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10.1371/journal.pcbi.1007226 | Energy-efficient information transfer at thalamocortical synapses | We have previously shown that the physiological size of postsynaptic currents maximises energy efficiency rather than information transfer across the retinothalamic relay synapse. Here, we investigate information transmission and postsynaptic energy use at the next synapse along the visual pathway: from relay neurons i... | Compared to other organs, the brain consumes a vast amount of energy for its size. Most of this energy is used to power the electrical and chemical processes that support neural computation. As the energy supply to the brain is limited, it follows that this computation should be energetically efficient. Previously, we ... | Information transmission in the brain is energetically expensive [1–7], yet has to satisfy demands of speed and signal-to-noise reliability [8, 9]. In order to balance these competing demands, the brain may tend towards a design which prioritises energy efficiency at the expense of computational power. For instance, th... |
10.1371/journal.pntd.0005883 | Decoding the similarities and differences among mycobacterial species | Mycobacteriaceae comprises pathogenic species such as Mycobacterium tuberculosis, M. leprae and M. abscessus, as well as non-pathogenic species, for example, M. smegmatis and M. thermoresistibile. Genome comparison and annotation studies provide insights into genome evolutionary relatedness, identify unique and pathoge... | Members of the Mycobacteriaceae family, which are known to adapt to different environmental niches, comprise bacterial species with varied genome sizes. They are unique in their cell-wall composition, which is remarkably thick and lipid-rich as compared to other bacteria. We performed a comparative analysis at the prot... | Mycobacteriacea are known etiological agents for a variety of human infections and are broadly classified as Mycobacterium tuberculosis (M. tuberculosis) complex (MTBC) and Non-Tuberculous Mycobacteria (NTM). The MTBC includes several pathogenic species including M. tuberculosis that causes tuberculosis (TB) in ~10.4 m... |
10.1371/journal.pcbi.1002283 | Chemotaxis when Bacteria Remember: Drift versus Diffusion | Escherichia coli (E. coli) bacteria govern their trajectories by switching between running and tumbling modes as a function of the nutrient concentration they experienced in the past. At short time one observes a drift of the bacterial population, while at long time one observes accumulation in high-nutrient regions. R... | The chemotaxis of Escherichia coli is a prototypical model of navigational strategy. The bacterium maneuvers by switching between near-straight motion, termed runs, and tumbles which reorient its direction. To reach regions of high nutrient concentration, the run-durations are modulated according to the nutrient concen... | The bacterium E. coli moves by switching between two types of motions, termed ‘run’ and ‘tumble’ [1]. Each results from a distinct movement of the flagella. During a run, flagella motors rotate counter-clockwise (when looking at the bacteria from the back), inducing an almost constant forward velocity of about , along ... |
10.1371/journal.pcbi.1001039 | Widespread Compensatory Evolution Conserves DNA-Encoded Nucleosome Organization in Yeast | Evolution maintains organismal fitness by preserving genomic information. This is widely assumed to involve conservation of specific genomic loci among species. Many genomic encodings are now recognized to integrate small contributions from multiple genomic positions into quantitative dispersed codes, but the evolution... | Purifying selection is a major force in conserving genomic features. It pushes deleterious mutations to extinction while conserving the specific DNA sequence. Here we show that a large proportion of the yeast genome evolves under compensatory dynamics that conserve genomic properties while modifying the genomic sequenc... | With the complete sequencing of a large number of genomes, and with the rapid progress in the development and application of methodologies for functional annotation of whole genomes [1], it is becoming evident that our basic concepts of genomic function must be updated. The view of genomes as “bags of genes” is challen... |
10.1371/journal.pcbi.1005984 | Self-crowding of AMPA receptors in the excitatory postsynaptic density can effectuate anomalous receptor sub-diffusion | AMPA receptors (AMPARs) and their associations with auxiliary transmembrane proteins are bulky structures with large steric-exclusion volumes. Hence, self-crowding of AMPARs, depending on the local density, may affect their lateral diffusion in the postsynaptic membrane as well as in the highly crowded postsynaptic den... | The transmembrane AMPA receptors (AMPARs) prominently exhibit lateral diffusion in the postsynaptic membrane at excitatory synapses. Steric obstructions to AMPAR diffusion due to the crowd of other relatively static transmembrane proteins and binding of AMPARs to the submembranous scaffold proteins in the specialized r... | Glutamate-binding transmembrane alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-type receptors (AMPARs) are the pivotal element of fast synaptic transmission at excitatory synapses in the central nervous system [1, 2]. At the site of synaptic contact, these receptors are present at high density within ... |
10.1371/journal.pcbi.1005151 | High-Accuracy HLA Type Inference from Whole-Genome Sequencing Data Using Population Reference Graphs | Genetic variation at the Human Leucocyte Antigen (HLA) genes is associated with many autoimmune and infectious disease phenotypes, is an important element of the immunological distinction between self and non-self, and shapes immune epitope repertoires. Determining the allelic state of the HLA genes (HLA typing) as a b... | Determining an individual’s HLA type (the sequence of the exons of the HLA genes) is important in many areas of biomedical research. For example, HLA types shape immune epitope repertoires, which are relevant in cancer immunotherapy, and influence autoimmune and infectious disease risk. Whole-genome sequencing data, cu... | Genetic variation at HLA loci, both classical and non-classical, is associated with many medical phenotypes including risk of autoimmune [1–3] and infectious [4] disease, adverse drug reactions [5, 6], success of tissue and organ transplants [7], and, via epitope presentation preferences, the success of cancer immunoth... |
10.1371/journal.pntd.0003500 | Species-Specific Antimonial Sensitivity in Leishmania Is Driven by Post-Transcriptional Regulation of AQP1 | Leishmania is a digenetic protozoan parasite causing leishmaniasis in humans. The different clinical forms of leishmaniasis are caused by more than twenty species of Leishmania that are transmitted by nearly thirty species of phlebotomine sand flies. Pentavalent antimonials (such as Pentostam or Glucantime) are the fir... | The degree of response to antimonial drugs varies widely between species and even among strains of the same species of the protozoan parasite Leishmania. However, the molecular mechanism(s) is unknown. In this study, we show that Leishmania aquaglyceroporin AQP1 drives this species-specific antimonial resistance. Aquag... | Leishmaniasis is a protozoan parasitic infection in humans and other mammals that is transmitted by the bites of sandflies. The infection is caused by more than 20 different Leishmania species. The clinical manifestations range from self-healing cutaneous leishmaniasis (CL) to a potentially life threatening mucocutaneo... |
10.1371/journal.pbio.1002369 | Chromosome Synapsis Alleviates Mek1-Dependent Suppression of Meiotic DNA Repair | Faithful meiotic chromosome segregation and fertility require meiotic recombination between homologous chromosomes rather than the equally available sister chromatid, a bias that in Saccharomyces cerevisiae depends on the meiotic kinase, Mek1. Mek1 is thought to mediate repair template bias by specifically suppressing ... | Chromosome segregation errors during meiosis may cause infertility, fetal loss, or birth defects. To avoid meiotic chromosome segregation errors, recombination-mediated linkages are established between previously unattached homologous chromosomes. Such recombination events initiate with breaks in the DNA, but how these... | Meiosis is a specialized cell division that produces haploid gametes from diploid progenitors and is essential for sexual reproduction. The reduction in ploidy is achieved by a unique chromosome division phase (meiosis I) that segregates homologous chromosomes (homologues). Errors in this process are a leading cause of... |
10.1371/journal.pntd.0004320 | Costs of Three Wolbachia Infections on the Survival of Aedes aegypti Larvae under Starvation Conditions | The mosquito Aedes aegypti, the principal vector of dengue virus, has recently been infected experimentally with Wolbachia: intracellular bacteria that possess potential as dengue biological control agents. Wolbachia depend on their hosts for nutrients they are unable to synthesize themselves. Consequently, competition... | Dengue is currently the most important arboviral disease in the world. With no effective treatment or commercial vaccine available, strategies to control dengue focus on its mosquito vectors, primarily Aedes aegypti. A recent effort to reduce the burden of dengue aims to replace native Ae. aegypti with those refractory... | Dengue fever is an increasing threat to global health. An estimated 50 to 390 million new cases of dengue occur annually, with 2.5 billion people living in areas at risk of infection [1,2]. At present, dengue lacks an effective treatment or vaccine that protects against all serotypes of the virus. Thus, strategies to r... |
10.1371/journal.pcbi.1002164 | Network-Based Prediction and Analysis of HIV Dependency Factors | HIV Dependency Factors (HDFs) are a class of human proteins that are essential for HIV replication, but are not lethal to the host cell when silenced. Three previous genome-wide RNAi experiments identified HDF sets with little overlap. We combine data from these three studies with a human protein interaction network to... | Medicines to cure infectious diseases usually target proteins in the pathogens. Since pathogens have short life cycles, the targeted proteins can rapidly evolve and make the medicines ineffective, especially in viruses such as HIV. However, since viruses have very small genomes, they must exploit the cellular machinery... | Conventional high-throughput antiviral discovery often targets the activities of specific viral enzymes. These approaches have been ineffective in stemming the emergence of drug-resistant variants, especially in the face of rapidly-mutating RNA viruses. One powerful yet under-explored avenue is the evolutionarily resil... |
10.1371/journal.pmed.1002472 | Estimated clinical impact of the Xpert MTB/RIF Ultra cartridge for diagnosis of pulmonary tuberculosis: A modeling study | The Xpert MTB/RIF (Xpert) assay offers rapid and accurate diagnosis of tuberculosis (TB) but still suffers from imperfect sensitivity. The newer Xpert MTB/RIF Ultra cartridge has shown improved sensitivity in recent field trials, but at the expense of reduced specificity. The clinical implications of switching from the... | Xpert Ultra is a new version of a widely used molecular test for tuberculosis (TB) that has a better ability to detect TB (higher sensitivity) but also more frequently gives false-positive results (lower specificity).
These differences in sensitivity and specificity will have different clinical implications in settings... | Introduced in 2010, Xpert MTB/RIF (Xpert)—a molecular assay for the detection of tuberculosis (TB) and resistance to rifampin—provides substantial improvements in sensitivity over sputum smear microscopy, previously the cornerstone of TB diagnosis [1]. The sensitivity of Xpert remains imperfect, however, particularly i... |
10.1371/journal.pgen.1003079 | The CPEB Protein Orb2 Has Multiple Functions during Spermatogenesis in Drosophila melanogaster | Cytoplasmic Polyadenylation Element Binding (CPEB) proteins are translational regulators that can either activate or repress translation depending on the target mRNA and the specific biological context. There are two CPEB subfamilies and most animals have one or more genes from each. Drosophila has a single CPEB gene, ... | Cytoplasmic Polyadenylation Element Binding (CPEB) proteins bind and recognize CPE sequences in the 3′ UTRs of target mRNAs and can activate and/or repress their translation depending on the mRNA species and the biological context. Drosophila has two CPEB family genes, orb and orb2. orb is expressed in the germline of ... | Proteins in the Cytoplasmic Polyadenylation Element Binding (CPEB) family were first identified in Drosophila ovaries and Xenopus oocytes [1]–[4]. In both organisms the CPEB proteins function in the localization and translational regulation of mRNAs encoding key developmental and polarity determinants as well as factor... |
10.1371/journal.pgen.1004439 | Recombination Accelerates Adaptation on a Large-Scale Empirical Fitness Landscape in HIV-1 | Recombination has the potential to facilitate adaptation. In spite of the substantial body of theory on the impact of recombination on the evolutionary dynamics of adapting populations, empirical evidence to test these theories is still scarce. We examined the effect of recombination on adaptation on a large-scale empi... | One of the most challenging issues in evolutionary biology concerns the question of why most organisms exchange genetic material with each other, e.g. during sexual reproduction. Gene shuffling can create genetic diversity that facilitates adaptation to new environments, but theory shows that this effect is highly depe... | Recombination, here broadly defined as the shuffling of genetic material, is widespread in nature and occurs among a wide range of taxa, including most eukaryotes but also bacteria and viruses. It has long been believed that sex and recombination facilitate adaptation by increasing the genetic variance upon which natur... |
10.1371/journal.ppat.1000460 | Mycobacterium tuberculosis Universal Stress Protein Rv2623 Regulates Bacillary Growth by ATP-Binding: Requirement for Establishing Chronic Persistent Infection | Tuberculous latency and reactivation play a significant role in the pathogenesis of tuberculosis, yet the mechanisms that regulate these processes remain unclear. The Mycobacterium tuberculosis universal stress protein (USP) homolog, rv2623, is among the most highly induced genes when the tubercle bacillus is subjected... | Mycobacterium tuberculosis poses serious threats to public health worldwide. The ability of this pathogen to establish in the host a clinically silent, persistent latent infection that can subsequently reactivate to cause diseases constitutes a major challenge in controlling tuberculosis. Our study showed that an M. tu... | Mycobacterium tuberculosis, one of the most successful human pathogens, infects one-third of the world's population, causing nearly two million deaths per year [1]. Epidemiological data estimate that, in the immunocompetent host, only ∼10% of M. tuberculosis infection progress to active pulmonary disease. The remaining... |
10.1371/journal.pntd.0004856 | Spatiotemporal Co-existence of Two Mycobacterium ulcerans Clonal Complexes in the Offin River Valley of Ghana | In recent years, comparative genome sequence analysis of African Mycobacterium ulcerans strains isolated from Buruli ulcer (BU) lesion specimen has revealed a very limited genetic diversity of closely related isolates and a striking association between genotype and geographical origin of the patients. Here, we compared... | Infection with Mycobacterium ulcerans causes the debilitating skin disease Buruli ulcer. Until today, transmission pathways and reservoirs of this emerging pathogen are not well understood. Generally, it is assumed that infection occurs after contact with potential environmental sources of M. ulcerans through puncture ... | Mycobacterium ulcerans is an emerging pathogen with elusive reservoirs and transmission pathways. It causes the devastating skin disease Buruli ulcer (BU) that mainly affects rural populations in West Africa [1]. M. ulcerans is a descendant of the fish and occasionally human pathogen Mycobacterium marinum [2], from whi... |
10.1371/journal.ppat.1006533 | Structural basis of Zn(II) induced metal detoxification and antibiotic resistance by histidine kinase CzcS in Pseudomonas aeruginosa | Pseudomonas aeruginosa (P. aeruginosa) is a major opportunistic human pathogen, causing serious nosocomial infections among immunocompromised patients by multi-determinant virulence and high antibiotic resistance. The CzcR-CzcS signal transduction system in P. aeruginosa is primarily involved in metal detoxification an... | P. aeruginosa inhabits diverse environments and is one of the most prevalent opportunistic human pathogens of immunocompromised patients. The high antibiotic resistance is a major cause of therapeutic failure in the treatment of P. aeruginosa infections. The opportunistic pathogen P. aeruginosa co-regulates cross-resis... | Bacteria are extremely versatile that can regulate cellular processes in a sophisticated manner and thereby survive in changing environments. The two-component system (TCS) is the predominant strategy for coupling various extracellular stimuli to appropriate cellular responses in microorganisms [1–5]. In Pseudomonas ae... |
10.1371/journal.ppat.1003185 | Nosema ceranae Escapes Fumagillin Control in Honey Bees | Fumagillin is the only antibiotic approved for control of nosema disease in honey bees and has been extensively used in United States apiculture for more than 50 years for control of Nosema apis. It is toxic to mammals and must be applied seasonally and with caution to avoid residues in honey. Fumagillin degrades or is... | Nosema ceranae, a microsporidian pathogen described from Asian honey bees, was discovered infecting European honey bees coincident with early reports of Colony Collapse Disorder (CCD) and has been suggested to be a factor in honey bee declines. Use of fumagillin, the only known reliable treatment for the naturally occu... | Bicyclohexylammonium fumagillin, an antibiotic isolated from the fungus Aspergillus fumigatus, has been the only widely used treatment for nosemosis, or “nosema disease”, in western honey bees, Apis mellifera, [1], [2] for nearly 60 years [2]. The antibiotic (hereafter “fumagillin”), in the form of a 3% concentration f... |
10.1371/journal.pntd.0004260 | Quantifying Poverty as a Driver of Ebola Transmission | Poverty has been implicated as a challenge in the control of the current Ebola outbreak in West Africa. Although disparities between affected countries have been appreciated, disparities within West African countries have not been investigated as drivers of Ebola transmission. To quantify the role that poverty plays in... | Despite recognition that resource constraints contributed to the difficulty in controlling West Africa’s ongoing Ebola outbreak, no previous study has been conducted to quantify the impact of poverty on transmission. In particular, the extent to which within country heterogeneity in socioeconomic status (SES) could be ... | The 2014–2015 Ebola outbreak continues to have a global impact. Prevention and preparedness measures remain in place at airports and hospitals across the United States and Europe, while ongoing transmission in West Africa has led to a case count exceeding 28,450 [1]. Since October 2014, however, the epidemic has been d... |
10.1371/journal.pgen.1005839 | Repeat-Associated Fission Yeast-Like Regional Centromeres in the Ascomycetous Budding Yeast Candida tropicalis | The centromere, on which kinetochore proteins assemble, ensures precise chromosome segregation. Centromeres are largely specified by the histone H3 variant CENP-A (also known as Cse4 in yeasts). Structurally, centromere DNA sequences are highly diverse in nature. However, the evolutionary consequence of these structura... | Centromeres aid in high fidelity chromosome segregation. Paradoxically, centromere DNA sequences are rapidly evolving in fungi, plants, and animals. Centromere DNA sequences in fungi can be unique in each chromosome or share conserved features such as motifs for sequence specific protein binding, pericentric repeats, o... | The high fidelity segregation of replicated chromosomes to daughter cells during cell division is essential in maintaining genome integrity. It is achieved by a dynamic and well-coordinated kinetochore-microtubule interaction on a specialized chromosomal element, known as the centromere. Strikingly, the centromere DNA ... |
10.1371/journal.pcbi.1004342 | Posterior Probability Matching and Human Perceptual Decision Making | Probability matching is a classic theory of decision making that was first developed in models of cognition. Posterior probability matching, a variant in which observers match their response probabilities to the posterior probability of each response being correct, is being used increasingly often in models of percepti... | Decision making is partly random: a person can make different decisions at different times based on the same information. The theory of probability matching says that one reason for this randomness is that people usually choose the response that they think is most likely to be correct, but they sometimes intentionally ... | Human decision making is partly random, in the sense that a person can make different decisions on different occasions based on the same information. Probability matching is a theory of decision making that aims to account for this randomness. Suppose a person believes that response A has a 70% probability of being cor... |
10.1371/journal.pcbi.1005337 | A Looping-Based Model for Quenching Repression | We model the regulatory role of proteins bound to looped DNA using a simulation in which dsDNA is represented as a self-avoiding chain, and proteins as spherical protrusions. We simulate long self-avoiding chains using a sequential importance sampling Monte-Carlo algorithm, and compute the probabilities for chain loopi... | Biological regulation-at-a-distance, whereby a transcription factor (TF) is able to generate susbstantial regulatory effects on gene expression even though it may be bound a large distance away from its target (500 bp–1 Mbp), is only partially understood. Using a biophysical model and a computer simulation that take ds... | Polymer looping is a phenomenon that is critical for the understanding of many chemical and biological processes. In particular, DNA looping has been implicated in transcriptional regulation across many organisms, and as a result plays a crucial role in how organisms develop and respond to their environments. While DNA... |
10.1371/journal.pgen.0030030 | Phenotypic Plasticity in Drosophila Pigmentation Caused by Temperature Sensitivity of a Chromatin Regulator Network | Phenotypic plasticity is the ability of a genotype to produce contrasting phenotypes in different environments. Although many examples have been described, the responsible mechanisms are poorly understood. In particular, it is not clear how phenotypic plasticity is related to buffering, the maintenance of a constant ph... | The phenotype of an individual is not fully controlled by its genes. Environmental conditions (food, light, temperature, pathogens, etc.) can also contribute to phenotypic variation. This phenomenon is called phenotypic plasticity. We investigate here the genetic basis of the phenotypic plasticity of pigmentation in th... | Phenotypic plasticity and buffering are concepts describing the phenotypic outcome of genotype-environment interactions. Phenotypic plasticity is the ability of a given genotype to produce different phenotypes in different environments [1]. It has been the subject of increasing interest as it is involved in adaptation ... |
10.1371/journal.ppat.1004429 | Novel Cyclic di-GMP Effectors of the YajQ Protein Family Control Bacterial Virulence | Bis-(3′,5′) cyclic di-guanylate (cyclic di-GMP) is a key bacterial second messenger that is implicated in the regulation of many critical processes that include motility, biofilm formation and virulence. Cyclic di-GMP influences diverse functions through interaction with a range of effectors. Our knowledge of these eff... | Cyclic di-GMP is a bacterial second messenger that acts to regulate a wide range of functions including those that contribute to the virulence of pathogens. Our knowledge of the different actions and receptors for this nucleotide is far from complete. An understanding of the action of these elements may be key to inter... | Cyclic di-GMP (bis-(3′-5′) cyclic di-guanylate) is a second messenger in bacteria that acts to regulate a wide range of functions that include adhesion, biofilm formation, motility, synthesis of polysaccharides and synthesis of virulence factors in pathogens (recently reviewed by [1], [2], [3], [4]). The cellular level... |
10.1371/journal.ppat.1005644 | Neutrophil Attack Triggers Extracellular Trap-Dependent Candida Cell Wall Remodeling and Altered Immune Recognition | Pathogens hide immunogenic epitopes from the host to evade immunity, persist and cause infection. The opportunistic human fungal pathogen Candida albicans, which can cause fatal disease in immunocompromised patient populations, offers a good example as it masks the inflammatory epitope β-glucan in its cell wall from ho... | Opportunistic fungal infections, including those caused by C. albicans, have emerged as a significant global health burden and the disseminated form of these infections still have unacceptably high mortality rates despite modern antifungal treatments. The fungal cell wall controls its interaction with the host environm... | Innate immune recognition of pathogen-specific patterns plays a crucial role in initial infection control and activation of appropriate adaptive immune responses [1, 2]. Recognition through Toll-like, C-type lectin, Nod-like and Rig-I-like receptors elicits production of autocrine, paracrine and endocrine immunity. Thi... |
10.1371/journal.pcbi.1000122 | Memory Switches in Chemical Reaction Space | Just as complex electronic circuits are built from simple Boolean gates, diverse biological functions, including signal transduction, differentiation, and stress response, frequently use biochemical switches as a functional module. A relatively small number of such switches have been described in the literature, and th... | How does a cell know what type of cell it is supposed to become? How do external chemical signals change the underlying “state” of the cell? How are response pathways triggered on the application of a stress? Such questions of differentiation, signal transduction, and stress response, while seemingly diverse, all perta... | Most chemical reaction systems have a single steady state, but a few interesting cases are known to oscillate [1], form spatial patterns [2], or have multiple stable states [3],[4]. Aside from their intrinsic mathematical and chemical significance, systems with multiple stable states are of particular biological intere... |
10.1371/journal.ppat.1006120 | HTLV-1 bZIP Factor Enhances T-Cell Proliferation by Impeding the Suppressive Signaling of Co-inhibitory Receptors | Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATL) and inflammatory diseases. To enhance cell-to-cell transmission of HTLV-1, the virus increases the number of infected cells in vivo. HTLV-1 bZIP factor (HBZ) is constitutively expressed in HTLV-1 infected cells and ATL cells and pro... | Since HTLV-1 infects only through cell-to-cell transmission, increasing the number of infected cells is critical for transmission of HTLV-1. Proliferation of HTLV-1 infected cells is critical for development of leukemia and inflammatory diseases. In this study, we showed that HBZ promotes the proliferation of infected ... | Human T-cell leukemia virus type 1 (HTLV-1) belongs to the delta type retrovirus group, which also includes bovine leukemia virus and HTLV-2. HTLV-1 causes adult T-cell leukemia-lymphoma (ATL) and inflammatory diseases [1–4]. This virus induces clonal proliferation of infected cells to enhance its transmission, since H... |
10.1371/journal.pmed.1002855 | Operative versus non-operative treatment for 2-part proximal humerus fracture: A multicenter randomized controlled trial | Although increasingly used, the benefit of surgical treatment of displaced 2-part proximal humerus fractures has not been proven. This trial evaluates the clinical effectiveness of surgery with locking plate compared with non-operative treatment for these fractures.
The NITEP group conducted a superiority, assessor-bli... | Proximal humerus fractures (PHFs) are among the most common fractures in older adults. The risks for suffering a PHF increase with age, especially after the age of 60 years.
Non-operative treatment of non-displaced PHF is uniformly approved, but the treatment of displaced 2-part PHF remains controversial. Recently, sev... | Proximal humerus fractures (PHFs) are among the most common fractures in the older adult population [1,2]. In a Swedish nationwide study, the person-based incidence of PHF in adults was 175 per 100,000 person-years in women and 68 per 100,000 person-years in men [3]. The risk for having a PHF increases with age, especi... |
10.1371/journal.pcbi.1004534 | Bayesian Estimation of Conditional Independence Graphs Improves Functional Connectivity Estimates | Functional connectivity concerns the correlated activity between neuronal populations in spatially segregated regions of the brain, which may be studied using functional magnetic resonance imaging (fMRI). This coupled activity is conveniently expressed using covariance, but this measure fails to distinguish between dir... | Significant neuroscientific effort is devoted to elucidating functional connectivity between spatially segregated brain regions. This requires that we are able to quantify the degree of dependence between the signals of different areas. Yet how this must be accomplished—using which measures, each with their own limitat... | In the early days of neuroscience much attention was devoted to identifying the functional specialization of different brain areas [1]. More recently, this focus has shifted towards revealing how these areas are organized into networks and how these networks, rather than their individual constituents, are related to co... |
10.1371/journal.ppat.1003194 | Environmental Predictors of Seasonal Influenza Epidemics across Temperate and Tropical Climates | Human influenza infections exhibit a strong seasonal cycle in temperate regions. Recent laboratory and epidemiological evidence suggests that low specific humidity conditions facilitate the airborne survival and transmission of the influenza virus in temperate regions, resulting in annual winter epidemics. However, thi... | Human influenza infections have a pronounced seasonal cycle in temperate regions. Recent laboratory and epidemiological evidence suggests that low humidity conditions in the winter may increase virus survival and enable the virus to transmit efficiently between hosts. However, seasonal influenza activity in some tropic... | Influenza exerts a significant health burden on human populations across temperate, subtropical and tropical regions [1]. The striking seasonal pattern that characterizes influenza in temperate populations has long suggested a causal link between seasonal fluctuations in climatic and social factors and influenza transm... |
10.1371/journal.pgen.1006801 | C. elegans DAF-16/FOXO interacts with TGF-ß/BMP signaling to induce germline tumor formation via mTORC1 activation | Activation of the FOXO transcription factor DAF-16 by reduced insulin/IGF signaling (IIS) is considered to be beneficial in C. elegans due to its ability to extend lifespan and to enhance stress resistance. In the germline, cell-autonomous DAF-16 activity prevents stem cell proliferation, thus acting tumor-suppressive.... | The transcription factor FOXO is a well-known tumor suppressor whose activity is controlled by nutrients and stress signaling. In the roundworm C. elegans, the activity of the FOXO protein DAF-16 is best known for its beneficial role in stress response and long lifespan. However, FOXO proteins may also promote tumor ce... | The C. elegans FOXO transcription factor DAF-16 is one of the most intensively studied transcription factors due to its ability to extend lifespan and confer stress resistance [1]. In well-fed and stress-free animals, DAF-16 is inactivated by the insulin/IGF-1 signaling (IIS) through the IIS receptor DAF-2, phosphatidy... |
10.1371/journal.pcbi.1005376 | Elucidation of molecular kinetic schemes from macroscopic traces using system identification | Overall cellular responses to biologically-relevant stimuli are mediated by networks of simpler lower-level processes. Although information about some of these processes can now be obtained by visualizing and recording events at the molecular level, this is still possible only in especially favorable cases. Therefore t... | Unraveling the lower-level (microscopic) processes underlying the overall (macroscopic) cell response to a given stimulus is a challenging problem in cell physiology. This has been a classic problem in biophysics, where the ability to record the activity of single ion channels that generate a macroscopic ion current ha... | In order to ensure their survival and correct physiological function, cells must respond appropriately to many different kinds of stimuli, such as the presence of various neurotransmitters or hormones in the extracellular fluid, the depolarization of the cell membrane, or stimuli such as mechanical force or light [1]. ... |
10.1371/journal.pgen.1003555 | Distinct and Atypical Intrinsic and Extrinsic Cell Death Pathways between Photoreceptor Cell Types upon Specific Ablation of Ranbp2 in Cone Photoreceptors | Non-autonomous cell-death is a cardinal feature of the disintegration of neural networks in neurodegenerative diseases, but the molecular bases of this process are poorly understood. The neural retina comprises a mosaic of rod and cone photoreceptors. Cone and rod photoreceptors degenerate upon rod-specific expression ... | The secondary demise of healthy neurons upon the degeneration of neurons harboring primary genetic defect(s) is hallmark to neurodegenerative diseases. However, the factors and mechanisms driving these cell-death processes are not understood, a severe limitation which has hampered the therapeutic development of neuropr... | The disintegration of neuronal networks owing to the non-autonomous death of neurons without primary damage is a hallmark manifestation of many neurodegenerative diseases and contributes determinately to their onset or progression [1]–[3]. Cone or rod photoreceptor neurons employ cell type-specific spectrally tuned and... |
10.1371/journal.pbio.2000420 | Bordetella bronchiseptica exploits the complex life cycle of Dictyostelium discoideum as an amplifying transmission vector | Multiple lines of evidence suggest that Bordetella species have a significant life stage outside of the mammalian respiratory tract that has yet to be defined. The Bordetella virulence gene (BvgAS) two-component system, a paradigm for a global virulence regulon, controls the expression of many “virulence factors” expre... | Bordetella species are infectious bacterial respiratory pathogens of a range of animals, including humans. Bordetellae grow in two phenotypically distinct “phases,” each specifically expressing a large set of genes. The Bvg+ phase is primarily associated with respiratory tract infection (RTI) and has been well studied.... | Bordetella species are gram-negative bacteria that infect the respiratory tracts of mammals. The highly genetically conserved classical Bordetella species comprise B. pertussis and B. parapertussis, the etiological agents of whooping cough in humans [1], as well as B. bronchiseptica, which infects a variety of mammals ... |
10.1371/journal.pntd.0001627 | Regulatory T Cells in the Pathogenesis and Healing of Chronic Human Dermal Leishmaniasis Caused by Leishmania (Viannia) Species | The inflammatory response is prominent in the pathogenesis of dermal leishmaniasis. We hypothesized that regulatory T cells (Tregs) may be diminished in chronic dermal leishmaniasis (CDL) and contribute to healing during treatment.
The frequency and functional capacity of Tregs were evaluated at diagnosis and following... | The immune inflammatory response is a double edged sword. During infectious diseases, regulatory T cells can prevent eradication of the pathogen but can also limit inflammation and tissue damage. We investigated the role of regulatory T cells in chronic dermal leishmaniasis caused by species of the parasite Leishmania ... | Dermal leishmaniasis (DL) caused by species from the Viannia subgenus is characterized by a paucity of parasites in lesions associated with a robust inflammatory response and frequently follows a chronic course [1]. Both cutaneous and muco-cutaneous presentations of chronic dermal leishmaniasis (CDL) caused by Leishman... |
10.1371/journal.ppat.1003098 | Teleost Fish Mount Complex Clonal IgM and IgT Responses in Spleen upon Systemic Viral Infection | Upon infection, B-lymphocytes expressing antibodies specific for the intruding pathogen develop clonal responses triggered by pathogen recognition via the B-cell receptor. The constant region of antibodies produced by such responding clones dictates their functional properties. In teleost fish, the clonal structure of ... | In humans and mice, a broad and robust antibody response is the most effective system of defense against pathogens. While all vertebrates but the most ancient use an antibody system, it remains unknown if the clonal selection rules are conserved across vertebrates. Using high-throughput sequencing and antibody repertoi... | The immune system of mammals is characterized by the presence of B and T lymphocytes, each carrying a single receptor for antigen generated through somatic rearrangements of V-(D)-J genes. Upon infection specific B and T lymphocytes develop protective responses against the intruding pathogen, and after disease resoluti... |
10.1371/journal.ppat.1001157 | In Vitro and In Vivo Studies Identify Important Features of Dengue Virus pr-E Protein Interactions | Flaviviruses bud into the endoplasmic reticulum and are transported through the secretory pathway, where the mildly acidic environment triggers particle rearrangement and allows furin processing of the prM protein to pr and M. The peripheral pr peptide remains bound to virus at low pH and inhibits virus-membrane intera... | Enveloped viruses infect cells by fusing their membrane with that of the host cell. Dengue virus (DENV) is an important human pathogen whose membrane fusion is triggered by low pH during virus entry into the cell. However, newly synthesized DENV must also transit through a low pH environment during virus exit. DENV is ... | The emergence and resurgence of human viral pathogens can be traced to a complex variety of causes including increased urbanization, human contact with animal reservoirs, a decrease in effective public health systems, and the spread of insect vectors that disseminate some viral infections [1], [2], [3]. Flaviviruses ar... |
10.1371/journal.pcbi.1005224 | A Graph-Centric Approach for Metagenome-Guided Peptide and Protein Identification in Metaproteomics | Metaproteomic studies adopt the common bottom-up proteomics approach to investigate the protein composition and the dynamics of protein expression in microbial communities. When matched metagenomic and/or metatranscriptomic data of the microbial communities are available, metaproteomic data analyses often employ a meta... | In recent years, meta-omic (including metatranscriptomic and metaproteomic) techniques have been adopted as complementary approaches to metagenomic sequencing to study functional characteristics and dynamics of microbial communities, aiming at a holistic understanding of a community to respond to the changes in the env... | Microbiome studies have produced massive metagenomic data, and more recently other meta-omics including metatranscriptomic and metaproteomic data [1]. Analyses of these data reveal insights into the composition, function and regulatory characteristics of the microbial communities associated with different ecosystems, h... |
10.1371/journal.pbio.1001184 | Structure and Evolution of Streptomyces Interaction Networks in Soil and In Silico | Soil grains harbor an astonishing diversity of Streptomyces strains producing diverse secondary metabolites. However, it is not understood how this genotypic and chemical diversity is ecologically maintained. While secondary metabolites are known to mediate signaling and warfare among strains, no systematic measurement... | Soil harbors a diverse spectrum of bacteria that secrete small molecules such as antibiotics. Streptomyces bacteria, considered the most prolific producers, have been mined for decades for novel products with therapeutic applications, yet little is known about the properties of the interaction networks these compounds ... | Sampling DNA from diverse ecosystems has revealed a breathtaking diversity of microbial life [1],[2], especially in soil [3]–[5]. But we have barely begun to explore, both experimentally and theoretically, how these complex communities coexist and function. We know that microbes can interact via secretion of a wide arr... |
10.1371/journal.pgen.1005392 | Molecular Clock of Neutral Mutations in a Fitness-Increasing Evolutionary Process | The molecular clock of neutral mutations, which represents linear mutation fixation over generations, is theoretically explained by genetic drift in fitness-steady evolution or hitchhiking in adaptive evolution. The present study is the first experimental demonstration for the molecular clock of neutral mutations in a ... | Mutations that have little influence on biological function are referred to as neutral mutations and frequently appear in molecular phylogenetic analyses. The fixation of neutral mutations in populations has been attributed to genetic drift in fitness-steady evolutionary processes or hitchhiking in adaptive evolution. ... | The dynamics of adaptive evolution are more intricate than a simple sum of mutation and selection due to the entanglement of several evolutionary events [1], which include rare adaptive mutations [2,3,4,5,6,7,8], epistasis [9,10,11] and hitchhiking [12,13,14] at the genome level and clonal interference [15], frequency-... |
10.1371/journal.pntd.0006192 | Polymorphisms in voltage-gated sodium channel gene and susceptibility of Aedes albopictus to insecticides in three districts of northern West Bengal, India | The control and prevention of dengue largely depends on vector control measures, environmental management, and personal protection. Dengue control programmes are facing great challenges due to development of insecticide resistance among vector mosquitoes. Information on susceptibility status to different insecticides i... | Dengue is one of the most important arboviral infections in India, and transmitted by Aedes mosquitoes. Control of dengue largely depends on effective vector control measures as no specific drugs or vaccines are available, to date. The knowledge of insecticide susceptibility status for local vector mosquitoes is essent... | Dengue is a mosquito-borne flavi-viral disease and a major public health problem in more than 120 countries [1, 2]. In recent years, dengue transmission has increased predominantly in urban, semi-urban areas and has even extended to the rural areas, becoming a major public health concern globally. A recent estimate sho... |
10.1371/journal.ppat.1002256 | The Human Papillomavirus E6 Oncogene Represses a Cell Adhesion Pathway and Disrupts Focal Adhesion through Degradation of TAp63β upon Transformation | Cervical carcinomas result from cellular transformation by the human papillomavirus (HPV) E6 and E7 oncogenes which are constitutively expressed in cancer cells. The E6 oncogene degrades p53 thereby modulating a large set of p53 target genes as shown previously in the cervical carcinoma cell line HeLa. Here we show tha... | High-risk human papillomavirus infection can cause cancer of the uterine cervix. The viral proteins leading to transformation of the infected keratinocytes are the E6 and E7 oncogenes which interact with and induce degradation of the cell cycle regulators p53 and pRB. In cervical carcinoma cells, repression of E6/E7 st... | Infection of the anogenital mucosal epithelium with high risk Human Papilloma Virus (HPV) is linked to 99% of cervical carcinomas [1]. Cell lines derived from these cervical carcinomas remain associated with HPV and contain part of the viral genome integrated in the cellular genome. However, not all viral genes are ret... |
10.1371/journal.ppat.1005082 | An siRNA Screen Identifies the U2 snRNP Spliceosome as a Host Restriction Factor for Recombinant Adeno-associated Viruses | Adeno-associated viruses (AAV) have evolved to exploit the dynamic reorganization of host cell machinery during co-infection by adenoviruses and other helper viruses. In the absence of helper viruses, host factors such as the proteasome and DNA damage response machinery have been shown to effectively inhibit AAV transd... | Mammalian cells have developed diverse innate/intrinsic immune strategies to counteract viral infections. Post-entry infection steps of a single-strand DNA virus, adeno-associated virus (AAV), are subject to such restrictions. Here, we screened an siRNA library to identify a novel cellular factor involved in AAV restri... | Viral pathogens are known to reorganize different components of the host cell machinery during the course of infection. For instance, adenoviruses have been shown to induce nuclear reorganization of host splicing factors and mislocalization of the DNA damage response machinery [1]. Similarly, herpesviruses can induce s... |
10.1371/journal.pbio.1000040 | The Atonal Proneural Transcription Factor Links Differentiation and Tumor Formation in Drosophila | The acquisition of terminal cell fate and onset of differentiation are instructed by cell type–specific master control genes. Loss of differentiation is frequently observed during cancer progression, but the underlying causes and mechanisms remain poorly understood. We tested the hypothesis that master regulators of di... | During embryonic development, cells become more and more specialized, and this process is referred to as differentiation. In contrast to normal adult cells, cancer cells—like embryonic cells—display fewer differentiated properties. It has been postulated that the acquisition of terminal differentiation helps inhibit tu... | Cell fate commitment in neural and neuroendocrine lineages of the peripheral nervous system (PNS) as well as secretory epithelia is controlled by genes of the basic helix-loop-helix (bHLH) superfamily of transcription factors. One of the most structurally and functionally conserved groups within this family is the Aton... |
10.1371/journal.pcbi.1005893 | Non-linear auto-regressive models for cross-frequency coupling in neural time series | We address the issue of reliably detecting and quantifying cross-frequency coupling (CFC) in neural time series. Based on non-linear auto-regressive models, the proposed method provides a generative and parametric model of the time-varying spectral content of the signals. As this method models the entire spectrum simul... | Neural oscillations synchronize information across brain areas at various anatomical and temporal scales. Of particular relevance, slow fluctuations of brain activity have been shown to affect high frequency neural activity, by regulating the excitability level of neural populations. Such cross-frequency-coupling can t... | The characterization of neural oscillations, which are observed in the mammalian brain at different temporal and spatial scales, have given rise to important mechanistic hypotheses regarding their functional role in neurosciences (e.g. [1, 2]). One working hypothesis suggests that the coupling across neural oscillation... |
10.1371/journal.pgen.1003463 | Functional Dissection of the Drosophila melanogaster Condensin Subunit Cap-G Reveals Its Exclusive Association with Condensin I | The heteropentameric condensin complexes have been shown to participate in mitotic chromosome condensation and to be required for unperturbed chromatid segregation in nuclear divisions. Vertebrates have two condensin complexes, condensin I and condensin II, which contain the same structural maintenance of chromosomes (... | The accurate duplication and segregation of chromosomes during cell divisions are prerequisites for ensuring genetic stability within an individual organism and in entire populations. Among the many components involved in regulating these processes, a protein complex called condensin plays a crucial role in shaping mit... | Chromosome condensation is a critical process ensuring faithful distribution of the replicated genetic information onto the daughter cells. While the exact mechanism underlying the longitudinal compaction of the dispersed interphase chromatin into the rod-like and sturdy metaphase chromosomes is still subject of intens... |
10.1371/journal.ppat.1000930 | Requirement of NOX2 and Reactive Oxygen Species for Efficient RIG-I-Mediated Antiviral Response through Regulation of MAVS Expression | The innate immune response is essential to the host defense against viruses, through restriction of virus replication and coordination of the adaptive immune response. Induction of antiviral genes is a tightly regulated process initiated mainly through sensing of invading virus nucleic acids in the cytoplasm by RIG-I l... | The understanding of the mechanisms allowing the host to mount a rapid and efficient innate immune response to RNA viruses has been the subject of intensive research in recent years. Major groundwork allowed the identification of key sensors of virus nucleic acids, including RIG-I and Mda5, which through association wi... | The capacity of the host to rapidly respond to virus infection is essential to establish an antiviral state that restricts virus replication and spreading, and to permit the production of proinflammatory chemokines and cytokines that attract and activate immune cells to the site of infection. Although major breakthroug... |
10.1371/journal.ppat.1004910 | The EBNA-2 N-Terminal Transactivation Domain Folds into a Dimeric Structure Required for Target Gene Activation | Epstein-Barr virus (EBV) is a γ-herpesvirus that may cause infectious mononucleosis in young adults. In addition, epidemiological and molecular evidence links EBV to the pathogenesis of lymphoid and epithelial malignancies. EBV has the unique ability to transform resting B cells into permanently proliferating, latently... | Epstein-Barr virus is an oncogenic γ-herpesvirus that may cause infectious mononucleosis in young adults and fatal lymphoproliferative disorders in immunocompromised patients and is associated with the pathogenesis of Burkitt's lymphoma, nasopharyngeal and gastric carcinoma. Epstein-Barr virus nuclear antigen 2 (EBNA-2... | Epstein-Barr virus (EBV) is a γ-herpesvirus that establishes a lifelong asymptomatic infection in the majority of human adults. EBV infection or reactivation can cause significant morbidity and mortality in immunocompromised transplant recipients of allogeneic hematopoietic stem cells or solid organs [1, 2]. EBV has th... |
10.1371/journal.pntd.0001552 | The Genome of Mycobacterium Africanum West African 2 Reveals a Lineage-Specific Locus and Genome Erosion Common to the M. tuberculosis Complex | M. africanum West African 2 constitutes an ancient lineage of the M. tuberculosis complex that commonly causes human tuberculosis in West Africa and has an attenuated phenotype relative to M. tuberculosis.
In search of candidate genes underlying these differences, the genome of M. africanum West African 2 was sequenced... | Mycobacterium africanum, a close relative of M. tuberculosis, is studied for the following reasons: M. africanum is commonly isolated from West African patients with tuberculosis yet has not spread beyond this region, it is more common in HIV infected patients, and it is less likely to lead to tuberculosis after one is... | Mycobacterium africanum causes up to half of human TB in West Africa and displays differences in patient characteristics and immunoepidemiological features with M. tuberculosis, as reviewed earlier in this journal [1]. First described in 1968 in Dakar, Senegal [2], M. africanum used to be classified using biochemical m... |
10.1371/journal.pntd.0000306 | Chlamydia trachomatis ompA Variants in Trachoma: What Do They Tell Us? | Trachoma, caused by Chlamydia trachomatis (Ct), is the leading infectious cause of blindness. Sequence-based analysis of the multiple strains typically present in endemic communities may be informative for epidemiology, transmission, response to treatment, and understanding the host response.
Conjunctival and nasal sam... | Trachoma is an important cause of blindness resulting from transmission of the bacterium Chlamydia trachomatis. One way to understand better how this infection is transmitted and how the human immune system controls it is to study the strains of bacteria associated with infection. Comparing strains before and after tre... | Trachoma is the leading infectious cause of blindness worldwide [1]. Repeated infection by Chlamydia trachomatis provokes chronic follicular conjunctivitis (clinically active trachoma), which leads to conjunctival scarring, entropion, trichiasis and ultimately blinding corneal opacification. Trachoma is a major public ... |
10.1371/journal.pntd.0003590 | Unprogrammed Deworming in the Kibera Slum, Nairobi: Implications for Control of Soil-Transmitted Helminthiases | Programs for control of soil-transmitted helminth (STH) infections are increasingly evaluating national mass drug administration (MDA) interventions. However, “unprogrammed deworming” (receipt of deworming drugs outside of nationally-run STH control programs) occurs frequently. Failure to account for these activities m... | In countries with endemic soil-transmitted helminth infections, deworming medications are widely available from multiple sources, including over the counter. However, in many countries, national programs already provide deworming medications in mass drug administrations to primary school students, as part of World Heal... | Soil-transmitted helminth (STH) infections affect approximately 2 billion persons worldwide [1], with school-aged children generally having the highest-intensity infections and highest prevalence of infection [2–6]. Improper disposal of human feces contaminated with helminth eggs exposes humans to infection following i... |
10.1371/journal.ppat.1007069 | Langerin+ DCs regulate innate IL-17 production in the oral mucosa during Candida albicans-mediated infection | The opportunistic fungal pathogen Candida albicans frequently causes diseases such as oropharyngeal candidiasis (OPC) in immunocompromised individuals. Although it is well appreciated that the cytokine IL-17 is crucial for protective immunity against OPC, the cellular source and the regulation of this cytokine during i... | IL-17 is a key cytokine for immune homeostasis and host defense in barrier tissues, which can also drive inflammatory diseases and immunopathology under certain conditions. Most studies addressing IL-17-mediated processes focus on the lower gastrointestinal tract, while other barrier tissues such as the oral mucosa rem... | As part of the upper gastrointestinal tract, the oral cavity is colonized by microbes and constitutes an important entry point for hazardous pathogens. However, despite the relevance of the oral mucosa as a first site of interaction between microbes and the host, it remains little studied and its cellular composition i... |
10.1371/journal.pntd.0007412 | Malaria vector species in Amazonian Peru co-occur in larval habitats but have distinct larval microbial communities | In Amazonian Peru, the primary malaria vector, Nyssorhynchus darlingi (formerly Anopheles darlingi), is difficult to target using standard vector control methods because it mainly feeds and rests outdoors. Larval source management could be a useful supplementary intervention, but to determine its feasibility, more deta... | The standard methods used to combat mosquitoes that transmit malaria, long-lasting insecticide treated nets and indoor residual spraying, target mosquitoes that bite people indoors and rest indoors after biting. In Amazonian Peru, the major malaria vector, Nyssorhynchus darlingi (formerly Anopheles darlingi), is known ... | Despite substantial progress in reducing the global burden of malaria over the last two decades, no progress was made in decreasing the total number of malaria cases worldwide between 2015 and 2017 [1]. This emphasizes the need not only for continued commitment to the two most effective malaria vector control methods, ... |
10.1371/journal.pntd.0004625 | First Chikungunya Outbreak in Suriname; Clinical and Epidemiological Features | In June 2014, Suriname faced the first Chikungunya outbreak. Since international reports mostly focus on hospitalized patients, the least affected group, a study was conducted to describe clinical characteristics of mainly outpatients including children. In addition, the cumulative incidence of this first epidemic was ... | Chikungunya virus is transmitted to humans by mosquito bites and causes fever and joint pain. Chikungunya was first detected in Africa, but recently became a worldwide concern with outbreaks in many (sub)-tropical countries. We report the characteristics of the first outbreak in Suriname (2014–2015). Mainly non-hospita... | Chikungunya fever is caused by a classical arbovirus (genus Alphavirus, family Togaviridae), which is transmitted to humans primarily through Aedes aegypti and Aedes albopictus mosquitoes [1]. Acute onset of fever and polyarthralgia, mainly affecting the extremities (wrists, ankles, phalanges), are the primary reported... |
10.1371/journal.pgen.1002597 | Cis-by-Trans Regulatory Divergence Causes the Asymmetric Lethal Effects of an Ancestral Hybrid Incompatibility Gene | The Dobzhansky and Muller (D-M) model explains the evolution of hybrid incompatibility (HI) through the interaction between lineage-specific derived alleles at two or more loci. In agreement with the expectation that HI results from functional divergence, many protein-coding genes that contribute to incompatibilities b... | When two different species mate, the hybrid progeny are often sterile or lethal. Such hybrid incompatibilities cause reproductive isolation between species and are an important mechanism for maintaining species as separate units. A gene called Lethal hybrid rescue (Lhr) is part of the cause of hybrid lethality between ... | Species can be isolated from one another by a variety of reproductive barriers. One widely observed barrier is hybrid incompatibility (HI), the inviability or sterility of interspecies offspring. The key premise of the Dobzhansky-Muller (D-M) model explaining the evolution of HI is that genetic changes fixed in one pop... |
10.1371/journal.ppat.1000474 | MARCO, TLR2, and CD14 Are Required for Macrophage Cytokine Responses to Mycobacterial Trehalose Dimycolate and Mycobacterium tuberculosis | Virtually all of the elements of Mycobacterium tuberculosis (Mtb) pathogenesis, including pro-inflammatory cytokine production, granuloma formation, cachexia, and mortality, can be induced by its predominant cell wall glycolipid, trehalose 6,6′-dimycolate (TDM/cord factor). TDM mediates these potent inflammatory respon... | The causative agent of tuberculosis, Mycobacterium tuberculosis, has a lipid-rich cell wall that contains a high percentage of mycolic acids. These mycolic acids contribute to both the impermeable nature of the cell wall and to the immunostimulatory properties of the bacterium. Indeed, it has been known for over 50 yea... | Mycobacterium tuberculosis (Mtb), a causative agent of human tuberculosis, is responsible for 8 million new infections and 2 million deaths yearly. One third of the world population is currently estimated to be infected with M. tuberculosis, although less than 10% of those infected show clinical signs of infection [1].... |
10.1371/journal.pbio.1001429 | Inhibition of the Prokaryotic Pentameric Ligand-Gated Ion Channel ELIC by Divalent Cations | The modulation of pentameric ligand-gated ion channels (pLGICs) by divalent cations is believed to play an important role in their regulation in a physiological context. Ions such as calcium or zinc influence the activity of pLGIC neurotransmitter receptors by binding to their extracellular domain and either potentiate... | Pentameric ligand-gated ion channels (pLGICs) are ionotropic neurotransmitter receptors that mediate electrical signaling at chemical synapses. The pLGIC family includes receptors for acetylcholine, serotonin, GABA and glycine, which share a similar structural organization and activation mechanism: the channels are clo... | The pentameric ligand-gated ion channels (pLGICs) are ionotropic neurotransmitter receptors, which are activated by the binding of ligands to specific sites of the protein. The family includes both cation-selective channels, such as nicotinic Acetylcholine- (nAChRs) and Serotonin receptors (5HT3Rs), and anion-selective... |
10.1371/journal.ppat.1005151 | Inhibition of Translation Initiation by Protein 169: A Vaccinia Virus Strategy to Suppress Innate and Adaptive Immunity and Alter Virus Virulence | Vaccinia virus (VACV) is the prototypic orthopoxvirus and the vaccine used to eradicate smallpox. Here we show that VACV strain Western Reserve protein 169 is a cytoplasmic polypeptide expressed early during infection that is excluded from virus factories and inhibits the initiation of cap-dependent and cap-independent... | Long after smallpox was eradicated by vaccination with vaccinia virus, the study of this virus continues to reveal novel aspects of the interactions between a virus and the host in which it replicates. In this work we investigated the function of a previously uncharacterized VACV protein, called 169. The results show t... | The study of virus-host interactions continues to provide valuable information about the complex relationships between cells and pathogens. Large DNA viruses, in particular, encode many proteins that modify the intracellular environment to promote viral survival, replication and spread. Vaccinia virus (VACV) is the pro... |
10.1371/journal.pcbi.1003438 | Robustness of DNA Repair through Collective Rate Control | DNA repair and other chromatin-associated processes are carried out by enzymatic macromolecular complexes that assemble at specific sites on the chromatin fiber. How the rate of these molecular machineries is regulated by their constituent parts is poorly understood. Here we quantify nucleotide-excision DNA repair in m... | The nucleotide-excision repair pathway removes mutagen-inflicted DNA lesions from the genome. Repair proteins recognize DNA lesions and form multi-protein complexes that catalyze the excision of the lesion and the re-synthesis of the excised part. Imaging the dynamics of fluorescently labeled repair proteins in living ... | Chromatin-associated processes, including transcription, replication, DNA repair and epigenetic control, are executed by macromolecular complexes that assemble at specific sites on the chromatin fiber. The stepwise, cooperative ‘recruitment’ of components into stable complexes has, until recently, been the prevailing m... |
10.1371/journal.ppat.1000541 | Interplay in the Selection of Fluoroquinolone Resistance and Bacterial Fitness | Fluoroquinolones are antibacterial drugs that inhibit DNA Gyrase and Topoisomerase IV. These essential enzymes facilitate chromosome replication and RNA transcription by regulating chromosome supercoiling. High-level resistance to fluoroquinolones in E. coli requires the accumulation of multiple mutations, including th... | The increasing frequency of human pathogens resistant to important classes of antibiotics poses a serious and growing challenge for medicine and society. We need improved strategies to reduce the rate of resistance development, for established and novel drugs, based on knowledge of the factors that drive the increase i... | Fluoroquinolones are potent antibacterial drugs [1] that bind to bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) when they are in complex with DNA. The drugs inhibit chromosome re-ligation after enzyme-mediated cleavage [2]. Fluoroquinolones are effective against many bacteria including invasive E. c... |
10.1371/journal.pntd.0002017 | A Multiplex PCR for the Simultaneous Detection and Genotyping of the Echinococcus granulosus Complex | Echinococcus granulosus is characterized by high intra-specific variability (genotypes G1–G10) and according to the new molecular phylogeny of the genus Echinococcus, the E. granulosus complex has been divided into E. granulosus sensu stricto (G1–G3), E. equinus (G4), E. ortleppi (G5), and E. canadensis (G6–G10). The m... | The dog tapeworm Echinococcus granulosus (E. granulosus) is a cosmopolitan parasite. The adult worms reside in the small intestine of their definitive hosts (dogs). Infective eggs are shed with the feces into the environment and are orally ingested by intermediate hosts where they develop into the metacestode (larval) ... | Historically, four species have been recognized within the genus Echinococcus: E. multilocularis, E. oligarthrus, E. vogeli and E. granulosus [1]. E. shiquicus and E. felidis are two newly discovered additional species isolated from small Tibetan mammals and African lions, respectively [2], [3]. Extensive research on g... |
10.1371/journal.ppat.1004375 | Helminth Infections Coincident with Active Pulmonary Tuberculosis Inhibit Mono- and Multifunctional CD4+ and CD8+ T Cell Responses in a Process Dependent on IL-10 | Tissue invasive helminth infections and tuberculosis (TB) are co-endemic in many parts of the world and can trigger immune responses that might antagonize each other. We have previously shown that helminth infections modulate the Th1 and Th17 responses to mycobacterial-antigens in latent TB. To determine whether helmin... | While it has long been recognized that helminth infections alter the pathophysiology of allergic and autoimmune disease, data suggest that helminth infections also exert an important immunological effect on concomitant infections and vaccine responses. In particular, helminth coinfection can modulate the severity, path... | Helminth parasites are complex eukaryotic organisms, characterized by their ability to maintain long-standing infections in humans, sometimes lasting decades. Two of the most common persistent helminth infections are Wuchereria bancrofti, the major causative agent of lymphatic filariasis, and Strongyloides stercoralis,... |
10.1371/journal.pgen.1006111 | Genetic Drift, Purifying Selection and Vector Genotype Shape Dengue Virus Intra-host Genetic Diversity in Mosquitoes | Due to their error-prone replication, RNA viruses typically exist as a diverse population of closely related genomes, which is considered critical for their fitness and adaptive potential. Intra-host demographic fluctuations that stochastically reduce the effective size of viral populations are a challenge to maintaini... | During infection of their arthropod vectors, arthropod-borne viruses (arboviruses) such as dengue viruses traverse several anatomical barriers that are believed to cause dramatic reductions in population size. Such population bottlenecks challenge the maintenance of viral genetic diversity, which is considered critical... | Due to the low fidelity of their RNA-dependent RNA polymerase, rapid replication kinetics and large population size, RNA viruses consist of a heterogeneous intra-host population of related mutants, sometimes referred to as a quasispecies [1]. This mutant swarm as a whole defines the properties of the viral population, ... |
10.1371/journal.pcbi.1003316 | Conformational Changes in Talin on Binding to Anionic Phospholipid Membranes Facilitate Signaling by Integrin Transmembrane Helices | Integrins are heterodimeric (αβ) cell surface receptors that are activated to a high affinity state by the formation of a complex involving the α/β integrin transmembrane helix dimer, the head domain of talin (a cytoplasmic protein that links integrins to actin), and the membrane. The talin head domain contains four su... | Transmission of signals across the cell membrane is an essential process for all living organisms. Integrins are one example of cell surface receptors (αβ) which, uniquely, form a bidirectional signalling pathway across the membrane. Integrins are crucial for many cellular processes and play key roles in pathological d... | Integrins are cell surface receptors involved in many essential cellular processes, such as cell migration, and in pathological defects, such as thrombosis and cancer [1]. Integrins are αβ heterodimers. Each subunit has a large ectodomain, a single transmembrane (TM) helix and a short flexible cytoplasmic tail [2]. Int... |
10.1371/journal.ppat.1004630 | Cell Cycle-Independent Phospho-Regulation of Fkh2 during Hyphal Growth Regulates Candida albicans Pathogenesis | The opportunistic human fungal pathogen, Candida albicans, undergoes morphological and transcriptional adaptation in the switch from commensalism to pathogenicity. Although previous gene-knockout studies have identified many factors involved in this transformation, it remains unclear how these factors are regulated to ... | The fungus Candida albicans is a commensal in the human microbiota, responsible for superficial infections such as oral and vaginal thrush. However, it can become highly virulent, causing life-threatening systemic candidemia in severely immunocompromised patients, including those taking immunosuppressive drugs for tran... | The fungus Candida albicans is commonly found as a harmless commensal on the skin and mucosal surfaces of the vaginal and gastrointestinal tracts of healthy people. However, it is also an opportunistic pathogen causing diseases that range from superficial infections, such as vaginal and oral thrush in otherwise healthy... |
10.1371/journal.ppat.1006093 | A Large Collection of Novel Nematode-Infecting Microsporidia and Their Diverse Interactions with Caenorhabditis elegans and Other Related Nematodes | Microsporidia are fungi-related intracellular pathogens that may infect virtually all animals, but are poorly understood. The nematode Caenorhabditis elegans has recently become a model host for studying microsporidia through the identification of its natural microsporidian pathogen Nematocida parisii. However, it was ... | Microsporidia are microbial parasites that live inside their host cells and can cause disease in humans and many other animals. The small nematode worm Caenorhabditis elegans has recently become a convenient model host for studying microsporidian infections. In this work, we sample Caenorhabditis and other small nemato... | Microsporidia are fungi-related obligate intracellular pathogens, with over 1400 described species [1,2]. Interest in these organisms started 150 years ago when researchers, especially Louis Pasteur, studied silkworm disease that was caused by a microsporidian species later named Nosema bombycis [3]. In the past decade... |
10.1371/journal.pbio.2004786 | Morphological changes of plasma membrane and protein assembly during clathrin-mediated endocytosis | Clathrin-mediated endocytosis (CME) proceeds through a series of morphological changes of the plasma membrane induced by a number of protein components. Although the spatiotemporal assembly of these proteins has been elucidated by fluorescence-based techniques, the protein-induced morphological changes of the plasma me... | Cells communicate with their environments via the plasma membrane and various membrane proteins. Clathrin-mediated endocytosis (CME) plays a central role in such communication and proceeds with a series of multiprotein assembly, deformation of the plasma membrane, and production of a membrane vesicle that delivers extr... | Cells communicate with the extracellular environment via the plasma membrane and membrane proteins. They transduce extracellular signals and substances into the cellular plasma via cell surface receptors, channels, and pumps, as well as by various endocytic processes [1–3]. Cells also disseminate their intracellular co... |
10.1371/journal.pcbi.1004373 | Dynamics of the Heat Stress Response of Ceramides with Different Fatty-Acyl Chain Lengths in Baker’s Yeast | The article demonstrates that computational modeling has the capacity to convert metabolic snapshots, taken sequentially over time, into a description of cellular, dynamic strategies. The specific application is a detailed analysis of a set of actions with which Saccharomyces cerevisiae responds to heat stress. Using t... | The heat stress response in yeast is a model system for elucidating how cells organize and execute complex tasks. While a genomic response to heat is necessary, it is by itself too slow for immediate means of protecting the cell against damage. However, one observes changes in the physiology of the cells within a few m... | Decades of research on sphingolipids have documented the enormous importance of this class of lipids in mediating a variety of critical cell functions. Sphingolipids exist in eukaryotic cells, where they serve not only as constituents of membranes but also as second messengers in different signaling transduction pathwa... |
10.1371/journal.pntd.0004828 | Dengue Virus Nonstructural Protein 1 Induces Vascular Leakage through Macrophage Migration Inhibitory Factor and Autophagy | Dengue virus (DENV) is the most common mosquito-borne flavivirus; it can either cause mild dengue fever or the more severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). One of the characteristic features of DHF/DSS is vascular leakage; although DENV nonstructural protein 1 (NS1) has been proved to ind... | Dengue is a viral disease transmitted by mosquitoes. The symptoms of dengue are often mild; however, severe dengue is one of the leading causes of hospitalization and death among children in Asian and Latin American countries. A symptom of severe dengue is vascular leakage, which can result in fluid accumulation, hypot... | Dengue virus (DENV) is the most common mosquito-borne flavivirus that spreads in tropical and sub-tropical areas. The World Health Organization estimates that more than 2.5 billion people, over 40% of the world’s population, are now at risk of dengue infection [1, 2]. DENV infection generally causes dengue fever (DF), ... |
10.1371/journal.pbio.2004328 | The Plasmodium falciparum transcriptome in severe malaria reveals altered expression of genes involved in important processes including surface antigen–encoding var genes | Within the human host, the malaria parasite Plasmodium falciparum is exposed to multiple selection pressures. The host environment changes dramatically in severe malaria, but the extent to which the parasite responds to—or is selected by—this environment remains unclear. From previous studies, the parasites that cause ... | Infection by Plasmodium falciparum—the parasite responsible for malaria in humans—can result in a severe disease that can be fatal or in an uncomplicated disease that can be resolved by the host immune system. However, whether the parasites causing severe disease differ from those causing uncomplicated disease is unkno... | P. falciparum is the leading cause of fatal malaria and is responsible for the death of over 400,000 people annually, primarily in sub-Saharan Africa [1]. However, severe disease also occurs in Southeast Asia, and Papua is the Indonesian province with the highest prevalence of malaria [1]. Severe malaria due to P. falc... |
10.1371/journal.pntd.0004299 | Genomic and Proteomic Studies on the Mode of Action of Oxaboroles against the African Trypanosome | SCYX-7158, an oxaborole, is currently in Phase I clinical trials for the treatment of human African trypanosomiasis. Here we investigate possible modes of action against Trypanosoma brucei using orthogonal chemo-proteomic and genomic approaches. SILAC-based proteomic studies using an oxaborole analogue immobilised onto... | The mode of action of a new class of boron-containing chemicals (the oxaboroles), currently under development for the treatment of human African trypanosomiasis, is unknown. Here we identify a number of potential candidate proteins that could be involved either in the mode of action of these compounds or in the mechani... | Human African trypanosomiasis (HAT) is caused by two subspecies of the unicellular parasite Trypanosoma brucei, an infection which is transmitted by the bite of a tsetse fly. HAT progresses through a haemo-lymphatic stage into a meningo-encephalitic stage [1] and has a fatality rate close to 100% if left untreated [2].... |
10.1371/journal.pcbi.1000852 | The Construction and Use of Log-Odds Substitution Scores for Multiple Sequence Alignment | Most pairwise and multiple sequence alignment programs seek alignments with optimal scores. Central to defining such scores is selecting a set of substitution scores for aligned amino acids or nucleotides. For local pairwise alignment, substitution scores are implicitly of log-odds form. We now extend the log-odds form... | Multiple sequence alignment is a fundamental tool of biological research, widely used to identify important regions of DNA or protein molecules, to infer their biological functions, to reconstruct ancestries, and in numerous other applications. The effectiveness and accuracy of sequence comparison programs depends cruc... | Protein and DNA sequence alignment is a fundamental tool of computational molecular biology. It is used for functional prediction, genome annotation, the discovery of functional elements and motifs, homology-based structure prediction and modeling, phylogenetic reconstruction, and in numerous other applications. The ef... |
10.1371/journal.pntd.0006260 | Taenia solium, Taenia saginata, Taenia asiatica, their hybrids and other helminthic infections occurring in a neglected tropical diseases' highly endemic area in Lao PDR | Most part of Southeast Asia is considered endemic for human-infecting Taenia tapeworms; Taenia solium, T. saginata, and T. asiatica. However, until now there was no report of the occurrence of human cases of T. asiatica in Lao PDR. This study, conducted in Savannakhet Province, Lao PDR, microscopically examined a total... | Southeast Asian Countries are endemic for several foodborne and soil-transmitted helminths occurring in different levels and areas, depending on environmental and cultural conditions. This study aimed to study the soil-transmitted helminths (STHs) and foodborne parasites in Savannakhet Province of Lao PDR, bordering wi... | Only human are the definitive hosts for Taenia solium, Taenia saginata, and Taenia asiatica, which are referred as the human-Taenia. The distribution of each of the 3 species of human Taenia depends on peoples’ cultural characteristics which involve the consumption of undercooked meat or organs of intermediate hosts in... |
10.1371/journal.pntd.0000791 | A Major Role for Mammals in the Ecology of Mycobacterium ulcerans | Mycobacterium ulcerans is the causative agent of Buruli ulcer (BU), a destructive skin disease found predominantly in sub-Saharan Africa and south-eastern Australia. The precise mode(s) of transmission and environmental reservoir(s) remain unknown, but several studies have explored the role of aquatic invertebrate spec... | Mycobacterium ulcerans is the causative agent of Buruli ulcer (BU), a destructive skin disease found predominantly in sub-Saharan Africa and south-eastern Australia. The mode of transmission and environmental reservoir remain unknown, but several studies have explored the role of aquatic insects, such as water bugs, an... | Buruli ulcer (BU) is caused by the environmental mycobacterium, Mycobacterium ulcerans. Infection with M. ulcerans often leads to extensive necrosis of the skin and soft tissue with the formation of large ulcers, usually on the leg or arm, due to the production of the destructive polyketide toxin, mycolactone [1]. Alth... |
10.1371/journal.pcbi.1000966 | Biosensor Approach to Psychopathology Classification | We used a multi-round, two-party exchange game in which a healthy subject played a subject diagnosed with a DSM-IV (Diagnostic and Statistics Manual-IV) disorder, and applied a Bayesian clustering approach to the behavior exhibited by the healthy subject. The goal was to characterize quantitatively the style of play el... | Human social interaction is exquisitely complex, and perturbed social interaction is a hallmark of psychological pathogy. When someone has a psychological disorder the focus is generally on their behavior, but this behavior is rarely something displayed in isolation and typically induces profound changes in the people ... | Social interactions among humans reflect the execution of some of the most important and complex behavioral software with which humans are endowed. Consequently, we should expect the computations involved in human social exchange to be subtle and perhaps even difficult to expose and study in controlled settings. Howeve... |
10.1371/journal.ppat.1006253 | A self-perpetuating repressive state of a viral replication protein blocks superinfection by the same virus | Diverse animal and plant viruses block the re-infection of host cells by the same or highly similar viruses through superinfection exclusion (SIE), a widely observed, yet poorly understood phenomenon. Here we demonstrate that SIE of turnip crinkle virus (TCV) is exclusively determined by p28, one of the two replication... | Superinfection exclusion (SIE) is employed by many viruses to guard their host cells against secondary invasions by the same or highly similar viruses. We describe a transformative discovery that self-perpetuating coalescence of a virus-encoded replication protein serves as a novel mechanism for SIE. Our findings furth... | Superinfection exclusion (SIE) refers to the ability of a pre-existing virus (the primary invader) to exclude secondary infections by the same or closely related viruses (superinfectors) at cellular and/or organismal levels. SIE has been observed with many human and animal pathogenic viruses, including the reverse-tran... |
10.1371/journal.ppat.1006668 | Merkel cell polyomavirus recruits MYCL to the EP400 complex to promote oncogenesis | Merkel cell carcinoma (MCC) frequently contains integrated copies of Merkel cell polyomavirus DNA that express a truncated form of Large T antigen (LT) and an intact Small T antigen (ST). While LT binds RB and inactivates its tumor suppressor function, it is less clear how ST contributes to MCC tumorigenesis. Here we s... | Merkel cell carcinoma (MCC) is a highly aggressive, neuroendocrine cancer of the skin. MCC frequently contains integrated copies of Merkel cell polyomavirus DNA and expresses two viral transcripts including a truncated form of Large T antigen (LT) and an intact Small T antigen (ST). While LT binds the Retinoblastoma pr... | Merkel cell carcinoma (MCC) is an aggressive skin cancer with a high rate of mortality. Risk factors for developing MCC include immunosuppression and UV-induced DNA damage from excessive exposure to sunlight [1]. Recognition of the immunosuppressive risk for MCC prompted a search to identify pathogens and led to the di... |
10.1371/journal.ppat.1007978 | Structural Insights into Curli CsgA Cross-β Fibril Architecture Inspire Repurposing of Anti-amyloid Compounds as Anti-biofilm Agents | Curli amyloid fibrils secreted by Enterobacteriaceae mediate host cell adhesion and contribute to biofilm formation, thereby promoting bacterial resistance to environmental stressors. Here, we present crystal structures of amyloid-forming segments from the major curli subunit, CsgA, revealing steric zipper fibrils of t... | Atomic resolution structural insights into the biofilm-associated curli amyloid fibril secreted by Enterobacteriaceae revealed elements of fibrillar architecture conserved between bacterial and human amyloids. This inspired us to repurpose anti-amyloid drugs designed to target human pathological amyloids as a novel cla... | Amyloid formation has traditionally been viewed as a hallmark of protein misfolding diseases, such as amyloidosis, Alzheimer’s and Parkinson’s [1]. In a groundbreaking study, Chapman and coworkers discovered that Escherichia coli secrete extracellular fibers called curli, that biochemically and biophysically resemble h... |
10.1371/journal.ppat.1004503 | IFI16 Restricts HSV-1 Replication by Accumulating on the HSV-1 Genome, Repressing HSV-1 Gene Expression, and Directly or Indirectly Modulating Histone Modifications | Interferon-γ inducible factor 16 (IFI16) is a multifunctional nuclear protein involved in transcriptional regulation, induction of interferon-β (IFN-β), and activation of the inflammasome response. It interacts with the sugar-phosphate backbone of dsDNA and modulates viral and cellular transcription through largely und... | HSV-1, a ubiquitous human pathogen that establishes a life-long infection, has evolved several mechanisms to evade host immune detection and responses. However, it is still subject to regulation by cellular factors. Recently, a host nuclear protein, IFI16, was shown to be involved in the innate defense response to HSV-... | Herpes simplex virus type I (HSV-1) is a ubiquitous and highly contagious virus that establishes a life-long infection in host organisms. It typically enters the host through mucosal epithelia and causes a lytic, productive infection in many cell types, including fibroblast, epithelial, and endothelial cells, during wh... |
10.1371/journal.pntd.0004668 | Underestimation of Leptospirosis Incidence in the French West Indies | Leptospirosis is a neglected zoonosis affecting mainly tropical and subtropical regions worldwide, particularly South America and the Caribbean. As in many other countries, under-reporting of cases was suspected in the French West Indies because of inadequate access to diagnostic tests for the general population.
In or... | Leptospirosis is a common disease in tropical regions around the world. It is caused by a bacteria excreted in environmental waters by mammals, especially rodents, through their urine. Leptospirosis has symptoms similar to other tropical diseases, including dengue fever, and early laboratory diagnosis is crucial to pro... | Leptospirosis is a zoonotic bacterial disease which is particularly widespread in tropical and subtropical regions. It produces a wide array of clinical symptoms, ranging from an undifferentiated mild fever to severe multi-organ failure [1]. None of these symptoms is specific to the disease. Until recently, diagnosis w... |
10.1371/journal.pntd.0005362 | Schistosome infectivity in the snail, Biomphalaria glabrata, is partially dependent on the expression of Grctm6, a Guadeloupe Resistance Complex protein. | Schistosomiasis is one of the most important neglected tropical diseases. Despite effective chemotherapeutic treatments, this disease continues to afflict hundreds of millions of people. Understanding the natural intermediate snail hosts of schistosome parasites is vital to the suppression of this disease. A recently i... | Schistosomiasis is one of the most prevalent parasitic diseases in the world. Though treatments for schistosomiasis infection exist, there is no vaccine, and reinfection is common in areas where the parasite occurs. One possible way to mitigate schistosomiasis is by controlling the transmission of the parasite larvae f... | The World Health Organization (WHO) has estimated that schistosomiasis, a detrimental parasitic helminth disease, affects approximately 258 million people, making it one of the most important parasitic diseases in the world [1, 2]. Millions of people are chemotherapeutically treated for schistosomiasis, but in areas wh... |
10.1371/journal.pbio.1002243 | Insulin and mTOR Pathway Regulate HDAC3-Mediated Deacetylation and Activation of PGK1 | Phosphoglycerate kinase 1 (PGK1) catalyzes the reversible transfer of a phosphoryl group from 1, 3-bisphosphoglycerate (1, 3-BPG) to ADP, producing 3-phosphoglycerate (3-PG) and ATP. PGK1 plays a key role in coordinating glycolytic energy production with one-carbon metabolism, serine biosynthesis, and cellular redox re... | Phosphoglycerate kinase (PGK1) catalyzes the reversible phosphotransfer reaction from 1, 3-bisphosphoglycerate (1, 3-BPG) to ADP to form 3-phosphoglycerate (3-PG) and ATP. By controlling ATP and 3-PG levels, PGK1 plays an important role in coordinating energy production with biosynthesis and redox balance. In contrast ... | Phosphoglycerate kinase (EC 2.7.2.3; PGK) catalyzes the reversible phosphotransfer reaction from 1, 3-bisphosphoglycerate (1, 3-BPG) to ADP to form 3-phosphoglycerate (3-PG) and ATP. The PGK-catalyzed reaction is the first ATP-yielding step of glycolysis and is essential for energy generation by the glycolytic pathway ... |
10.1371/journal.pgen.1003396 | Robust Prediction of Expression Differences among Human Individuals Using Only Genotype Information | Many genetic variants that are significantly correlated to gene expression changes across human individuals have been identified, but the ability of these variants to predict expression of unseen individuals has rarely been evaluated. Here, we devise an algorithm that, given training expression and genotype data for a ... | Variation in gene expression across different individuals has been found to play a role in susceptibility to different diseases. In addition, many genetic variants that are linked to changes in expression have been found to date. However, their joint ability to accurately predict these changes is not well understood an... | Variation in gene expression among human individuals plays a key role in the susceptibility to different diseases and phenotypes [1]–[7]. Some of this variation has been linked to genetic variation that exists among individuals [8]–[16]. For this reason, a major goal is to predict gene expression changes among individu... |
10.1371/journal.ppat.1002693 | Age of the Association between Helicobacter pylori and Man | When modern humans left Africa ca. 60,000 years ago (60 kya), they were already infected with Helicobacter pylori, and these bacteria have subsequently diversified in parallel with their human hosts. But how long were humans infected by H. pylori prior to the out-of-Africa event? Did this co-evolution predate the emerg... | We previously showed that the population history of H. pylori may be used as a marker for human migrations, including the demonstration that humans carried H. pylori out of Africa 60,000 years ago during their recent global expansions. But how long were humans infected by H. pylori prior to the out-of-Africa event? Her... | The Gram-negative bacterium Helicobacter pylori infects the stomachs of at least 50% of all humans, causing gastric inflammation in all infected individuals, gastric or duodenal ulcers in 10–15% and gastric carcinoma or lymphoma of the mucosa-associated lymphoid tissue in ∼1% [1]. H. pylori infection is predominantly t... |
10.1371/journal.ppat.1004087 | Noncanonical Role for the Host Vps4 AAA+ ATPase ESCRT Protein in the Formation of Tomato Bushy Stunt Virus Replicase | Assembling of the membrane-bound viral replicase complexes (VRCs) consisting of viral- and host-encoded proteins is a key step during the replication of positive-stranded RNA viruses in the infected cells. Previous genome-wide screens with Tomato bushy stunt tombusvirus (TBSV) in a yeast model host have revealed the in... | Replication of positive-stranded RNA viruses depends on recruitment of host proteins and cellular membranes to assemble the viral replicase complexes. Tombusviruses, small RNA viruses of plants, co-opt the cellular ESCRT (endosomal sorting complexes required for transport) proteins to facilitate replicase assembly on t... | Plus-stranded (+)RNA viruses replicate by assembling membrane-bound viral replicase complexes (VRCs) consisting of viral- and host-coded proteins in combination with the viral RNA template in the infected cells. Although major progress has recently been made in understanding the functions of the viral replication prote... |
10.1371/journal.pcbi.1005677 | Bow-tie signaling in c-di-GMP: Machine learning in a simple biochemical network | Bacteria of many species rely on a simple molecule, the intracellular secondary messenger c-di-GMP (Bis-(3'-5')-cyclic dimeric guanosine monophosphate), to make a vital choice: whether to stay in one place and form a biofilm, or to leave it in search of better conditions. The c-di-GMP network has a bow-tie shaped archi... | How does evolution shape living organisms that seem so well adapted that they could be intelligently designed? Here, we address this question by analyzing a simple biochemical network that directs social behavior in bacteria; we find that it works analogously to a machine learning algorithm that learns from data. Inspi... | Cells use networks of biochemical reactions to collect cues from the world around them, process that information internally and respond appropriately [1]. Understanding how evolution by natural selection has turned biochemical reactions into information-processing circuits remains a major challenge [2]. The intracellul... |
10.1371/journal.pntd.0001759 | Research on Motor Neuron Diseases Konzo and Neurolathyrism: Trends from 1990 to 2010 | Konzo (caused by consumption of improperly processed cassava, Manihot esculenta) and neurolathyrism (caused by prolonged overconsumption of grass pea, Lathyrus sativus) are two distinct non-infectious upper motor neurone diseases with identical clinical symptoms of spastic paraparesis of the legs. They affect many thou... | The irreversible crippling diseases konzo and neurolathyrism with identical clinical symptoms occur among poor subsistence farmers in Africa and Asia. The victims are mostly illiterate and among the poorest section of the population who can only afford the cheapest food in a monotonous diet: bitter cassava roots (Manih... | Konzo and neurolathyrism are toxico-nutritional neurodegenerations that afflict many thousands of people among poor populations in low income countries, especially in Sub Saharan Africa and in the Indian Sub-continent, respectively. In both cases, the victims are mainly illiterate subsistence farmers living in remote r... |
10.1371/journal.ppat.1003260 | DNA Break Site at Fragile Subtelomeres Determines Probability and Mechanism of Antigenic Variation in African Trypanosomes | Antigenic variation in African trypanosomes requires monoallelic transcription and switching of variant surface glycoprotein (VSG) genes. The transcribed VSG, always flanked by ‘70 bp’-repeats and telomeric-repeats, is either replaced through DNA double-strand break (DSB) repair or transcriptionally inactivated. Howeve... | Previous studies on antigenic variation in African trypanosomes relied upon positive or negative selection, yielding only cells that underwent variation. This made it difficult to define individual switched clones as independent, potentially introduced bias in the relative contribution of each switching mechanism and p... | Several important parasites, including those that cause malaria and Human African Trypanosomiasis (HAT), achieve antigenic variation and evasion of the host adaptive immune response through monoallelic expression and clonal phenotypic variation of surface proteins [1], [2]. The African trypanosomes are flagellated para... |
10.1371/journal.pcbi.1005446 | Navigating in foldonia: Using accelerated molecular dynamics to explore stability, unfolding and self-healing of the β-solenoid structure formed by a silk-like polypeptide | The β roll molecules with sequence (GAGAGAGQ)10 stack via hydrogen bonding to form fibrils which have been themselves been used to make viral capsids of DNA strands, supramolecular nanotapes and pH-responsive gels. Accelerated molecular dynamics (aMD) simulations are used to investigate the unfolding of a stack of two ... | Silk-inspired repeated sequences, variants of the sequence from Bombyx Mori silk, have been used to make supramolecular nanotapes, pH-responsive gels, and most importantly self-assembled coat for artificial viruses. Silk-inspired repeated sequences have shown great potential as promising delivery vehicles in targeted d... | An increasing number of functional proteins are reported to have β solenoid structure, such as antifreeze protein [1–3], curli [4], and carbonic anhydrase enzyme [5]. Formed by winding the peptide chain in a left-handed or right-handed fashion, a β solenoid structure usually has a repeat unit consisting of 2, 3, or 4 β... |
10.1371/journal.pcbi.1006364 | Comparative structural dynamic analysis of GTPases | GTPases regulate a multitude of essential cellular processes ranging from movement and division to differentiation and neuronal activity. These ubiquitous enzymes operate by hydrolyzing GTP to GDP with associated conformational changes that modulate affinity for family-specific binding partners. There are three major G... | GTPases are a large superfamily of essential enzymes that regulate a variety of cellular processes. They share a common core structure supporting nucleotide binding and hydrolysis, and are potentially descended from the same ancestor. Yet their biological functions diverge dramatically, ranging from cell division and m... | Guanosine Triphosphate Phosphohydrolases (GTPases) are ubiquitous molecular machines mediating a variety of essential cellular processes [1]. Harnessing the GTP hydrolysis to modulate the affinity of partner molecule binding, GTPases transduce intracellular signals, control cell division and differentiation, and direct... |
10.1371/journal.ppat.1006636 | Nanobodies targeting norovirus capsid reveal functional epitopes and potential mechanisms of neutralization | Norovirus is the leading cause of gastroenteritis worldwide. Despite recent developments in norovirus propagation in cell culture, these viruses are still challenging to grow routinely. Moreover, little is known on how norovirus infects the host cells, except that histo-blood group antigens (HBGAs) are important bindin... | We determined the binding sites of six novel human norovirus specific Nanobodies (Nano-4, Nano-14, Nano-26, Nano-27, Nano-32, and Nano-42) using X-ray crystallography. The unique Nanobody recognition epitopes were correlated with their potential neutralizing capacities. We showed that one Nanobody (Nano-26) bound numer... | Human norovirus is recognized as the most important cause of outbreaks of acute gastroenteritis [1]. The virus is a non-enveloped single-stranded RNA virus within the Caliciviridae family. The human norovirus genome contains three open reading frames (ORFs), where ORF1 encodes non-structural proteins, ORF2 encodes the ... |
10.1371/journal.pntd.0002860 | Comparative Assessment of ELISAs Using Recombinant Saposin-Like Protein 2 and recombinant Cathepsin L-1 from Fasciola hepatica for the Serodiagnosis of Human Fasciolosis | Two recombinant Fasciola hepatica antigens, saposin-like protein-2 (recSAP2) and cathepsin L-1 (recCL1), were assessed individually and in combination in enzyme-linked immunosorbent assays (ELISA) for the specific serodiagnosis of human fasciolosis in areas of low endemicity as encountered in Central Europe. Antibody d... | To improve the serodiagnosis of human fasciolosis caused by Fasciola hepatica, we comparatively evaluated the accuracy of two different enzyme-linked immunosorbent assays (ELISAs) based on the use of two published recombinant antigens. The best performance was achieved with the recombinant F. hepatica saposin-like prot... | In Central Europe, the most frequently encountered autochthonous helminthic infections that require appropriate immunodiagnostic support include both forms of echinococcosis (Echinococcus multilocularis and Echinococcus granulosus), toxocarosis (Toxocara spp.), trichinellosis (Trichinella spp.), ascariosis (Ascaris lum... |
10.1371/journal.pntd.0006112 | Tracking the career development of scientists in low- and middle-income countries trained through TDR’s research capacity strengthening programmes: Learning from monitoring and impact evaluation | The Special Programme for Research and Training in Tropical Diseases (TDR) co-sponsored by UNICEF, UNDP, World Bank and WHO has been supporting research capacity strengthening in low- and middle-income countries for over 40 years. In order to assess and continuously optimize its capacity strengthening approaches, an ev... | The Special Programme for Research and Training in Tropical Diseases (TDR) co-sponsored by UNICEF, UNDP, World Bank and WHO has been providing training grants to strengthen research capacity in low- and middle-income countries for over 40 years. In order to assess to what extent TDR’s grants made a difference on the ca... | The Special Programme for Research and Training in Tropical Diseases (TDR), co-sponsored by UNICEF, UNDP, the World Bank and WHO, has a long track record in research capacity strengthening. Created in 1975 to support research and research capacity strengthening in the fight against tropical diseases, TDR’s goal is to i... |
10.1371/journal.ppat.1003193 | Phylodynamic Analysis of the Emergence and Epidemiological Impact of Transmissible Defective Dengue Viruses | Intra-host sequence data from RNA viruses have revealed the ubiquity of defective viruses in natural viral populations, sometimes at surprisingly high frequency. Although defective viruses have long been known to laboratory virologists, their relevance in clinical and epidemiological settings has not been established. ... | Defective viruses are viral particles with genetic mutations or deletions that eliminate essential functions, so that they cannot complete their life cycles independently. They can reproduce only by co-infecting host cells with functional viruses and ‘borrowing’ their functional elements. Defective viruses have been ob... | Although the high deleterious mutation rate of RNA viruses ensures that many genomes are defective [1], the long-term evolutionary and epidemiological consequences of the presence and transmission of defective viruses rarely have been discussed. To date, most work has focused on laboratory studies of defective-interfer... |
10.1371/journal.ppat.1006777 | Two classes of protective antibodies against Pseudorabies virus variant glycoprotein B: Implications for vaccine design | Pseudorabies virus (PRV) belongs to the Herpesviridae family, and is an important veterinary pathogen. Highly pathogenic PRV variants have caused severe epidemics in China since 2011, causing huge economic losses. To tackle the epidemics, we identified a panel of mouse monoclonal antibodies (mAbs) against PRV glycoprot... | Pseudorabies virus (PRV) is an emerging veterinary pathogen that infects many domestic animals. Since 2011, highly pathogenic PRV variants have emerged in many farms in China and posed great economic burdens to the animal industry. However, the current marketed vaccines cannot provide effective protection against these... | Pseudorabies virus (PRV) belongs to the family Herpesviridae, subfamily Alphaherpesvirinae, and genus Varicellovirus [1]. It is an important nervous system tropic pathogen in livestock and infects a variety of mammalian species, including ruminants, carnivores, and rodents [2]. Pigs, the natural host of PRV, are a uniq... |
10.1371/journal.pntd.0001783 | Re-Visiting Trichuris trichiura Intensity Thresholds Based on Anemia during Pregnancy | The intensity categories, or thresholds, currently used for Trichuris trichiura (ie. epg intensities of 1–999 (light); 1,000–9,999 epg (moderate), and ≥10,000 epg (heavy)) were developed in the 1980s, when there were little epidemiological data available on dose-response relationships. This study was undertaken to dete... | Infection by the soil-transmitted helminth Trichuris trichiura is defined as ‘light’, ‘moderate’ and ‘heavy’ depending on its intensity. However, these intensity categories were developed in the 1980s, before any epidemiological data were available on the association between specific T. trichiura infection intensities ... | The most recent comprehensive estimation of the prevalences of the soil-transmitted helminthiases (STH) documents a global prevalence of 17% for Trichuris trichiura infection, with approximately 800 million persons infected at any one time [1], [2]. Community-wide prevalences are frequently over 30–40% and it is not un... |
10.1371/journal.ppat.1006020 | Merkel Cell Polyomavirus Small T Antigen Promotes Pro-Glycolytic Metabolic Perturbations Required for Transformation | Merkel cell polyomavirus (MCPyV) is an etiological agent of Merkel cell carcinoma (MCC), a highly aggressive skin cancer. The MCPyV small tumor antigen (ST) is required for maintenance of MCC and can transform normal cells. To gain insight into cellular perturbations induced by MCPyV ST, we performed transcriptome anal... | In 2008, Merkel cell polyomavirus (MCPyV) was identified as clonally integrated in a majority of Merkel cell carcinomas (MCC), a rare but highly aggressive neuroendocrine carcinoma of the skin. Since then, studies have highlighted the roles of the MCPyV T antigens in promoting and sustaining MCC oncogenesis. In particu... | Human polyomaviruses are a diverse family of small DNA tumor viruses that typically cause asymptomatic, lifelong infections in healthy individuals [1, 2]. However, immune deficiencies enable more severe polyomavirus induced diseases including Merkel cell carcinoma (MCC). MCC is a rare and aggressive skin cancer that pr... |
10.1371/journal.pgen.0030093 | Selection for Robustness in Mutagenized RNA Viruses | Mutational robustness is defined as the constancy of a phenotype in the face of deleterious mutations. Whether robustness can be directly favored by natural selection remains controversial. Theory and in silico experiments predict that, at high mutation rates, slow-replicating genotypes can potentially outcompete faste... | Understanding the conditions that favor the constancy of phenotypes in the face of deleterious mutation pressure—mutational robustness—is an outstanding question in evolutionary biology. Theoretical and in silico studies utilizing digital organisms predict that slow-replicating populations can outcompete those with hig... | Lethal mutagenesis consists of overwhelming viral populations with an excessive number of deleterious mutations and has been proposed as a candidate therapeutic strategy against RNA viruses [1–4]. Several mutagens have been used to artificially increase error rates in RNA viruses such as vesicular stomatitis virus (VSV... |
10.1371/journal.pcbi.1005231 | Synchronization and Random Triggering of Lymphatic Vessel Contractions | The lymphatic system is responsible for transporting interstitial fluid back to the bloodstream, but unlike the cardiovascular system, lacks a centralized pump-the heart–to drive flow. Instead, each collecting lymphatic vessel can individually contract and dilate producing unidirectional flow enforced by intraluminal c... | For decades, cardiovascular physiology has been an area of intense research, and we have a fundamental understanding of the mechanisms the heart uses to drive blood flow through the distributed network of vessels in the body. The lymphatic system is now receiving similar attention as more is learned about its functiona... | To maintain fluid homeostasis, interstitial fluid drains into the lymphatic system through initial lymphatic vessels that carry it to the collecting lymphatic vessels. The collecting lymphatic vessels transport the fluid (known as lymph) both passively and actively to lymph nodes and back to the systemic blood circulat... |
10.1371/journal.pntd.0005764 | Unraveling the genetic diversity and phylogeny of Leishmania RNA virus 1 strains of infected Leishmania isolates circulating in French Guiana | Leishmania RNA virus type 1 (LRV1) is an endosymbiont of some Leishmania (Vianna) species in South America. Presence of LRV1 in parasites exacerbates disease severity in animal models and humans, related to a disproportioned innate immune response, and is correlated with drug treatment failures in humans. Although the ... | Leishmaniasis is a well-known parasitosis due to an infection by the protozoan Leishmania parasites firmly established in South America. In French Guiana, where leishmaniasis is a public health problem, having an annual incidence of 5.6 cases/10,000 inhabitants, 80% of Leishmania spp. parasites are infected by an endos... | Protozoan parasites of the genus Leishmania are unicellular eukaryotes with a complex digenetic cycle. In the vertebrate host, they are obligatory intracellular parasites. They cause a broad spectrum of diseases, collectively known as leishmaniases, that occur predominantly in tropical and subtropical regions [1]. Give... |
10.1371/journal.pntd.0000555 | Seroprevalence to the Antigens of Taenia solium Cysticercosis among Residents of Three Villages in Burkina Faso: A Cross-Sectional Study | There is limited published information on the prevalence of human cysticercosis in West Africa. The aim of this pilot study was to estimate the prevalence of Taenia solium cysticercosis antigens in residents of three villages in Burkina Faso.
Three villages were selected: The village of Batondo, selected to represent v... | Taenia solium cysticercosis is a neglected tropical zoonosis transmitted between humans and pigs. This infection is particularly prevalent in areas where sanitation, hygiene and pig management practices are poor. There is very little information about the importance of this infection in West Africa, even though pork me... | Taenia solium is a tapeworm transmitted among humans and between humans and pigs. Taeniasis is acquired by humans when eating raw or undercooked pork contaminated with cysticerci, the larval stage of T. solium. When ingested, the cysticerci migrate to the intestine of humans where they establish and become adults. Thes... |
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