesity during pregnancy increase the risks of severe maternal and infant complications [1–4]. In Sweden, the proportion of women with overweight and obesity (body mass index [BMI] ≥ 25 kg/m2) in early pregnancy increased from 26% in 1992 to 38% in 2010 [5]. In the US, 58% of women between 20 an... |
10.1371/journal.pgen.1006896 | MiR-1254 suppresses HO-1 expression through seed region-dependent silencing and non-seed interaction with TFAP2A transcript to attenuate NSCLC growth | MicroRNAs (miRNAs) are a class of small non-coding RNAs, which direct post-transcriptional gene silencing (PTGS) and function in a vast range of biological events including cancer development. Most miRNAs pair to the target sites through seed region near the 5’ end, leading to mRNA cleavage and/or translation repressio... | It is generally accepted that miRNAs bind to 3`UTR of target mRNAs and direct post-transcriptional gene silencing (PTGS) via its seed sequence. Here we report a new dual regulatory mechanism of miRNA. We described that miR-1254 repressed HO-1 at post-transcriptional level by directly targeting HO-1 3’UTR via its seed s... | MicroRNAs (miRNAs) are a class of small non-coding RNAs, which direct post-transcriptional gene silencing (PTGS) and play important regulatory roles in a vast range of cellular processes including cell differentiation, proliferation, apoptosis, and migration [1–3]. Aberrant expression of miRNAs may play an important ro... |
10.1371/journal.pcbi.1000143 | Falling towards Forgetfulness: Synaptic Decay Prevents Spontaneous Recovery of Memory | Long after a new language has been learned and forgotten, relearning a few words seems to trigger the recall of other words. This “free-lunch learning” (FLL) effect has been demonstrated both in humans and in neural network models. Specifically, previous work proved that linear networks that learn a set of associations... | If you learn a skill, then partially forget it, does relearning part of that skill induce recovery of other parts of the skill? More generally, if you learn a set of associations, then partially forget them, does relearning a subset induce recovery of the remaining associations? In previous work, in which participants ... | The idea that structural changes underpin the formation of new memories can be traced to the 19th century [1]. More recently, Hebb proposed that “When an axon of cell A is near enough to excite B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both c... |
10.1371/journal.pmed.1002597 | Chile’s 2014 sugar-sweetened beverage tax and changes in prices and purchases of sugar-sweetened beverages: An observational study in an urban environment | On October 1, 2014, the Chilean government modified its previous sugar-sweetened beverage (SSB) tax, increasing the tax rate from 13% to 18% on industrialized beverages with high levels of sugar (H-SSBs) (greater than 6.25 grams [g] sugar/100 milliliters [mL]) and decreasing the tax rate from 13% to 10% on industrializ... | Sugar-sweetened beverage (SSB) taxes have emerged as a strategy to prevent a continued rise in obesity prevalence and noncommunicable diseases (NCDs).
Recent studies in Mexico and the United States have shown that SSB taxes are associated with increased prices of taxed beverages and reduced purchases of those beverages... | In response to the increasing global burden of obesity and related chronic diseases in the last decade, taxes on industrially produced sugar-sweetened beverages (SSBs) have emerged as a regulatory strategy to prevent the continued rise of obesity [1,2]. Research has shown that raising the prices of SSBs leads to signif... |
10.1371/journal.ppat.1006401 | Suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice | We have established two mouse models of central nervous system (CNS) demyelination that differ from most other available models of multiple sclerosis (MS) in that they represent a mixture of viral and immune triggers. In the first model, ocular infection of different strains of mice with a recombinant HSV-1 that expres... | Several mouse models of multiple sclerosis (MS) are now available. We have established two new mouse models. In the first model, ocular infection of different strains of mice with HSV-IL-2 recombinant virus causes CNS demyelination. In the second model, CNS demyelination was induced by different strains of wild type HS... | Multiple sclerosis (MS) is due to degradation of the myelin sheath [1] and visual disorders due to demyelination of the optic nerve is the early sign of individuals diagnosed with MS [2,3]. Thus, optic neuritis can be used as an early factor for detection of MS. Both genetic and environmental factors are implicated in ... |
10.1371/journal.pcbi.1000858 | Categorial Compositionality: A Category Theory Explanation for the Systematicity of Human Cognition | Classical and Connectionist theories of cognitive architecture seek to explain systematicity (i.e., the property of human cognition whereby cognitive capacity comes in groups of related behaviours) as a consequence of syntactically and functionally compositional representations, respectively. However, both theories dep... | Our minds are not the sum of some arbitrary collection of mental abilities. Instead, our mental abilities come in groups of related behaviours. This property of human cognition has substantial biological advantage in that the benefits afforded by a cognitive behaviour transfer to a related situation without any of the ... | For more than two decades, since Fodor and Pylyshyn's seminal paper on the foundations of a theory of cognitive architecture (i.e., roughly, the component processes and their modes of composition that together comprise cognitive behaviour) [1], the problem of explaining systematicity has remained unresolved [2] despite... |
10.1371/journal.pntd.0005014 | Plasmodium vivax Reticulocyte Binding Proteins Are Key Targets of Naturally Acquired Immunity in Young Papua New Guinean Children | Major gaps in our understanding of Plasmodium vivax biology and the acquisition of immunity to this parasite hinder vaccine development. P. vivax merozoites exclusively invade reticulocytes, making parasite proteins that mediate reticulocyte binding and/or invasion potential key vaccine or drug targets. While protein i... | In parallel with the tremendous reduction in malaria burden, Plasmodium vivax (Pv) is now the predominant malaria species in the Asia-Pacific and Americas. Pv can only invade young erythrocytes (reticulocytes) and this restriction is thought to involve the Reticulocyte-Binding Protein family (PvRBP). Given their predic... | The two major malaria parasites, Plasmodium falciparum and Plasmodium vivax, differ in their ability to invade human erythrocytes. While P. falciparum invades both mature (normocytes) and young erythrocytes (reticulocytes), P. vivax can only invade the latter [1]. This differential specificity is believed to be mediate... |
10.1371/journal.ppat.1004161 | Ly49C-Dependent Control of MCMV Infection by NK Cells Is Cis-Regulated by MHC Class I Molecules | Natural Killer (NK) cells are crucial in early resistance to murine cytomegalovirus (MCMV) infection. In B6 mice, the activating Ly49H receptor recognizes the viral m157 glycoprotein on infected cells. We previously identified a mutant strain (MCMVG1F) whose variant m157 also binds the inhibitory Ly49C receptor. Here w... | We previously identified a viral murine cytomegalovirus (MCMV) strain whose variant m157 immunoevasin can bind the inhibitory Ly49C NK cell receptor in addition to activating Ly49H receptor in B6 mice. Here we show that simultaneous engagement of the two receptors by m157 hampers NK cell activation. Most Ly49H+ NK cell... | In humans, cytomegalovirus (CMV) is a pathogen responsible for causing significant mortality in immunocompromised patients [1] and in individuals lacking Natural Killer (NK) cells [2]. Mouse cytomegalovirus (MCMV) is a natural pathogen of mice. The similarities in structure and biology between human and mouse CMV make ... |
10.1371/journal.pgen.1002791 | GWAS Identifies Novel Susceptibility Loci on 6p21.32 and 21q21.3 for Hepatocellular Carcinoma in Chronic Hepatitis B Virus Carriers | Genome-wide association studies (GWAS) have recently identified KIF1B as susceptibility locus for hepatitis B virus (HBV)–related hepatocellular carcinoma (HCC). To further identify novel susceptibility loci associated with HBV–related HCC and replicate the previously reported association, we performed a large three-st... | Previous studies strongly suggest the importance of genetic susceptibility for hepatocellular carcinoma (HCC). However, the studies about genetic etiology on HBV–related HCC were limited. Our genome-wide association study included 523,663 autosomal SNPs in 1,538 HBV–positive HCC patients and 1,465 chronic HBV carriers ... | Hepatocellular carcinoma (HCC) is the sixth common cancer and the third common cause of cancer mortality worldwide [1]. The incidence rate of HCC varies considerably in the world, with the highest in East, Southeast Asia and Sub-Saharan Africa, and China alone accounts for approximately half of HCC malignancies [1], [2... |
10.1371/journal.pgen.1006854 | A genetic framework controlling the differentiation of intestinal stem cells during regeneration in Drosophila | The speed of stem cell differentiation has to be properly coupled with self-renewal, both under basal conditions for tissue maintenance and during regeneration for tissue repair. Using the Drosophila midgut model, we analyze at the cellular and molecular levels the differentiation program required for robust regenerati... | Adult tissue/organ function is maintained by stem cells. Key question in stem cell biology is how the pool of stem cells can be robustly expanded yet timely contracted through differentiation according to the need of a tissue. Over the last years, the mechanisms underlying stem cell activation have been extensively stu... | In metazoans, the digestive tract supports organismal growth and maintenance. Genetic disorders or microbial dysbiosis that prevent the digestion and absorption of nutrients are major causes of morbidity and mortality in humans. In mammals, mature intestinal cells are short-lived and constantly replaced by newborn diff... |
10.1371/journal.pntd.0005099 | ‘If an Eye Is Washed Properly, It Means It Would See Clearly’: A Mixed Methods Study of Face Washing Knowledge, Attitudes, and Behaviors in Rural Ethiopia | Face cleanliness is a core component of the SAFE (Surgery, Antibiotics, Facial cleanliness, and Environmental improvements) strategy for trachoma control. Understanding knowledge, attitudes, and behaviors related to face washing may be helpful for designing effective interventions for improving facial cleanliness.
In A... | Facial cleanliness is a core component of the SAFE (Surgery, Antibiotics, Facial cleanliness, and Environmental improvements) strategy for trachoma control. We conducted a mixed methods study in a trachoma hyperendemic region of rural Ethiopia to better understand knowledge, attitudes, and behaviors related to face was... | Trachoma is the leading cause of infectious blindness globally.[1–3] Caused by the bacterium Chlamydia trachomatis, trachoma is thought to be transmitted by direct contact from infected persons and clothing, as well as the moisture-seeking fly Musca sorbens.[4,5] Currently endemic in 53 countries[6], trachoma is estima... |
10.1371/journal.ppat.1000311 | An Antiviral Response Directed by PKR Phosphorylation of the RNA Helicase A | The double-stranded RNA-activated protein kinase R (PKR) is a key regulator of the innate immune response. Activation of PKR during viral infection culminates in phosphorylation of the α subunit of the eukaryotic translation initiation factor 2 (eIF2α) to inhibit protein translation. A broad range of regulatory functio... | Our manuscript explores the immune response to viral infection by investigating events triggered by the protein kinase PKR. This sentinel kinase is constitutively expressed in all cells as an inactive protein that is subsequently activated by viral RNA produced during an infection. The active kinase perturbs viral repl... | The primary detection of viral infection is by the host innate immune system, with the recognition of viral double-stranded RNA (dsRNA) a crucial early function. Responses to dsRNA are mediated by several protein receptors that recognize this pathogen-associated molecular pattern (PAMP). Most important of these recepto... |
10.1371/journal.pntd.0004508 | Evaluation of Parasiticide Treatment with Benznidazol in the Electrocardiographic, Clinical, and Serological Evolution of Chagas Disease | Chagas disease is one of the most important endemic parasitic diseases in Latin America. In its chronic phase, progression to cardiomyopathy has high morbidity and mortality. The persistence of a normal electrocardiogram (ECG) provides a similar prognosis to that of a non-diseased population. Benznidazole (BNZ) is the ... | Twenty years of follow-up of patients with Chagas disease treated with benznidazole is presented in this paper. The persistence of a normal electrocardiogram (ECG) provides a similar prognosis to that of a non-diseased population. Benznidazole (BNZ) is the only drug with trypanocidal action available in Brazil. A group... | Chagas’ disease (CD), described by Carlos Chagas in 1909[1], and caused by a parasite–Trypanosoma cruzi, is one of the most important endemic diseases in Latin America, where there are 10 million people infected (about two million in Brazil). The vectorial transmission has historically been the most important. The dise... |
10.1371/journal.pntd.0006934 | Antivirus effectiveness of ivermectin on dengue virus type 2 in Aedes albopictus | Dengue fever is the most rapidly spreading mosquito-borne viral disease over the past 50 years, with a 30-fold increase in global incidence. Dengue vector control is a key component for the dengue control strategy, since no absolutely effective vaccine or drug is available yet. However, the rapid rise and spread of mos... | Dengue fever is one of neglected vector-borne tropical diseases with a 30-fold increase in global incidence recently. In 2012, World Health Organization set a goal to reduce dengue mortality by at least 50% by 2020. Being faced with more challenges in the dengue control programs, such as the increase of dengue outbreak... | Dengue fever is the most rapidly spreading mosquito-borne viral disease over the past 50 years, with a 30-fold increase in global incidence [1]. To reverse the growing trend, comprehensive technical strategies involving diagnosis and case management, integrated surveillance and outbreak preparedness, sustainable vector... |
10.1371/journal.pgen.1004095 | Loss of Histone H3 Methylation at Lysine 4 Triggers Apoptosis in Saccharomyces cerevisiae | Monoubiquitination of histone H2B lysine 123 regulates methylation of histone H3 lysine 4 (H3K4) and 79 (H3K79) and the lack of H2B ubiquitination in Saccharomyces cerevisiae coincides with metacaspase-dependent apoptosis. Here, we discovered that loss of H3K4 methylation due to depletion of the methyltransferase Set1p... | Covalent histone modifications alter chromatin structure and DNA accessibility, which is playing important roles in a wide range of DNA-based processes, such as transcription regulation and DNA repair, but also cell division and apoptosis. Apoptosis is the most common form of programmed cell death and plays important r... | Apoptosis is the most common form of programmed cell death and plays important roles in the development and cellular homeostasis of all metazoans. Deregulation of apoptosis contributes to the pathogenesis of multiple diseases including autoimmune, neoplastic and neurodegenerative disorders [1]. The budding yeast Saccha... |
10.1371/journal.pcbi.1004068 | Prioritizing Therapeutics for Lung Cancer: An Integrative Meta-analysis of Cancer Gene Signatures and Chemogenomic Data | Repurposing FDA-approved drugs with the aid of gene signatures of disease can accelerate the development of new therapeutics. A major challenge to developing reliable drug predictions is heterogeneity. Different gene signatures of the same disease or drug treatment often show poor overlap across studies, as a consequen... | Computer algorithms that find new uses for known drugs can accelerate the development of new therapies for many diseases, including cancer. One promising strategy is to identify drugs that, at the transcriptional level, reverse the gene expression signature of a disease. A major difficulty with this strategy is variabi... | Lung cancer accounts for the largest number of cancer-related deaths, and the 5-year survival rate (across all stages) is only 16% [1]; there is an urgent need for new therapeutics to help treat it. Over the past two decades, the application of high-throughput technologies has led to the rapid accumulation of comprehen... |
10.1371/journal.pgen.1007618 | The thirsty fly: Ion transport peptide (ITP) is a novel endocrine regulator of water homeostasis in Drosophila | Animals need to continuously adjust their water metabolism to the internal and external conditions. Homeostasis of body fluids thus requires tight regulation of water intake and excretion, and a balance between ingestion of water and solid food. Here, we investigated how these processes are coordinated in Drosophila me... | Maintenance of energy and water balance is necessary for survival of all organisms. Even a mild dehydration triggers thirst, reduces appetite, and decreases diuresis (water excretion), thereby promoting conservation of water resources and survival under arid conditions. Homeostasis is regulated primarily by endocrine s... | Maintenance of homeostasis is based on ingestion and metabolism of water and nutrients in a manner that reflects the internal needs of the animal, but the precise regulatory mechanisms are incompletely understood [1]. Despite the strong evolutionary conservation of the main pathways underlying energy homeostasis [2–5],... |
10.1371/journal.pcbi.1006813 | Predicting kinase inhibitors using bioactivity matrix derived informer sets | Prediction of compounds that are active against a desired biological target is a common step in drug discovery efforts. Virtual screening methods seek some active-enriched fraction of a library for experimental testing. Where data are too scarce to train supervised learning models for compound prioritization, initial s... | In the early stages of drug discovery efforts, computational models are used to predict activity and prioritize compounds for experimental testing. New targets commonly lack the data necessary to build effective models, and the screening needed to generate that experimental data can be costly. We seek to improve the ef... | Early-stage drug discovery involves a search for pharmacologically active compounds (hits) that produce a desired response in an assay of protein function or disease-related phenotype. The active compounds serve as starting points for further structural optimization, with the ultimate goal of developing therapeutic age... |
10.1371/journal.pcbi.1003297 | Comparing Algorithms That Reconstruct Cell Lineage Trees Utilizing Information on Microsatellite Mutations | Organism cells proliferate and die to build, maintain, renew and repair it. The cellular history of an organism up to any point in time can be captured by a cell lineage tree in which vertices represent all organism cells, past and present, and directed edges represent progeny relations among them. The root represents ... | The history of an organism's cells, from a single cell until any particular moment in time, can be captured by a cell lineage tree. Many fundamental open questions in biology and medicine, such as which cells give rise to metastases, whether oocytes and beta cells renew, and what is the role of stem cells in brain deve... | A multi-cellular organism develops from a single cell – the zygote, through cell division and cell death, and displays an astonishing complexity of trillions of cells of different types, residing in different tissues and expressing different genes. The development of an organism from a single cell until any moment in t... |
10.1371/journal.pntd.0001470 | Climate-Based Models for Understanding and Forecasting Dengue Epidemics | Dengue dynamics are driven by complex interactions between human-hosts, mosquito-vectors and viruses that are influenced by environmental and climatic factors. The objectives of this study were to analyze and model the relationships between climate, Aedes aegypti vectors and dengue outbreaks in Noumea (New Caledonia), ... | Dengue fever is a major public health problem in the tropics and subtropics. Since no vaccine exists, understanding and predicting outbreaks remain of crucial interest. Climate influences the mosquito-vector biology and the viral transmission cycle. Its impact on dengue dynamics is of growing interest. We analyzed the ... | Dengue viruses are the most important arthropod-borne viruses affecting humans. During the past century, the four serotypes (DENV 1 - DENV 4) have spread to about a hundred countries in the tropical and subtropical world including Asia, Africa, the Americas and the Pacific. Each year, an estimated 50 million people con... |
10.1371/journal.ppat.1003820 | Systematic MicroRNA Analysis Identifies ATP6V0C as an Essential Host Factor for Human Cytomegalovirus Replication | Recent advances in microRNA target identification have greatly increased the number of putative targets of viral microRNAs. However, it is still unclear whether all targets identified are biologically relevant. Here, we use a combined approach of RISC immunoprecipitation and focused siRNA screening to identify targets ... | Human cytomegalovirus is a prevalent pathogen. Like other herpesviruses, human cytomegalovirus expresses small regulatory RNAs called microRNAs. The focus of this study was to understand the role of these RNAs in the context of viral infection and to use this information to identify novel host factors involved in human... | Human cytomegalovirus (HCMV) is a highly prevalent infectious disease, infecting greater than 30% of the population. Although normally asymptomatic in healthy individuals, HCMV infection is a significant cause of morbidity and mortality in immunocompromised populations, individuals with heart disease and recipients of ... |
10.1371/journal.ppat.1003792 | Parental Transfer of the Antimicrobial Protein LBP/BPI Protects Biomphalaria glabrata Eggs against Oomycete Infections | Vertebrate females transfer antibodies via the placenta, colostrum and milk or via the egg yolk to protect their immunologically immature offspring against pathogens. This evolutionarily important transfer of immunity is poorly documented in invertebrates and basic questions remain regarding the nature and extent of pa... | Vertebrate immune systems not only protect adult organisms against infections but also increase survival of offspring through parental transfer of innate and adaptive immune factors via the placenta, colostrum and milk or via the egg yolk. This maternal transfer of immunity is critical for species survival as embryos a... | The existence of complex immune systems implies that interactions with pathogens represent major selective forces shaping the evolution of animal and plant species [1]. Vertebrate immune systems not only protect the adult organism against infections but also increase reproductive success through parental transfer of in... |
10.1371/journal.pbio.2006507 | The evolution of the syrinx: An acoustic theory | The unique avian vocal organ, the syrinx, is located at the caudal end of the trachea. Although a larynx is also present at the opposite end, birds phonate only with the syrinx. Why only birds evolved a novel sound source at this location remains unknown, and hypotheses about its origin are largely untested. Here, we t... | The larynx is an important valve in the respiratory system of all air-breathing vertebrates that is located at the upper end of the trachea. In some amphibians, in nonavian reptiles, and in mammals, it has also assumed the function of a vocal organ. In contrast, birds have evolved a new and unique vocal organ, the syri... | Evolutionary novelty in physiological and morphological features can often be traced to specific adaptations that allow organisms to exploit the fitness landscape successfully. The avian clade is characterized by a number of striking synapomorphies, which frequently have been linked to the evolution of active flight [1... |
10.1371/journal.pgen.1008004 | The meiotic phosphatase GSP-2/PP1 promotes germline immortality and small RNA-mediated genome silencing | Germ cell immortality, or transgenerational maintenance of the germ line, could be promoted by mechanisms that could occur in either mitotic or meiotic germ cells. Here we report for the first time that the GSP-2 PP1/Glc7 phosphatase promotes germ cell immortality. Small RNA-induced genome silencing is known to promote... | The germ line of an organism is considered immortal in its capacity to give rise to an unlimited number of future generations. To protect the integrity of the germ line, mechanisms act to suppress the accumulation of transgenerational damage to the genome or epigenome. Loss of germ cell immortality can result from muta... | Animals, including humans, are comprised of two broad cell types: somatic cells and germ cells. Somatic cells consist of many diverse differentiated cell types, while germ cells are specialized to produce the next generation of offspring. An important difference between these two cell types is that somatic cells underg... |
10.1371/journal.pntd.0004319 | Ecological Drivers of Mansonella perstans Infection in Uganda and Patterns of Co-endemicity with Lymphatic Filariasis and Malaria | Mansonella perstans is a widespread, but relatively unknown human filarial parasite transmitted by Culicoides biting midges. Although it is found in many parts of sub-Saharan Africa, only few studies have been carried out to deepen the understanding of its ecology, epidemiology, and health consequences. Hence, knowledg... | Mansonella perstans is a widespread, but relatively unknown human filarial parasite that occurs in many parts of Africa. In a nationwide survey carried out in Uganda in 2000–2003, the distribution of M. perstans was assessed by screening school children. Here, we studied the underlying environmental drivers and ecologi... | The human filarial parasite Mansonella perstans has been considered as one of the most prevalent human parasites in Africa [1]. Despite the wide distribution, only very few studies have addressed its epidemiology and associated health consequences, and currently no effective drug therapy for treatment, control, and loc... |
10.1371/journal.pntd.0005805 | Mitochondria and lipid raft-located FOF1-ATP synthase as major therapeutic targets in the antileishmanial and anticancer activities of ether lipid edelfosine | Leishmaniasis is the world’s second deadliest parasitic disease after malaria, and current treatment of the different forms of this disease is far from satisfactory. Alkylphospholipid analogs (APLs) are a family of anticancer drugs that show antileishmanial activity, including the first oral drug (miltefosine) for leis... | Leishmaniasis is a major health problem worldwide, and can result in loss of human life or a lifelong stigma because of bodily scars. According to World Health Organization, leishmaniasis is considered as an emerging and uncontrolled disease, and its current treatment is far from ideal, with only a few drugs available ... | Leishmaniasis, caused by several species of the protozoan Leishmania parasite, is one of the world’s most neglected diseases in terms of drug research and development, and for which current therapy is not satisfactory [1]. At present, about 350 million people in 98 countries worldwide are at risk of contracting leishma... |
10.1371/journal.pntd.0003644 | Structural Analysis of the Synthetic Duffy Binding Protein (DBP) Antigen DEKnull Relevant for Plasmodium vivax Malaria Vaccine Design | The Plasmodium vivax vaccine candidate Duffy Binding Protein (DBP) is a protein necessary for P. vivax invasion of reticulocytes. The polymorphic nature of DBP induces strain-specific immune responses that pose unique challenges for vaccine development. DEKnull is a synthetic DBP based antigen that has been engineered ... | Plasmodium vivax is an oft neglected causative agent of human malaria. It inflicts tremendous burdens on public health infrastructures and causes significant detrimental effects on socio-economic growth throughout the world. P. vivax Duffy Binding Protein (DBP) is a surface protein that the parasite uses to invade host... | Plasmodium vivax is a causative agent of malaria, inflicting significant morbidity and impeding economic growth in highly endemic areas [1,2]. Increasing evidence indicates the severity of disease, economic impact, and burden of P. vivax has been severely underestimated [1,2]. Among the proposed methods for disease con... |
10.1371/journal.ppat.1001335 | HYR1-Mediated Detoxification of Reactive Oxygen
Species Is Required for Full Virulence in the Rice Blast Fungus | During plant-pathogen interactions, the plant may mount several types of defense
responses to either block the pathogen completely or ameliorate the amount of
disease. Such responses include release of reactive oxygen species (ROS) to
attack the pathogen, as w... | Reactive oxygen species (ROS) are antimicrobial compounds and also serve as
stimulators and products of plant defense reactions. ROS appear to be active in
the critical zone where pathogens and plants come in contact. Therefore,
understanding the source, the r... | Molecular oxygen, itself relatively nontoxic, is important to most living organisms
on this planet. However, its derivatives, reactive oxygen species (ROS), can lead to
oxidative destruction of cells [1]. For example, in mammals, ROS can accelerate aging by
making holes i... |
10.1371/journal.pgen.1007486 | Rad51 recruitment and exclusion of non-homologous end joining during homologous recombination at a Tus/Ter mammalian replication fork barrier | Classical non-homologous end joining (C-NHEJ) and homologous recombination (HR) compete to repair mammalian chromosomal double strand breaks (DSBs). However, C-NHEJ has no impact on HR induced by DNA nicking enzymes. In this case, the replication fork is thought to convert the DNA nick into a one-ended DSB, which lacks... | Genomic instability is a significant contributor to human disease, ranging from hereditary developmental disorders to cancer predisposition. Two major triggers to genomic instability are chromosomal double strand breaks (DSBs) and the stalling of replication forks during the DNA synthesis (S phase) of the cell cycle. T... | The stalling of replication forks at sites of abnormal DNA structure, following collisions with transcription complexes or due to nucleotide pool depletion—collectively termed “replication stress”—is a significant contributor to genomic instability. Inherited mutations in genes that regulate the replication stress resp... |
10.1371/journal.ppat.1002940 | Genome Analyses of an Aggressive and Invasive Lineage of the Irish Potato Famine Pathogen | Pest and pathogen losses jeopardise global food security and ever since the 19th century Irish famine, potato late blight has exemplified this threat. The causal oomycete pathogen, Phytophthora infestans, undergoes major population shifts in agricultural systems via the successive emergence and migration of asexual lin... | We have documented a dramatic shift in the population of the potato late blight pathogen Phytophthora infestans in northwest Europe in which an invasive and aggressive lineage called 13_A2 has emerged and rapidly displaced other genotypes. The genome of a 13_A2 isolate revealed a high rate of sequence polymorphism and ... | As the cause of potato late blight, Phytophthora infestans is one of the most destructive plant pathogens within this genus of fungus-like oomycetes and widely known as the Irish potato famine pathogen [1], [2]. P. infestans has migrated from Central or South America [3], [4], where it infects many native solanaceous h... |
10.1371/journal.pgen.1005422 | Retrohoming of a Mobile Group II Intron in Human Cells Suggests How Eukaryotes Limit Group II Intron Proliferation | Mobile bacterial group II introns are evolutionary ancestors of spliceosomal introns and retroelements in eukaryotes. They consist of an autocatalytic intron RNA (a “ribozyme”) and an intron-encoded reverse transcriptase, which function together to promote intron integration into new DNA sites by a mechanism termed “re... | Mobile group II introns are bacterial retrotransposons that are evolutionary ancestors of spliceosomal introns and retroelements in eukaryotes. They consist of an autocatalytic intron RNA (a ribozyme) and an intron-encoded reverse transcriptase, which together promote intron mobility to new DNA sites by a mechanism cal... | Mobile group II introns are retrotransposons that also function as self-splicing introns [1]. They are found in bacteria, archaea, and in the bacterial endosymbiont-derived mitochondrial and chloroplast genomes of some eukaryotes, particularly fungi and plants [2]. Despite their prokaryotic origin, mobile group II intr... |
10.1371/journal.pcbi.1006239 | A local uPAR-plasmin-TGFβ1 positive feedback loop in a qualitative computational model of angiogenic sprouting explains the in vitro effect of fibrinogen variants | In experimental assays of angiogenesis in three-dimensional fibrin matrices, a temporary scaffold formed during wound healing, the type and composition of fibrin impacts the level of sprouting. More sprouts form on high molecular weight (HMW) than on low molecular weight (LMW) fibrin. It is unclear what mechanisms regu... | Therapies for a range of medical conditions, including cancer, wound healing and diabetic retinopathy can benefit from a better control over the growth of blood vessels. The chemical properties of fibrin, the material that forms scabs in wounds and can also occur in large concentrations in tumors, can regulate the degr... | Tissues that are low in oxygen stimulate the outgrowth of side-branches from nearby blood vessels, in a process called neo-angiogenesis. A detailed understanding of angiogenesis is relevant for a range of physiological and pathological processes where obtaining a fine-level control of angiogenesis is of interest. Patho... |
10.1371/journal.pbio.1001451 | The Mechanism of Toxicity in HET-S/HET-s Prion Incompatibility | The HET-s protein from the filamentous fungus Podospora anserina is a prion involved in a cell death reaction termed heterokaryon incompatibility. This reaction is observed at the point of contact between two genetically distinct strains when one harbors a HET-s prion (in the form of amyloid aggregates) and the other e... | Filamentous fungi have the potential for genetically distinct individuals to fuse, resulting in a cell with multiple nuclei known as a heterokaryon. This fusion event is controlled by genetic variants that determine the compatibility of the individuals, such that the fusion of incompatible genotypes triggers a cell dea... | Amyloids have long been associated with dozens of diseases including Alzheimer, Parkinson, and prion diseases [1]. However, there are also amyloids with normal biological activities termed “functional amyloids” [2] of which the HET-s prion of the filamentous fungus P. anserina is an interesting example. This prion prot... |
10.1371/journal.pbio.1001237 | A Modular Library of Small Molecule Signals Regulates Social Behaviors in Caenorhabditis elegans | The nematode C. elegans is an important model for the study of social behaviors. Recent investigations have shown that a family of small molecule signals, the ascarosides, controls population density sensing and mating behavior. However, despite extensive studies of C. elegans aggregation behaviors, no intraspecific si... | Chemical signaling is an ancient form of inter-organismal communication. The nematode Caenorhabditis elegans exhibits a wide range of social behaviors, including mutual attraction and aggregation, and has served as a useful model towards investigating the signaling pathways that regulate these behaviors. Recent investi... | Communication among individuals of a species relies on a number of different sensory inputs including chemical, mechanical, auditory, or visual cues [1]. Chemical signaling is perhaps the most ancient form of interorganismal communication [1],[2], and analysis of the chemical signals and the behaviors they mediate is o... |
10.1371/journal.pgen.1001144 | Gene–Environment Interactions at Nucleotide Resolution | Interactions among genes and the environment are a common source of phenotypic variation. To characterize the interplay between genetics and the environment at single nucleotide resolution, we quantified the genetic and environmental interactions of four quantitative trait nucleotides (QTN) that govern yeast sporulatio... | Phenotypic variation among individuals is caused by naturally occurring genetic differences, or alleles. The relationship between an allele and the phenotype is extremely complex; for example, the effect of an allele often depends upon both the environment and the individual's genetic background. To better understand t... | As we identify more genetic loci that underlie complex traits, the challenge remains to understand and predict the effects of the causal genetic variants upon individuals' phenotypes. The relationship between genotype and phenotype is rarely simple. The effect of an allele often depends upon the environment, resulting ... |
10.1371/journal.pgen.1003509 | Imputation-Based Meta-Analysis of Severe Malaria in Three African Populations | Combining data from genome-wide association studies (GWAS) conducted at different locations, using genotype imputation and fixed-effects meta-analysis, has been a powerful approach for dissecting complex disease genetics in populations of European ancestry. Here we investigate the feasibility of applying the same appro... | Malaria kills nearly a million people every year, most of whom are young children in Africa. The risk of developing severe malaria is known to be affected by genetics, but so far only a handful of genetic risk factors for malaria have been identified. We studied over a million DNA variants in over 5,000 individuals wit... | Severe malaria, meaning life-threatening complications of Plasmodium falciparum infection, kills on the order of a million African children each year [1]. However this represents only a small proportion of the total number of infected individuals, the majority of whom recover without life-threatening complications. Und... |
10.1371/journal.pcbi.1003773 | Unveiling Time in Dose-Response Models to Infer Host Susceptibility to Pathogens | The biological effects of interventions to control infectious diseases typically depend on the intensity of pathogen challenge. As much as the levels of natural pathogen circulation vary over time and geographical location, the development of invariant efficacy measures is of major importance, even if only indirectly i... | While control options for plant, animal, and human pathogens are emerging rapidly, reliable assessment of the effect of interventions in biological systems presents many challenges. A major question is how to connect laboratory experiments and measurements with the relevant process in natural settings, where hosts are ... | Hosts exposed to disease-causing agents respond in accordance to the challenge dose. Therefore dose-response curves contain information about disease processes that can be extracted by suitable analytic frameworks. Early examples concerning microbial risk assessment include counting lesions caused by tobacco mosaic vir... |
10.1371/journal.pgen.1007394 | Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth | Preterm birth is a leading cause of morbidity and mortality in infants. Genetic and environmental factors play a role in the susceptibility to preterm birth, but despite many investigations, the genetic basis for preterm birth remain largely unknown. Our objective was to identify rare, possibly damaging, nucleotide var... | Preterm birth is the leading cause of infant mortality, and prematurity is further associated with serious morbidities in later life. Genetic and environmental risk factors play a role in the susceptibility to preterm birth. Despite numerous studies, the genetic basis for preterm birth remains poorly defined. We invest... | Preterm birth (PTB), defined as birth before 37 completed weeks of gestation, is a major global public health concern. Worldwide, over 15 million infants (more than one in ten babies) are born preterm and of those, more than one million die from complications related to preterm birth each year [1]. Preterm birth and it... |
10.1371/journal.pcbi.1000567 | A Threading-Based Method for the Prediction of DNA-Binding Proteins with Application to the Human Genome | Diverse mechanisms for DNA-protein recognition have been elucidated in numerous atomic complex structures from various protein families. These structural data provide an invaluable knowledge base not only for understanding DNA-protein interactions, but also for developing specialized methods that predict the DNA-bindin... | DNA-binding proteins represent only a small fraction of proteins encoded in genomes, yet they play a critical role in a variety of biological activities. Identifying these proteins and understanding how they function are important issues. The structures of solved DNA protein complexes of different protein families prov... | The past decade has witnessed tremendous progress in genome sequencing [1]–[5]. According to the Genomes On Line Database, the complete sequenced genomes of almost 1,000 cellular organisms have been released, and about 5,000 active genome sequencing projects are on the way [6]. The unprecedented amount of genetic infor... |
10.1371/journal.pntd.0000529 | Mosquito Infection Responses to Developing Filarial Worms | Human lymphatic filariasis is a mosquito-vectored disease caused by the nematode parasites Wuchereria bancrofti, Brugia malayi and Brugia timori. These are relatively large roundworms that can cause considerable damage in compatible mosquito vectors. In order to assess how mosquitoes respond to infection in compatible ... | Filarial worms that cause human lymphatic filariasis (LF) are transmitted by many species of mosquitoes. Within susceptible mosquitoes, Brugia malayi develop from microfilariae (mf) to infective-stage larvae (L3s), in approximately eight days. These nematodes develop as intracellular parasites within mosquito flight mu... | It is estimated that 120 million people are infected with Wuchereria bancrofti, Brugia malayi, or B. timori, the mosquito-transmitted, parasitic nematodes that cause human lymphatic filariasis (LF). In approximately 40% of cases, the disease is manifested by lymphedema of the extremities or hydrocoele. Although human L... |
10.1371/journal.pgen.1004144 | Relationship Estimation from Whole-Genome Sequence Data | The determination of the relationship between a pair of individuals is a fundamental application of genetics. Previously, we and others have demonstrated that identity-by-descent (IBD) information generated from high-density single-nucleotide polymorphism (SNP) data can greatly improve the power and accuracy of genetic... | The determination of the relationship between a pair of individuals is a fundamental application of genetics. The most accurate methods for relationship estimation rely on precise, localized estimates of genetic sharing between individuals. Earlier methods have generated these estimates from high-density genetic marker... | The identification of related individuals from genetic data has a broad range of applications. The validation of known relationships in familial disease-gene studies ensures that pedigree errors or sample switches do not adversely affect power [1]. In case-control studies, the removal of related individuals is a standa... |
10.1371/journal.pntd.0002551 | Venezuelan Equine Encephalitis Viruses (VEEV) in Argentina: Serological Evidence of Human Infection | Venezuelan equine encephalitis viruses (VEEV) are responsible for human diseases in the Americas, producing severe or mild illness with symptoms indistinguishable from dengue and other arboviral diseases. For this reason, many cases remain without certain diagnosis. Seroprevalence studies for VEEV subtypes IAB, ID, IF ... | Venezuelan equine encephalitis viruses (VEEV) are responsible for human diseases in the Americas. They produce severe or mild illnesses with symptoms indistinguishable from dengue and other arboviral diseases; for this reason, many cases remain undiagnosed. We detected neutralizing antibodies (NTAbs) against VEEV IAB, ... | Venezuelan equine encephalitis (VEE) is a reemerging mosquito-borne viral disease that is severely debilitating and sometimes fatal to humans [1]. The etiological agent, VEE virus (VEEV), belongs to the VEE complex (Togaviridae: Alphavirus), one of the major alphavirus serogroups found in the New World [2]. Members of ... |
10.1371/journal.pcbi.1000923 | Correlated Mutations: A Hallmark of Phenotypic Amino Acid Substitutions | Point mutations resulting in the substitution of a single amino acid can cause severe functional consequences, but can also be completely harmless. Understanding what determines the phenotypical impact is important both for planning targeted mutation experiments in the laboratory and for analyzing naturally occurring m... | Point mutations (i.e., changes of a single sequence element) can have a severe impact on protein function. Many diseases are caused by such minute defects. On the other hand, the majority of such mutations does not lead to noticeable effects. Although previous research has revealed important aspects that influence or p... | Most of the missense mutations do not lead to an appreciable phenotype when they occur in nature or are introduced experimentally. There are, however, numerous counterexamples where even a subtle change of the primary protein sequence results in severe phenotypical effects – i.e. genetic disease. Understanding the unde... |
10.1371/journal.pntd.0001521 | Estimating the Non-Monetary Burden of Neurocysticercosis in Mexico | Neurocysticercosis (NCC) is a major public health problem in many developing countries where health education, sanitation, and meat inspection infrastructure are insufficient. The condition occurs when humans ingest eggs of the pork tapeworm Taenia solium, which then develop into larvae in the central nervous system. A... | Neurocysticercosis (NCC) is a major public health problem caused by the larvae of the parasite Taenia solium. The condition occurs when humans ingest eggs of the pork tapeworm Taenia solium, which then develop into larvae in the central nervous system. The disease is predominantly found and considered important in Lati... | Neurocysticercosis (NCC) is a major public health problem caused by the larvae of the zoonotic cestode Taenia solium. Humans are the definitive hosts of T. solium and become infected with the intestinal adult tapeworm (taeniasis) by ingesting undercooked pork containing cysticerci. Humans can also become accidental int... |
10.1371/journal.pgen.1005140 | Spatio-temporal Remodeling of Functional Membrane Microdomains Organizes the Signaling Networks of a Bacterium | Lipid rafts are membrane microdomains specialized in the regulation of numerous cellular processes related to membrane organization, as diverse as signal transduction, protein sorting, membrane trafficking or pathogen invasion. It has been proposed that this functional diversity would require a heterogeneous population... | Cellular membranes organize proteins related to signal transduction, protein sorting and membrane trafficking into the so-called lipid rafts. It has been proposed that the functional diversity of lipid rafts would require a heterogeneous population of raft domains with varying compositions. However, a mechanism for suc... | Cells typically compartmentalize their cellular processes into subcellular structures (e.g. organelles) to optimize their efficiency and improve their activity. One of the most interesting concepts in cellular compartmentalization is the proposed existence of lipid rafts in the membranes of eukaryotic cells [1]. Eukary... |
10.1371/journal.pgen.1005819 | Strong Components of Epigenetic Memory in Cultured Human Fibroblasts Related to Site of Origin and Donor Age | Differentiating pluripotent cells from fibroblast progenitors is a potentially transformative tool in personalized medicine. We previously identified relatively greater success culturing dura-derived fibroblasts than scalp-derived fibroblasts from postmortem tissue. We hypothesized that these differences in culture suc... | Regenerative medicine specialists have been using a type of cell commonly found in the skin called the fibroblast because it is easily obtained from skin samples, grows well in culture, and can be manipulated in the laboratory to de-differentiate into a primordial state known as the induced pluripotent stem cell. These... | DNA methylation (DNAm) at CpG dinucleotides plays an important role in the epigenetic regulation of the human genome, contributing to diverse cellular phenotypes from the same underlying genetic sequence. For example, DNAm levels at particular genomic loci can accurately classify different tissues [1] and even underlyi... |
10.1371/journal.pcbi.1003557 | Influence of Wiring Cost on the Large-Scale Architecture of Human Cortical Connectivity | In the past two decades some fundamental properties of cortical connectivity have been discovered: small-world structure, pronounced hierarchical and modular organisation, and strong core and rich-club structures. A common assumption when interpreting results of this kind is that the observed structural properties are ... | Macroscopic regions in the grey matter of the human brain are intricately connected by white-matter pathways, forming the extremely complex network of the brain. Analysing this brain network may provide us insights on how anatomy enables brain function and, ultimately, cognition and consciousness. Various important pri... | The physical brain is a network of extraordinary complexity on multiple spatial scales. On the macroscopic scale, regions are connected by a large number of white-matter projections that form an intricate system: the connectome [1]. Understanding the principles of the large-scale architecture of the brain, how this arc... |
10.1371/journal.pntd.0003608 | Prevalence and Diversity of Small Mammal-Associated Bartonella Species in Rural and Urban Kenya | Several rodent-associated Bartonella species are human pathogens but little is known about their epidemiology. We trapped rodents and shrews around human habitations at two sites in Kenya (rural Asembo and urban Kibera) to determine the prevalence of Bartonella infection. Bartonella were detected by culture in five of ... | Bartonella are bacteria that infect many different mammal species and can cause illness in people. Several Bartonella species carried by rodents cause disease in humans but little is known about their distribution or the importance of bartonellosis as a cause of human illness. Data from Africa are particularly scarce. ... | Bartonella species are Gram-negative haemotrophic bacteria that infect mammalian erythrocytes and are transmitted between hosts by blood-sucking arthropods. Over 30 species of Bartonella have been described and members of this genus infect a broad range of mammalian hosts including rodents, bats, carnivores and ruminan... |
10.1371/journal.pgen.1006205 | Integrity of Narrow Epithelial Tubes in the C. elegans Excretory System Requires a Transient Luminal Matrix | Most epithelial cells secrete a glycoprotein-rich apical extracellular matrix that can have diverse but still poorly understood roles in development and physiology. Zona Pellucida (ZP) domain glycoproteins are common constituents of these matrices, and their loss in humans is associated with a number of diseases. Under... | Most organs in the body are made up of networks of tubes that transport fluids or gases. These tubes come in many different sizes and shapes, with some narrow capillaries being only one cell in diameter. As tubes develop and take their final shapes, they secrete various glycoproteins into their hollow interior or lumen... | Most epithelial and endothelial tube cells secrete an apical extracellular matrix (aECM) or glycocalyx that lines the tube lumen and consists of a complex mix of gel-forming and fibril-forming glycoproteins, including both secreted and transmembrane proteoglycans, mucins, and zona pellucida (ZP) domain proteins [1–4]. ... |
10.1371/journal.ppat.1006574 | The role of the C-terminal D0 domain of flagellin in activation of Toll like receptor 5 | Flagellin is a wide-spread bacterial virulence factor sensed by the membrane-bound Toll-like receptor 5 (TLR5) and by the intracellular NAIP5/NLRC4 inflammasome receptor. TLR5 recognizes a conserved region within the D1 domain of flagellin, crucial for the interaction between subunits in the flagellum and for bacterial... | Receptors of the innate immune system typically recognize conserved microbial patterns, crucial for pathogen fitness and survival. Flagellin, the main structural protein of bacterial flagella, is recognized by two receptors of the innate immune system, the intracellular inflammasome receptor NAIP5/NLRC4 and the membran... | Toll-like receptors (TLRs) belong to a family of germ-line encoded innate immune receptors able to sense pathogen-associated molecular patterns (PAMPs) [1]. Upon ligand binding, TLRs dimerize, recruiting adaptor molecules that bind to the intracellular TIR domain dimer and induce downstream signaling, resulting in the ... |
10.1371/journal.pntd.0003866 | A Systematic Review of the Mortality from Untreated Leptospirosis | Leptospirosis occurs worldwide, but the global incidence of human disease and its mortality are not well understood. Many patients are undiagnosed and untreated due to its non-specific symptoms and a lack of access to diagnostics. This study systematically reviews the literature to clarify the mortality from untreated ... | Leptospirosis is a common cause of fever in the developing world but often goes undiagnosed and untreated due to its non-specific clinical features and the limited availability of point-of-care diagnostics. This review systematically evaluated available literature to clarify the mortality from untreated leptospirosis. ... | Leptospirosis is a bacterial zoonosis caused by pathogenic Leptospira species which are transmitted to humans by exposure to water containing the urine of infected mammals, predominantly rodents [1]. The disease occurs worldwide and over 853,000 cases and 48,000 deaths are estimated to occur each year [2]. Incidence is... |
10.1371/journal.ppat.1007124 | Flap endonuclease 1 is involved in cccDNA formation in the hepatitis B virus | Hepatitis B virus (HBV) is one of the major etiological pathogens for liver cirrhosis and hepatocellular carcinoma. Chronic HBV infection is a key factor in these severe liver diseases. During infection, HBV forms a nuclear viral episome in the form of covalently closed circular DNA (cccDNA). Current therapies are not ... | Hepatitis B virus (HBV) infection remains a worldwide health problem that affects more than 350 million people. HBV is one of the major etiological pathogens for liver cirrhosis and hepatocellular carcinoma. HBV covalently closed circular DNA (cccDNA) is a key viral intermediate for persistent infection. However, the m... | Hepatitis B virus (HBV) is a major pathogenic cause of human cirrhosis and hepatocellular carcinoma [1]. Infectious HBV particles contain relaxed circular DNA (rcDNA) encapsidated by core proteins [2]. After entering the host hepatocyte, rcDNA is converted into covalently closed circular DNA (cccDNA), which is stably m... |
10.1371/journal.pgen.1000416 | The Complete Genome and Proteome of Laribacter hongkongensis Reveal Potential Mechanisms for Adaptations to Different Temperatures and Habitats | Laribacter hongkongensis is a newly discovered Gram-negative bacillus of the Neisseriaceae family associated with freshwater fish–borne gastroenteritis and traveler's diarrhea. The complete genome sequence of L. hongkongensis HLHK9, recovered from an immunocompetent patient with severe gastroenteritis, consists of a 3,... | Laribacter hongkongensis is a recently discovered bacterium associated with gastroenteritis and traveler's diarrhea. Freshwater fish is the reservoir of L. hongkongensis. In order to achieve a rapid understanding on the mechanisms by which the bacterium adapts to different habitats and its potential virulence factors, ... | Laribacter hongkongensis is a recently discovered, Gram-negative, facultative anaerobic, motile, seagull or S-shaped, asaccharolytic, urease-positive bacillus that belongs to the Neisseriaceae family of β-proteobacteria [1]. It was first isolated from the blood and thoracic empyema of an alcoholic liver cirrhosis patie... |
10.1371/journal.ppat.1005862 | MIF-Mediated Hemodilution Promotes Pathogenic Anemia in Experimental African Trypanosomosis | Animal African trypanosomosis is a major threat to the economic development and human health in sub-Saharan Africa. Trypanosoma congolense infections represent the major constraint in livestock production, with anemia as the major pathogenic lethal feature. The mechanisms underlying anemia development are ill defined, ... | Bovine African trypanosomosis is a parasitic disease of veterinary importance that adversely affects the public health and economic development of sub-Saharan Africa. Anemia is a major cause of death associated with this disease. Yet, the mechanisms underlying anemia development are not elucidated, which hampers the de... | African trypanosomosis (AT) is a neglected tropical disease of medical and veterinary importance that adversely affects human health and welfare, as well as the economic development in sub-Saharan Africa [1,2]. AT is caused by blood-borne hemoflagellated protozoan parasites from the Trypanosoma genus that are transmitt... |
10.1371/journal.pbio.1000080 | Impaired Antibody Response Causes Persistence of Prototypic T Cell–Contained Virus | CD8 T cells are recognized key players in control of persistent virus infections, but increasing evidence suggests that assistance from other immune mediators is also needed. Here, we investigated whether specific antibody responses contribute to control of lymphocytic choriomeningitis virus (LCMV), a prototypic mouse ... | Persistent viruses such as hepatitis C virus (HCV) or HIV can defeat the body's defense system and cause devastating epidemics worldwide. Recent attempts at vaccinating against HIV have relied on the induction of specific antiviral killer T lymphocytes but have failed to confer protection on the host. Better knowledge ... | Infections associated with persistent viremia include human immunodeficiency virus (HIV) and the hepatitis B and C viruses (HBV, HCV), which affect more than 500 million people worldwide. However, available options to prevent and treat particularly HIV and HCV are unsatisfactory. To refine existing strategies aimed at ... |
10.1371/journal.pcbi.1006794 | A complete statistical model for calibration of RNA-seq counts using external spike-ins and maximum likelihood theory | A fundamental assumption, common to the vast majority of high-throughput transcriptome analyses, is that the expression of most genes is unchanged among samples and that total cellular RNA remains constant. As the number of analyzed experimental systems increases however, different independent studies demonstrate that ... | We present a complete statistical model for the analysis of RNA-seq data from a population of cells using external RNA spike-ins and a maximum-likelihood method for genome-wide estimation of transcripts per cell. The model includes biological variability of cellular transcript number and sampling noise. We derive an un... | Accurate transcriptome measurements are central to understanding the fundamental mechanisms of gene expression. A main challenge presented by the RNA-seq method for digitizing information about cellular RNA content—both its composition and abundance—is correcting noise, errors, and biases introduced in the process of m... |
10.1371/journal.pcbi.1004527 | Reputation Effects in Public and Private Interactions | We study the evolution of cooperation in a model of indirect reciprocity where people interact in public and private situations. Public interactions have a high chance to be observed by others and always affect reputation. Private interactions have a lower chance to be observed and only occasionally affect reputation. ... | We study the evolution of cooperation based on reputation. This mechanism is called indirect reciprocity. In a world of binary reputations, people help a good individual but do not help a bad one. They also monitor their own reputation to receive reciprocation from others. We propose a novel model of indirect reciproci... | Most human interactions occur in situations where repetition is possible and reputation is at stake. Repeated interactions in a group of players facilitate evolution of cooperation via indirect reciprocity [1, 2]: here players use conditional strategies that depend on what has happened between others. Cooperation is co... |
10.1371/journal.pcbi.1003951 | The HIV Mutation Browser: A Resource for Human Immunodeficiency Virus Mutagenesis and Polymorphism Data | Huge research effort has been invested over many years to determine the phenotypes of natural or artificial mutations in HIV proteins—interpretation of mutation phenotypes is an invaluable source of new knowledge. The results of this research effort are recorded in the scientific literature, but it is difficult for vir... | Naturally occurring mutations within the HIV proteome are of therapeutic interest as they can affect the virulence of the virus or result in drug resistance. Furthermore, directed mutagenesis of specific residues is a common method to investigate the function and mechanism of the viral proteins. We have developed novel... | Human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS), infects millions of people worldwide and, to date, has been responsible for over 25 million deaths [1]. The clinical importance of the virus has prompted substantial funding of HIV/AIDS research across many diverse cli... |
10.1371/journal.ppat.1005042 | Human Non-neutralizing HIV-1 Envelope Monoclonal Antibodies Limit the Number of Founder Viruses during SHIV Mucosal Infection in Rhesus Macaques | HIV-1 mucosal transmission begins with virus or virus-infected cells moving through mucus across mucosal epithelium to infect CD4+ T cells. Although broadly neutralizing antibodies (bnAbs) are the type of HIV-1 antibodies that are most likely protective, they are not induced with current vaccine candidates. In contrast... | Antibodies specifically recognize antigenic sites on pathogens and can mediate multiple antiviral functions through engagement of effector cells via their Fc region. Current HIV-1 vaccine candidates induce polyclonal antibody responses with multiple antiviral functions, but do not induce broadly neutralizing antibodies... | The induction of HIV-1 broadly reactive neutralizing antibodies (bnAbs) by experimental vaccines is a critical goal of HIV-1 vaccine development efforts. However, bnAbs cannot be induced by existing HIV-1 vaccine candidates [1]. The RV144 ALVAC/AIDSVAX B/E HIV-1 vaccine efficacy trial demonstrated 31.2% estimated vacci... |
10.1371/journal.pcbi.1000608 | Predicting Functional Alternative Splicing by Measuring RNA Selection Pressure from Multigenome Alignments | High-throughput methods such as EST sequencing, microarrays and deep sequencing have identified large numbers of alternative splicing (AS) events, but studies have shown that only a subset of these may be functional. Here we report a sensitive bioinformatics approach that identifies exons with evidence of a strong RNA ... | Alternative splicing is an important mechanism for regulating gene function in complex organisms, and has been shown to play a key role in human diseases such as cancer. Recently, high-throughput technologies have been used in an effort to detect alternative splicing events throughout the human genome. However, validat... | Global analyses of alternative splicing (AS) have established its importance in protein diversity and gene regulation in higher eukaryotes [1],[2]. Alternative splicing can regulate biological function by altering the sequence of protein products and modulating transcript expression levels [3]. Alternative splicing can... |
10.1371/journal.ppat.1003213 | An Overexpression Screen of Toxoplasma gondii Rab-GTPases Reveals Distinct Transport Routes to the Micronemes | The basic organisation of the endomembrane system is conserved in all eukaryotes and comparative genome analyses provides compelling evidence that the endomembrane system of the last common eukaryotic ancestor (LCEA) is complex with many genes required for regulated traffic being present. Although apicomplexan parasite... | Eukaryotic cells evolved a highly complex endomembrane system, consisting of secretory and endocytic organelles. In the case of apicomplexan parasites unique secretory organelles have evolved that are essential for the invasion of the host cell. Surprisingly these protozoans show a paucity of trafficking factors, such ... | Eukaryotic cells evolved a complex internal membrane system, giving rise to specialised organelles that are linked to the endocytic or exocytic pathway. The basic organisation of the endomembrane system is conserved in all eukaryotes and includes the ER, Golgi and major exocytic pathways [1]. Indeed, recent efforts to ... |
10.1371/journal.ppat.1005126 | Extracellular Adenosine Protects against Streptococcus pneumoniae Lung Infection by Regulating Pulmonary Neutrophil Recruitment | An important determinant of disease following Streptococcus pneumoniae (pneumococcus) lung infection is pulmonary inflammation mediated by polymorphonuclear leukocytes (PMNs). We found that upon intratracheal challenge of mice, recruitment of PMNs into the lungs within the first 3 hours coincided with decreased pulmona... | Despite the presence of vaccines and antibiotic therapies, invasive Streptococcus pneumoniae (pneumococcus) infections, such as pneumonia, bacteremia and meningitis, remain a leading cause of mortality and morbidity worldwide. Understanding the host factors that influence the outcome of S. pneumoniae infection will all... | Despite vaccines and antibiotic therapies, invasive Streptococcus pneumoniae (pneumococcus) infections such as pneumonia, meningitis and bacteremia remain a considerable health and economic burden [1,2]. A major determinant of disease following S. pneumoniae infection is pulmonary inflammation, which, if excessive, can... |
10.1371/journal.pgen.1002506 | A Regulatory Network for Coordinated Flower Maturation | For self-pollinating plants to reproduce, male and female organ development must be coordinated as flowers mature. The Arabidopsis transcription factors AUXIN RESPONSE FACTOR 6 (ARF6) and ARF8 regulate this complex process by promoting petal expansion, stamen filament elongation, anther dehiscence, and gynoecium matura... | Perfect flowers have both male organs that produce and release pollen and female organs that make and harbor seeds. Flowers also often attract pollinators using visual or chemical signals. So that male, female, and pollinator attraction functions occur at the right time, flower organs must grow and mature in a coordina... | In typical angiosperms, late in flower development, sepals open to expose the inner organs; the petals, stamen filaments, and style elongate; the anthers dehisce to release pollen; and the stigma and transmitting tract mature so as to permit pollen germination and pollen tube growth. These events often occur quite quic... |
10.1371/journal.pbio.2005750 | A systems genetics resource and analysis of sleep regulation in the mouse | Sleep is essential for optimal brain functioning and health, but the biological substrates through which sleep delivers these beneficial effects remain largely unknown. We used a systems genetics approach in the BXD genetic reference population (GRP) of mice and assembled a comprehensive experimental knowledge base com... | Sleep is essential for optimal brain functioning and health, but the biological substrates through which sleep delivers these beneficial effects remain largely unknown. We used a systems genetics approach in a large, diverse reference population of mice and assembled a comprehensive experimental knowledge base comprisi... | Insufficient or disrupted sleep characterizes the 24 h lifestyle of modern society and represents a serious public health concern, as it is associated with increased risk for, e.g., obesity, diabetes, and high blood pressure, and impairs cognitive performance, which in turn increases the likelihood of accidents, medica... |
10.1371/journal.pntd.0003922 | Elimination of Onchocerciasis from Mexico | Mexico is one of the six countries formerly endemic for onchocerciasis in Latin America. Transmission has been interrupted in the three endemic foci of that country and mass drug distribution has ceased. Three years after mass drug distribution ended, post-treatment surveillance (PTS) surveys were undertaken which empl... | Onchocerciasis, or river blindness, is one of the neglected tropical diseases targeted by the international community for elimination. In Mexico, onchocerciasis was historically endemic in three foci, which included Northern Chiapias, Southern Chiapas and Oaxaca. Both the criteria for verification of elimination and fo... | Onchocerciasis (river blindness) is caused by chronic infection with Onchocerca volvulus, a filarial nematode that is transmitted by Simulium spp. (Diptera: Simuliidae). The disease historically has constituted a serious public health concern and an enormous source of socio-economic disruption in many developing countr... |
10.1371/journal.pgen.1007194 | Paternal lineage early onset hereditary ovarian cancers: A Familial Ovarian Cancer Registry study | Given prior evidence that an affected woman conveys a higher risk of ovarian cancer to her sister than to her mother, we hypothesized that there exists an X-linked variant evidenced by transmission to a woman from her paternal grandmother via her father. We ascertained 3,499 grandmother/granddaughter pairs from the Fam... | Our article uses the largest familial study of ovarian cancer to argue that there exists an ovarian cancer susceptibility gene on the X-chromosome acting independently of BRCA1 and BRCA2. This observation implies that there may be many cases of seemingly sporadic ovarian cancer that are actually inherited; for example,... | A history of ovarian cancer among first-order relatives remains the strongest and best-characterized predictor of ovarian cancer risk [1–3] and a main determinant of genetic testing referral [4, 5]. The evidence for a monogenic, autosomal dominant mode of inherited risk dates to the pre-BRCA era where studies focused o... |
10.1371/journal.pcbi.1003962 | Intrinsic Neuronal Properties Switch the Mode of Information Transmission in Networks | Diverse ion channels and their dynamics endow single neurons with complex biophysical properties. These properties determine the heterogeneity of cell types that make up the brain, as constituents of neural circuits tuned to perform highly specific computations. How do biophysical properties of single neurons impact ne... | Differences in ion channel composition endow different neuronal types with distinct computational properties. Understanding how these biophysical differences affect network-level computation is an important frontier. We focus on a set of biophysical properties, experimentally observed in developing cortical neurons, th... | Gain scaling refers to the ability of neurons to scale the gain of their responses when stimulated with currents of different amplitudes. A common property of neural systems, gain scaling adjusts the system's response to the size of the input relative to the input's standard deviation [1]. This form of adaptation maxim... |
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