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10.1371/journal.pntd.0001779 | The MASP Family of Trypanosoma cruzi: Changes in Gene Expression and Antigenic Profile during the Acute Phase of Experimental Infection | Trypanosoma cruzi is the etiological agent of Chagas disease, a debilitating illness that affects millions of people in the Americas. A major finding of the T. cruzi genome project was the discovery of a novel multigene family composed of approximately 1,300 genes that encode mucin-associated surface proteins (MASPs). ... | The parasite Trypanosoma cruzi is the etiologic agent of Chagas disease, a neglected tropical disease. A major finding of the T. cruzi genome project was the discovery of a multigene family that encodes mucin-associated surface proteins (MASP), a highly polymorphic family expressed at the surface of infective forms of ... | Trypanosoma cruzi is the etiological agent of Chagas disease, a major public health problem in Central and South America. Currently there are approximately 10 million people infected and 40 million people at risk of acquiring the disease [1], [2]. Trypomastigotes are the bloodstream circulating form that infect a wide ... |
10.1371/journal.pcbi.0030031 | Unsupervised Learning of Visual Features through Spike Timing Dependent Plasticity | Spike timing dependent plasticity (STDP) is a learning rule that modifies synaptic strength as a function of the relative timing of pre- and postsynaptic spikes. When a neuron is repeatedly presented with similar inputs, STDP is known to have the effect of concentrating high synaptic weights on afferents that systemati... | The paper describes a new biologically plausible mechanism for generating intermediate-level visual representations using an unsupervised learning scheme. These representations can then be used very effectively to perform categorization tasks using natural images. While the basic hierarchical architecture of the system... | Temporal constraints pose a major challenge to models of object recognition in cortex. When two images are simultaneously flashed to the left and right of fixation, human subjects can make reliable saccades to the side where there is a target animal in as little as 120–130 ms [1]. If we allow 20–30 ms for motor delays ... |
10.1371/journal.ppat.0040030 | A Role for NKG2D in NK Cell–Mediated Resistance to Poxvirus Disease | Ectromelia virus (ECTV) is an orthopoxvirus (OPV) that causes mousepox, the murine equivalent of human smallpox. C57BL/6 (B6) mice are naturally resistant to mousepox due to the concerted action of innate and adaptive immune responses. Previous studies have shown that natural killer (NK) cells are a component of innate... | Ectromelia virus (ECTV) causes mousepox, a murine disease that is the equivalent of human smallpox. ECTV normally penetrates through the periphery but rapidly spreads through the lymphatic system to vital organs. In mousepox-sensitive strains of mice, ECTV infection culminates with either rapid death or overt symptoms ... | Ectromelia virus (ECTV), the causative agent of mousepox, is an orthopoxvirus (OPV) with host specificity for the mouse. It is genetically very similar to vaccinia virus (VACV), the human pathogen variola virus (the agent of smallpox), and monkeypox virus [1], which sporadically infects people in Africa and produced a ... |
10.1371/journal.ppat.1006686 | TRIM5α SPRY/coiled-coil interactions optimize avid retroviral capsid recognition | Restriction factors are important components of intrinsic cellular defense mechanisms against viral pathogens. TRIM5α is a restriction factor that intercepts the incoming capsid cores of retroviruses such as HIV and provides an effective species-specific barrier to retroviral infection. The TRIM5α SPRY domain directly ... | TRIM5α is a cytosolic protein that provides effective protection for mammalian cells against retroviral infection. This anti-viral defense mechanism is an unprecedented example of how the cell can recognize entire capsids, which are large, megadalton-sized particles. TRIM5α achieves this by assembling into a hexagonal ... | TRIM5α is a restriction factor that recognizes and binds the incoming cores of retroviruses such as HIV [1–3], and represents a first-line intracellular antiviral defense mechanism. Upon core binding, TRIM5α induces accelerated capsid dissociation or uncoating, inhibits reverse transcription, and activates innate immun... |
10.1371/journal.pntd.0004072 | An Estimation of Private Household Costs to Receive Free Oral Cholera Vaccine in Odisha, India | Service provider costs for vaccine delivery have been well documented; however, vaccine recipients’ costs have drawn less attention. This research explores the private household out-of-pocket and opportunity costs incurred to receive free oral cholera vaccine during a mass vaccination campaign in rural Odisha, India.
F... | The price of vaccine and the costs of its delivery are two important economic measures considered by governments and various international organizations in their decisions on the use of a new vaccine. However, the costs to the vaccine recipients resulting from their travel, time and wage loss are hardly considered and ... | Several large cholera outbreaks in the sub Saharan Africa, Asia and Caribbean regions [1–3] have renewed interest in the use of oral cholera vaccines (OCV) in recent years. Considering the public health importance of cholera, the World Health Organization (WHO) recommends targeting OCVs to vulnerable populations living... |
10.1371/journal.pcbi.1004005 | Systems Level Analysis of Systemic Sclerosis Shows a Network of Immune and Profibrotic Pathways Connected with Genetic Polymorphisms | Systemic sclerosis (SSc) is a rare systemic autoimmune disease characterized by skin and organ fibrosis. The pathogenesis of SSc and its progression are poorly understood. The SSc intrinsic gene expression subsets (inflammatory, fibroproliferative, normal-like, and limited) are observed in multiple clinical cohorts of ... | Systemic sclerosis (SSc) is a rare autoimmune disease characterized by skin thickening (fibrosis) and progressive organ failure. Previous studies of SSc skin biopsies have identified molecular subsets of SSc based upon gene expression termed the inflammatory, fibroproliferative, normal-like, and limited intrinsic subse... | Genome-scale gene expression profiling of systemic sclerosis (SSc) skin has identified distinct intrinsic molecular subsets (inflammatory, fibroproliferative, and normal-like) within the subset of patients diagnosed with diffuse cutaneous SSc (dSSc) based upon the extent of skin involvement. These subsets are identifie... |
10.1371/journal.pbio.0050328 | Basic Math in Monkeys and College Students | Adult humans possess a sophisticated repertoire of mathematical faculties. Many of these capacities are rooted in symbolic language and are therefore unlikely to be shared with nonhuman animals. However, a subset of these skills is shared with other animals, and this set is considered a cognitive vestige of our common ... | Adult humans possess mathematical abilities that are unmatched by any other member of the animal kingdom. Yet, there is increasing evidence that the ability to enumerate sets of objects nonverbally is a capacity that humans share with other animal species. That is, like humans, nonhuman animals possess the ability to e... | The fact that humans and nonhuman animals represent numerical values nonverbally using a common cognitive process is well established [1–7]. Both human and nonhuman animals can nonverbally estimate the numerical values of arrays of dots or sequences of tones [8–12] and determine which of two sets is numerically larger ... |
10.1371/journal.pgen.1005035 | A Meta-analysis of Gene Expression Signatures of Blood Pressure and Hypertension | Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, c... | The focus of blood pressure (BP) GWAS has been the identification of common DNA sequence variants associated with the phenotype; this approach provides only one dimension of molecular information about BP. While it is a critical dimension, analyzing DNA variation alone is not sufficient for achieving an understanding o... | Systolic and diastolic blood pressure (SBP and DBP) are complex physiological traits that are affected by the interplay of multiple genetic and environmental factors. Hypertension (HTN) is a critical risk factor for stroke, renal failure, heart failure, and coronary heart disease [1]. Genome-wide association studies (G... |
10.1371/journal.pgen.1000361 | Deletion of the Mitochondrial Superoxide Dismutase sod-2 Extends Lifespan in Caenorhabditis elegans | The oxidative stress theory of aging postulates that aging results from the accumulation of molecular damage caused by reactive oxygen species (ROS) generated during normal metabolism. Superoxide dismutases (SODs) counteract this process by detoxifying superoxide. It has previously been shown that elimination of either... | In this paper, we examine the oxidative stress theory of aging using C. elegans as a model system. This theory proposes that aging results from the accumulation of molecular damage caused by reactive oxygen species (ROS). To test this theory, we examined the effect of deleting each of the five individual superoxide dis... | The oxidative stress theory of aging proposes that reactive oxygen species (ROS) generated by normal metabolism cause damage to macromolecules within the cell and that the accumulation of this damage over time leads to cellular dysfunction and eventually organismal death [1]–[3]. The majority of ROS present in the cell... |
10.1371/journal.pntd.0006453 | The role of case proximity in transmission of visceral leishmaniasis in a highly endemic village in Bangladesh | Visceral leishmaniasis (VL) is characterised by a high degree of spatial clustering at all scales, and this feature remains even with successful control measures. VL is targeted for elimination as a public health problem in the Indian subcontinent by 2020, and incidence has been falling rapidly since 2011. Current cont... | Visceral leishmaniasis (VL), a fatal parasitic disease transmitted by sandflies, has been targeted for elimination as a public health problem in the Indian subcontinent by 2020. The goal has been reached in the majority of endemic regions in Bangladesh, India and Nepal, but the disease persists in several hotspots. Bet... | Visceral leishmaniasis (VL), the world’s second most lethal vector-borne parasitic disease, has been targeted for elimination as a public health problem in the Indian subcontinent (ISC) by 2020 [1]. The target is an incidence of less than 1 VL case/10,000 people/year at subdistrict level in Bangladesh and India and dis... |
10.1371/journal.pcbi.1003456 | In Silico Single-Molecule Manipulation of DNA with Rigid Body Dynamics | We develop a new powerful method to reproduce in silico single-molecule manipulation experiments. We demonstrate that flexible polymers such as DNA can be simulated using rigid body dynamics thanks to an original implementation of Langevin dynamics in an open source library called Open Dynamics Engine. We moreover impl... | Video game techniques are designed to simulate rigid body dynamics of macroscopic bodies, e.g. characters or vehicles, in a realistic manner. However they are not able to deal with temperature effects, hence they are not able to deal with molecules. In order to extend these powerful techniques to molecular modeling, we... | The mechanical and topological properties of DNA and protein-DNA assemblies are of primary importance in many biological processes, including transcription, replication, chromatin organization and remodeling. Since techniques have become available enabling the manipulation of single-molecules [1], [2], a large amount o... |
10.1371/journal.pntd.0003138 | The Spatial Dynamics of Dengue Virus in Kamphaeng Phet, Thailand | Dengue is endemic to the rural province of Kamphaeng Phet, Northern Thailand. A decade of prospective cohort studies has provided important insights into the dengue viruses and their generated disease. However, as elsewhere, spatial dynamics of the pathogen remain poorly understood. In particular, the spatial scale of ... | Transmission of dengue virus has long been studied in Kamphaeng Phet, Northern Thailand, but how cases are related in time and space is still unclear, as is the role of human movement in generating these patterns. Because of these knowledge gaps, public health officials cannot make educated decisions on how to target v... | Dengue remains a major public health concern throughout global tropical and subtropical regions. An estimated 390 million people are infected by the mosquito-borne virus each year, of which 96 million develop symptomatic disease [1]. Thailand, like most countries in Southeast Asia, has experienced endemic dengue circul... |
10.1371/journal.pgen.1005512 | Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots | Genetic recombination during meiosis functions to increase genetic diversity, promotes elimination of deleterious alleles, and helps assure proper segregation of chromatids. Mammalian recombination events are concentrated at specialized sites, termed hotspots, whose locations are determined by PRDM9, a zinc finger DNA-... | During formation of sperm and eggs chromosomes exchange DNA in a process known as recombination, creating new combinations responsible for much of the enormous diversity in populations. In some mammals, including humans, the locations of recombination are chosen by a DNA-binding protein named PRDM9. Importantly, there ... | Genetic recombination in mammals is restricted to hotspots: short, 1–2 kb-long sites scattered throughout the genome [1,2]. With the exception of canids [3,4], their locations in mammals are determined by the sequence-specific DNA binding protein, PRDM9 (MGI:2384854) [5,6,7]. PRDM9 initiates recombination by binding DN... |
10.1371/journal.pntd.0002025 | Coverage and Effectiveness of Kyasanur Forest Disease (KFD) Vaccine in Karnataka, South India, 2005–10 | Kyasanur forest disease (KFD), a tick-borne viral disease with hemorrhagic manifestations, is localised in five districts of Karnataka state, India. Annual rounds of vaccination using formalin inactivated tissue-culture vaccine have been conducted in the region since 1990. Two doses of vaccine are administered to indiv... | Kyasanur forest disease (KFD), a tick-borne viral disease with hemorrhagic manifestations, occurs as seasonal outbreaks in five districts of Karnataka state, India. Vaccination with formalin inactivated tissue-culture vaccine is the key strategy for the prevention of the disease in the region. In spite of high effectiv... | Kyasanur forest disease (KFD) is a tick-borne viral disease characterised by sudden onset of fever and/or headache followed by hemorrhagic manifestations such as conjunctival congestion, bleeding gums, epistaxis, haemoptysis, haematemesis and malena [1]–[3]. The disease which was reported for the first time from Shimog... |
10.1371/journal.pcbi.1007184 | Network analyses to quantify effects of host movement in multilevel disease transmission models using foot and mouth disease in Cameroon as a case study | The dynamics of infectious diseases are greatly influenced by the movement of both susceptible and infected hosts. To accurately represent disease dynamics among a mobile host population, detailed movement models have been coupled with disease transmission models. However, a number of different host movement models hav... | Epidemics of infectious disease vary geographically and vary through time. A large part of this variation is caused by movement of individuals who are susceptible to the disease or infected with the disease. To study how movement affects epidemics, researchers often combine movement models with transmission models. How... | Host movement influences disease dynamics [1–3]. In situations where the population size is too small to sustain long-term chains of transmission, movement of infected hosts can spark local outbreaks and increase incidence counts. Alternatively, migration of susceptible hosts away from outbreak locations can reduce abu... |
10.1371/journal.pcbi.1005293 | Normal Modes Expose Active Sites in Enzymes | Accurate prediction of active sites is an important tool in bioinformatics. Here we present an improved structure based technique to expose active sites that is based on large changes of solvent accessibility accompanying normal mode dynamics. The technique which detects EXPOsure of active SITes through normal modEs is... | In this paper, we present an improved technique to predict active sites in enzymes. Our technique is based on changes of solvent accessibility that accompany normal mode dynamics. We assert the technique strength using several enzyme datasets with known catalytic residues. We show the technique successfully locates the... | Prediction of functional sites in proteins is essential for a range of bioinformatics applications such as molecular docking, and structure based drug design. Traditional methods for predicting functional sites include three approaches: 1). The first approach uses sequence homology to find evolutionary conserved residu... |
10.1371/journal.pntd.0004202 | Parasitological, Hematological and Biochemical Characteristics of a Model of Hyper-microfilariaemic Loiasis (Loa loa) in the Baboon (Papio anubis) | Loiasis, a filarial infection caused by Loa loa usually thought to cause relatively minor morbidity, can cause serious and often fatal reactions in patients carrying very high levels of circulating Loa loa microfilariae (mf) following administration of microfilaricidal drugs. An experimental model of this condition wou... | Loiasis is a filarial infection of humans that, in addition to causing severe direct clinical effects, is of concern to the global community’s efforts to eliminate the important filarial diseases, onchocerciasis and lymphatic filariasis, through causing interruption to mass drug distribution activities. Hyper-microfila... | Loa loa is a parasitic filarial nematode of humans, and a member the super family Filariodea which includes infections that are targeted for elimination, such as lymphatic filariasis (Wuchereria bancrofti, Brugia sp), and onchocerciasis (Onchocerca volvulus). L. loa is found in the tropics [1] restricted to the rainfor... |
10.1371/journal.pgen.1006118 | OVATE Family Protein 8 Positively Mediates Brassinosteroid Signaling through Interacting with the GSK3-like Kinase in Rice | OVATE gene was first identified as a key regulator of fruit shape in tomato. OVATE family proteins (OFPs) are characterized as plant-specific transcription factors and conserved in Arabidopsis, tomato, and rice. Roles of OFPs involved in plant development and growth are largely unknown. Brassinosteroids (BRs) are a cla... | OVATE family proteins (OFPs) are characterized as plant-specific transcription factors and mainly function in affecting fruit shape, but the molecular mechanisms by which they function are largely unknown. Rice genome contains 31 OFPs, the roles of these OsOFPs involved in plant development and growth are not understoo... | OVATE gene was first cloned in tomato and demonstrated to encode a hydrophilic protein with putative bipartite nuclear localization signal, and a C-terminal domain of approximate 70 amino acids which is designated as the OVATE domain and conserved in tomato, Arabidopsis, and rice [1–3]. As a plant-specific transcriptio... |
10.1371/journal.pgen.1003316 | Genome-Wide Diversity in the Levant Reveals Recent Structuring by Culture | The Levant is a region in the Near East with an impressive record of continuous human existence and major cultural developments since the Paleolithic period. Genetic and archeological studies present solid evidence placing the Middle East and the Arabian Peninsula as the first stepping-stone outside Africa. There is, h... | Population stratification caused by nonrandom mating between groups of the same species is often due to geographical distances leading to physical separation followed by genetic drift of allele frequencies in each group. In humans, population structures are also often driven by geographical barriers or distances; howev... | The Levant is a geographical area in the eastern Mediterranean region bounded by Anatolia, Egypt, and the Arabian Desert. It includes Lebanon, Syria, Jordan, Israel, Palestine, and often Cyprus and historical Armenia. The region has been central to human cultural development, embracing the earliest civilizations, agric... |
10.1371/journal.pbio.1002399 | The Structural Basis of Coenzyme A Recycling in a Bacterial Organelle | Bacterial Microcompartments (BMCs) are proteinaceous organelles that encapsulate critical segments of autotrophic and heterotrophic metabolic pathways; they are functionally diverse and are found across 23 different phyla. The majority of catabolic BMCs (metabolosomes) compartmentalize a common core of enzymes to metab... | In metabolism, molecules with “high-energy” bonds (e.g., ATP and Acetyl~CoA) are critical for both catabolic and anabolic processes. Accordingly, the retention of these bonds during biochemical transformations is incredibly important. The phosphotransacylase (Pta) enzyme catalyzes the conversion between acyl-CoA and ac... | Bacterial Microcompartments (BMCs) are organelles that encapsulate enzymes for sequential biochemical reactions within a protein shell [1–4]. The shell is typically composed of three types of protein subunits, which form either hexagonal (BMC-H and BMC-T) or pentagonal (BMC-P) tiles that assemble into a polyhedral shel... |
10.1371/journal.ppat.1001143 | Wolbachia Stimulates Immune Gene Expression and Inhibits Plasmodium Development in Anopheles gambiae | The over-replicating wMelPop strain of the endosymbiont Wolbachia pipientis has recently been shown to be capable of inducing immune upregulation and inhibition of pathogen transmission in Aedes aegypti mosquitoes. In order to examine whether comparable effects would be seen in the malaria vector Anopheles gambiae, tra... | Malaria is one of the world's most devastating diseases, particularly in Africa, and new control strategies are desperately needed. Here we show that the presence of Wolbachia bacteria inhibits the development of a malaria parasite in the most important Anopheles mosquito species of Africa. In addition we show that the... | Wolbachia pipientis is an intracellular maternally inherited bacterial symbiont of invertebrates that is very common in insects, including a number of mosquito species [1], [2]. It can manipulate host reproduction in several ways, including cytoplasmic incompatibility (CI), whereby certain crosses are rendered effectiv... |
10.1371/journal.pbio.1000235 | An aPKC-Exocyst Complex Controls Paxillin Phosphorylation and Migration through Localised JNK1 Activation | Atypical protein kinase C (aPKC) isoforms have been implicated in cell polarisation and migration through association with Cdc42 and Par6. In distinct migratory models, the Exocyst complex has been shown to be involved in secretory events and migration. By RNA interference (RNAi) we show that the polarised delivery of ... | Cell migration is an essential process in multicellular organisms during such events as embryonic development, the immune response, and wound healing. Cell migration is also instrumental in the development of pathologies such as cancer cell invasion of healthy tissues. To make cells move, key molecules must be engaged ... | Migration of cells is critical to the development and the normal physiology of organisms; it also plays a more sinister role in the dissemination of cancer towards metastatic disease, a process typically associated with poor prognosis. The process of migration involves a combination of cellular functions including thos... |
10.1371/journal.pcbi.1006406 | A fully autonomous terrestrial bat-like acoustic robot | Echolocating bats rely on active sound emission (echolocation) for mapping novel environments and navigating through them. Many theoretical frameworks have been suggested to explain how they do so, but few attempts have been made to build an actual robot that mimics their abilities. Here, we present the ‘Robat’—a fully... | Many animals are able of mapping a new environment even while moving through it for the first time. Bats can do this by emitting sound and extracting information from the echoes reflected from objects in their surroundings. In this study, we mimicked this ability by developing a robot that emits sound like a bat and an... | The growing use of autonomous robots emphasizes the need for new sensory approaches to facilitate tasks such as obstacle avoidance, object recognition and path planning. One of the most challenging tasks, faced by many robots, is the problem of generating a map of an unknown environment, while simultaneously navigating... |
10.1371/journal.pgen.0030161 | Capturing Heterogeneity in Gene Expression Studies by Surrogate Variable Analysis | It has unambiguously been shown that genetic, environmental, demographic, and technical factors may have substantial effects on gene expression levels. In addition to the measured variable(s) of interest, there will tend to be sources of signal due to factors that are unknown, unmeasured, or too complicated to capture ... | In scientific and medical studies, great care must be taken when collecting data to understand the relationship between two variables, such as a drug and its effect on a disease. In any given study there will be many other variables at play, such as the effects of age and sex on the disease. We show that in studies whe... | Large-scale gene expression studies allow one to characterize transcriptional variation with respect to measured variables of interest, such as differing environments, treatments, time points, phenotypes, or clinical outcomes. However, a number of unmeasured or unmodeled factors may also influence the expression of any... |
10.1371/journal.pcbi.1005545 | Low-dimensional spike rate models derived from networks of adaptive integrate-and-fire neurons: Comparison and implementation | The spiking activity of single neurons can be well described by a nonlinear integrate-and-fire model that includes somatic adaptation. When exposed to fluctuating inputs sparsely coupled populations of these model neurons exhibit stochastic collective dynamics that can be effectively characterized using the Fokker-Plan... | Characterizing the dynamics of biophysically modeled, large neuronal networks usually involves extensive numerical simulations. As an alternative to this expensive procedure we propose efficient models that describe the network activity in terms of a few ordinary differential equations. These systems are simple to solv... | There is prominent evidence that information in the brain, about a particular stimulus for example, is contained in the collective neuronal spiking activity averaged over populations of neurons with similar properties (population spike rate code) [1, 2]. Although these populations can comprise a large number of neurons... |
10.1371/journal.pbio.2001750 | Rictor positively regulates B cell receptor signaling by modulating actin reorganization via ezrin | As the central hub of the metabolism machinery, the mammalian target of rapamycin complex 2 (mTORC2) has been well studied in lymphocytes. As an obligatory component of mTORC2, the role of Rictor in T cells is well established. However, the role of Rictor in B cells still remains elusive. Rictor is involved in B cell d... | As the central hub of cell metabolism, the mammalian target of rapamycin complex (mTORC) integrates immune signals and metabolic cues for the maintenance and activation of these systems. Rictor is the core component of the mammalian target of rapamycin complex 2 (mTORC2), and loss of this protein leads to an immunodefi... | B cell receptor (BCR) signaling is vital for B cell development and function. When BCRs are cross-linked by antigens, it induces the conformational changes of signaling subunits immunoglobulin α chain (Igα) and immunoglobulin β chain (Igβ). The conformational changes of Igα and Igβ lead to the phosphorylation of immuno... |
10.1371/journal.pgen.1005685 | Sae2 Function at DNA Double-Strand Breaks Is Bypassed by Dampening Tel1 or Rad53 Activity | The MRX complex together with Sae2 initiates resection of DNA double-strand breaks (DSBs) to generate single-stranded DNA (ssDNA) that triggers homologous recombination. The absence of Sae2 not only impairs DSB resection, but also causes prolonged MRX binding at the DSBs that leads to persistent Tel1- and Rad53-depende... | Genome instability is one of the most pervasive characteristics of cancer cells and can be due to DNA repair defects and failure to arrest the cell cycle. Among the many types of DNA damage, the DNA double strand break (DSB) is one of the most severe, because it can cause mutations and chromosomal rearrangements. Gener... | Programmed DNA double-strand breaks (DSBs) are formed during meiotic recombination and rearrangement of the immunoglobulin genes in lymphocytes. Furthermore, potentially harmful DSBs can arise by exposure to environmental factors, such as ionizing radiations and radiomimetic chemicals, or by failures in DNA replication... |
10.1371/journal.pcbi.1004799 | Conflicting Selection Pressures Will Constrain Viral Escape from Interfering Particles: Principles for Designing Resistance-Proof Antivirals | The rapid evolution of RNA-encoded viruses such as HIV presents a major barrier to infectious disease control using conventional pharmaceuticals and vaccines. Previously, it was proposed that defective interfering particles could be developed to indefinitely control the HIV/AIDS pandemic; in individual patients, these ... | A major obstacle to effective antimicrobial therapy campaigns is the rapid evolution of drug resistance. Given the static nature of current pharmaceuticals and vaccines, natural selection inevitably drives pathogens to mutate into drug-resistant variants that can resume productive replication. Further, these drug-resis... | Defective interfering particles (DIPs) are ‘cheaters’ in a viral population. Rather than carrying a full set of genes essential for their own replication, these deletion mutants require co-infection by replication-competent ‘helper’ viruses to provide their missing components for replication, packaging, and spread [1, ... |
10.1371/journal.pcbi.1006471 | Quantum chemistry reveals thermodynamic principles of redox biochemistry | Thermodynamics dictates the structure and function of metabolism. Redox reactions drive cellular energy and material flow. Hence, accurately quantifying the thermodynamics of redox reactions should reveal design principles that shape cellular metabolism. However, only few redox potentials have been measured, and mostly... | Redox reactions define the energetic constraints within which life can exist. However, measurements of reduction potentials are scarce and unstandardized, and current prediction methods fall short of desired accuracy and coverage. Here, we harness quantum chemistry tools to enable the high-throughput prediction of redu... | In order to understand life we need to understand the forces that support and constrain it. Thermodynamics provides the fundamental constraints that shape metabolism [1–5]. Redox reactions constitute the primary metabolic pillars that support life. Life itself can be viewed as an electron transport process that conserv... |
10.1371/journal.pcbi.1005574 | Adaptation towards scale-free dynamics improves cortical stimulus discrimination at the cost of reduced detection | Fundamental to the function of nervous systems is the ability to reorganize to cope with changing sensory input. Although well-studied in single neurons, how such adaptive versatility manifests in the collective population dynamics and function of cerebral cortex remains unknown. Here we measured population neural acti... | The cerebral cortex is versatile; depending on changes in behavioral context, the same neural circuit can exhibit dramatically different neural activity and perform different functions. A long-standing hypothesis at the interface of physics and neuroscience posits that such shifts in cortical operation are governed by ... | Depending on behavioral and environmental context, the same neural circuits can perform different functions. Two essential functions performed by sensory cortices are stimulus detection and discrimination [1]. The ability to detect the presence or absence of certain stimuli is crucial when seeking or avoiding aspects o... |
10.1371/journal.pgen.1008039 | Loss of atrx cooperates with p53-deficiency to promote the development of sarcomas and other malignancies | The SWI/SNF-family chromatin remodeling protein ATRX is a tumor suppressor in sarcomas, gliomas and other malignancies. Its loss of function facilitates the alternative lengthening of telomeres (ALT) pathway in tumor cells, while it also affects Polycomb repressive complex 2 (PRC2) silencing of its target genes. To fur... | Somatic mutations in genes coding for epigenetic regulators such as ATRX are found across a diverse group of cancer types, suggesting their broad relevance in tumor induction and progression. However, tumors that have been linked to these chromatin remodelers can arise in many different molecular and cellular contexts,... | The alpha thalassemia/mental retardation syndrome X-linked (ATRX) protein is involved in the epigenetic regulation of gene expression. It is classified as a SWI/SNF-family chromatin remodeling factor due to its ATP-dependent helicase domain. In humans, germline loss of ATRX function causes mental retardation and alpha ... |
10.1371/journal.pcbi.1003357 | Determinants of Cell-to-Cell Variability in Protein Kinase Signaling | Cells reliably sense environmental changes despite internal and external fluctuations, but the mechanisms underlying robustness remain unclear. We analyzed how fluctuations in signaling protein concentrations give rise to cell-to-cell variability in protein kinase signaling using analytical theory and numerical simulat... | Cells sense their surroundings and respond to soluble factors in the extracellular space. Extracellular factors frequently induce heterogeneous responses, thereby restricting the biological outcome to a fraction of the cell population. However, the question arises how such cell-to-cell variability can be controlled, be... | External stimuli typically induce cellular responses by binding to cell surface receptors. Intracellular signaling networks transduce the signal, ultimately triggering gene expression responses in the nucleus. The basic building blocks of eukaryotic signaling networks are protein kinase cascades (Figure 1A): The signal... |
10.1371/journal.ppat.1004183 | The PhoP-Dependent ncRNA Mcr7 Modulates the TAT Secretion System in Mycobacterium tuberculosis | The PhoPR two-component system is essential for virulence in Mycobacterium tuberculosis where it controls expression of approximately 2% of the genes, including those for the ESX-1 secretion apparatus, a major virulence determinant. Mutations in phoP lead to compromised production of pathogen-specific cell wall compone... | One of the best characterized two-component systems in Mycobacterium tuberculosis is represented by the PhoPR pair, with PhoR being the transmembrane sensor kinase and PhoP playing an essential part in controlling expression of virulence-associated genes, such as those encoding the ESX-1 secretion apparatus. Previous s... | Mycobacterium tuberculosis, the etiologic agent of tuberculosis in humans, is arguably the world's most important intracellular pathogen. The bacterium disseminates via the aerosol route from open pulmonary lesions of an infectious case and on reaching the alveoli of a susceptible individual is phagocytosed by resident... |
10.1371/journal.pntd.0004529 | Evaluation of PCR Approaches for Detection of Bartonella bacilliformis in Blood Samples | The lack of an effective diagnostic tool for Carrion’s disease leads to misdiagnosis, wrong treatments and perpetuation of asymptomatic carriers living in endemic areas. Conventional PCR approaches have been reported as a diagnostic technique. However, the detection limit of these techniques is not clear as well as if ... | Carrion’s disease is an endemic illness in the Andean valleys of Peru that achieves high mortality rates in the absence of antibiotic treatment. There are three clinical manifestations, febrile acute patients, chronic patients as well as asymptomatic carriers. No effective diagnostic tool exists nowadays leading to mis... | Bartonella bacilliformis is the etiological agent of Carrion’s disease, an overlooked illness with a lethal febrile stage and a warty phase. Its endemicity is restricted to Peru, Ecuador and Colombia, with some cases having been described in Bolivia and Chile. The transmission is by a sandfly of the genera Luyzomyia, m... |
10.1371/journal.ppat.1001278 | NS2 Protein of Hepatitis C Virus Interacts with Structural and Non-Structural Proteins towards Virus Assembly | Growing experimental evidence indicates that, in addition to the physical virion components, the non-structural proteins of hepatitis C virus (HCV) are intimately involved in orchestrating morphogenesis. Since it is dispensable for HCV RNA replication, the non-structural viral protein NS2 is suggested to play a central... | Hepatitis C virus (HCV) causes major health problems worldwide. Understanding the major steps of the life cycle of this virus is essential to developing new and more efficient antiviral molecules. Virus assembly is the least understood step of the HCV life cycle. Growing experimental evidence indicates that, in additio... | The hepatitis C virus (HCV) has a high propensity to establish a persistent infection in the human liver. Approximately 170 million people suffer from chronic hepatitis C and are at risk to develop cirrhosis and hepatocellular carcinoma [1]. Current antiviral therapy is based on the use of polyethylene glycol conjugate... |
10.1371/journal.pntd.0002646 | LmaPA2G4, a Homolog of Human Ebp1, Is an Essential Gene and Inhibits Cell Proliferation in L. major | We have identified LmaPA2G4, a homolog of the human proliferation-associated 2G4 protein (also termed Ebp1), in a phosphoproteomic screening. Multiple sequence alignment and cluster analysis revealed that LmaPA2G4 is a non-peptidase member of the M24 family of metallopeptidases. This pseudoenzyme is structurally relate... | Leishmaniasis is a disease caused by protozoan parasites of the genus Leishmania. Its clinical manifestations are widespread, ranging from ulcerative skin lesions to life-threatening visceral infections. Approximately 1.5–2 million new cases of leishmaniasis are reported each year with an estimated 70,000 deaths. Durin... | Protozoan parasites of the genus Leishmania are the causative agents of leishmaniasis, a disease that is characterized by a spectrum of clinical manifestations ranging from ulcerative skin lesions to fatal visceral infections [1]. Leishmaniasis is a poverty-related disease and is associated with malnutrition, displacem... |
10.1371/journal.pntd.0005757 | Serum levels of interleukin-6 are linked to the severity of the disease caused by Andes Virus | Andes virus (ANDV) is the etiological agent of hantavirus cardiopulmonary syndrome in Chile. In this study, we evaluated the profile of the pro-inflammatory cytokines IL-1β, IL-12p70, IL-21, TNF-α, IFN-γ, IL-10 and IL-6 in serum samples of ANDV-infected patients at the time of hospitalization. The mean levels of circul... | Andes virus (ANDV) causes hantavirus cardiopulmonary syndrome (HCPS) that is characterized by the development of vascular leakage syndrome, eventually leading to massive pulmonary edema, shock and, in many cases, death. To date, no FDA-approved immunotherapeutics, specific antivirals, or vaccines are available for use ... | Andes virus (ANDV) is a rodent-borne hantavirus member of the Bunyaviridae family, and is unique for its ability to be transmitted from person-to-person [1,2]. ANDV is endemic in Chile and according to the Chilean Ministry of Health (Department of Epidemiology, Chilean Ministry of Health; http://www.minsal.cl), 1087 ca... |
10.1371/journal.pgen.1005451 | Strong Selective Sweeps on the X Chromosome in the Human-Chimpanzee Ancestor Explain Its Low Divergence | The human and chimpanzee X chromosomes are less divergent than expected based on autosomal divergence. We study incomplete lineage sorting patterns between humans, chimpanzees and gorillas to show that this low divergence can be entirely explained by megabase-sized regions comprising one-third of the X chromosome, wher... | Because the speciation events that led to human, chimpanzee and gorilla were close in time, the genetic relationship of these species varies along the genome. While human and chimpanzee are the closest related species, in 15% of the genome, human and gorilla are more closely related, and in another 15% of the genome th... | Despite constituting only 5–6% of the human genome, the human X chromosome is important for elucidating evolutionary mechanisms. Because of its particular inheritance pattern and its cosegregation with the very different Y chromosome, evolutionary forces may act upon it in different ways than on the autosomes [1,2]. Th... |
10.1371/journal.ppat.1002492 | The Murine Coronavirus Hemagglutinin-esterase Receptor-binding Site: A Major Shift in Ligand Specificity through Modest Changes in Architecture | The hemagglutinin-esterases (HEs), envelope glycoproteins of corona-, toro- and orthomyxoviruses, mediate reversible virion attachment to O-acetylated sialic acids (O-Ac-Sias). They do so through concerted action of distinct receptor-binding (“lectin”) and receptor-destroying sialate O-acetylesterase (”esterase”) domai... | Glycans cover the surface of every living cell. In vertebrates, these sugar trees commonly terminate with sialic acid (Sia) and, in consequence, Sias have become the attachment factors of choice for a multitude of pathogens: protozoa, bacteria and viruses alike. To ensure selectivity, viruses evolved to target distinct... | To initiate infection viruses must bind to an appropriate host cell. Selectivity of binding is ensured by attachment proteins on the virion, tailored to recognize one -or at the most- a limited number of cell surface molecules. Remarkably, a large number of viruses, representative of at least 11 distinct families sever... |
10.1371/journal.pntd.0001344 | Canine Antibody Response to Phlebotomus perniciosus Bites Negatively Correlates with the Risk of Leishmania infantum Transmission | Phlebotomine sand flies are blood-sucking insects that can transmit Leishmania parasites. Hosts bitten by sand flies develop an immune response against sand fly salivary antigens. Specific anti-saliva IgG indicate the exposure to the vector and may also help to estimate the risk of Leishmania spp. transmission. In this... | Leishmania infantum is the causative agent of zoonotic visceral leishmaniasis in the Mediterranean Basin and Phlebotomus perniciosus serve as the major vector. In the endemic foci, Leishmania parasites are transmitted mostly to dogs, the main reservoir host, and to humans. We studied the canine humoral immune response ... | Leishmania infantum (syn. Leishmania chagasi) is a protozoan parasite that causes zoonotic leishmaniasis, including the life-threatening visceral form, occurring also in the Mediterranean Basin. Parasites are transmitted by the bite of infected phlebotomine sand flies to dogs, the major host and the main domestic reser... |
10.1371/journal.ppat.1000706 | Three Dimensional Structure of the MqsR:MqsA Complex: A Novel TA Pair Comprised of a Toxin Homologous to RelE and an Antitoxin with Unique Properties | One mechanism by which bacteria survive environmental stress is through the formation of bacterial persisters, a sub-population of genetically identical quiescent cells that exhibit multidrug tolerance and are highly enriched in bacterial toxins. Recently, the Escherichia coli gene mqsR (b3022) was identified as the ge... | Most bacteria live in biofilms, microbial communities that cause more than 80% of human infections. Biofilms have a genetically identical sub-population of dormant cells, named persister cells, which are the well-recognized source of antibiotic resistance. Recently, it was demonstrated that toxins are highly upregulate... | The emergence of increasing numbers of bacteria that are resistant to antibiotics portends a major public health crisis. One well-recognized but poorly understood mechanism used by bacteria to survive environmental stress is through the formation of persisters, a subpopulation of cells that survive prolonged exposure t... |
10.1371/journal.pbio.1000574 | Evidence of Activity-Specific, Radial Organization of Mitotic Chromosomes in Drosophila | The organization and the mechanisms of condensation of mitotic chromosomes remain unsolved despite many decades of efforts. The lack of resolution, tight compaction, and the absence of function-specific chromatin labels have been the key technical obstacles. The correlation between DNA sequence composition and its cont... | Mitotic chromosomes of eukaryotes are relatively large rod-like cellular organelles, about 1 µm in diameter and 10 µm long, of well-studied composition but unknown structure. The question of whether all DNA sequences equally contribute to the interactions leading to the formation of mitotic chromosomes has never been a... | Over the past decades mitotic chromosomes have been shown to have a high degree of organization. However, the exact configuration of the DNA molecule and its reproducibility within a chromosome are unknown. Consolidation of the results from diverse experimental approaches has not yet led to a thorough understanding of ... |
10.1371/journal.pgen.1005681 | Convergent Evolution of Hemoglobin Function in High-Altitude Andean Waterfowl Involves Limited Parallelism at the Molecular Sequence Level | A fundamental question in evolutionary genetics concerns the extent to which adaptive phenotypic convergence is attributable to convergent or parallel changes at the molecular sequence level. Here we report a comparative analysis of hemoglobin (Hb) function in eight phylogenetically replicated pairs of high- and low-al... | The convergent evolution of similar traits in different species could be due to repeated changes at the genetic level or different changes that produce the same phenotypic effect. To investigate the extent to which convergence in phenotype is caused by repeated mutations, we investigated the molecular basis of converge... | When multiple species evolve similar changes in phenotype in response to a shared environmental challenge, it suggests that the convergently evolved character state is adaptive under the changed conditions and that it evolved under the influence of directional selection. A key question in evolutionary genetics concerns... |
10.1371/journal.pbio.1002247 | The Maternal Maverick/GDF15-like TGF-β Ligand Panda Directs Dorsal-Ventral Axis Formation by Restricting Nodal Expression in the Sea Urchin Embryo | Specification of the dorsal-ventral axis in the highly regulative sea urchin embryo critically relies on the zygotic expression of nodal, but whether maternal factors provide the initial spatial cue to orient this axis is not known. Although redox gradients have been proposed to entrain the dorsal-ventral axis by actin... | A key event during development of bilaterians is specification of the anterior-posterior and dorsal-ventral axes of the embryo. In some species, such as the fly Drosophila, this process relies on the activity of maternal determinants localized into the egg during oogenesis. However, in other animals, such as mammals or... | In bilaterians, specification of the dorsal-ventral (D/V) axis is a crucial event during embryogenesis to establish the correct body plan. In many species, this process relies on gene products translated from maternal mRNAs deposited in the egg. For example, in Drosophila, specification of the D/V axis of the embryo is... |
10.1371/journal.pntd.0005963 | Impact of Enterobius vermicularis infection and mebendazole treatment on intestinal microbiota and host immune response | Previous studies on the association of enterobiasis and chronic inflammatory diseases have revealed contradictory results. The interaction of Enterobius vermicularis infection in particular with gut microbiota and induced immune responses has never been thoroughly examined.
In order to answer the question of whether ex... | Whether human pinworm infection plus mebendazole deworming treatment can shift intestinal microbiota to a composition that is beneficial to the host and influence their mucosal immune response is currently unclear. In a cohort of 109 primary school children, we discovered that Enterobius vermicularis infection is assoc... | The inverse epidemiology data of parasitosis and autoimmune diseases has led to the hypothesis that childhood exposure to parasites might have protective effects against the development of allergies and autoimmunity [1]. The immunomodulatory roles of helminth have been well studied, and several helminth-derived compone... |
10.1371/journal.pntd.0005290 | Evaluation of a Smartphone Decision-Support Tool for Diarrheal Disease Management in a Resource-Limited Setting | The emergence of mobile technology offers new opportunities to improve clinical guideline adherence in resource-limited settings. We conducted a clinical pilot study in rural Bangladesh to evaluate the impact of a smartphone adaptation of the World Health Organization (WHO) diarrheal disease management guidelines, incl... | Diarrheal disease is responsible for one in ten deaths among children less than five years of age globally. Innovative interventions to address gaps in the clinical care of these patients are lacking, yet will likely reduce the morbidity and mortality from diarrheal diseases. Therefore, the objective of this pilot stud... | The provision of high-quality clinical care in resource-limited settings is challenged by logistical, educational, and temporal constraints that are exacerbated by a high volume of patients. This is especially true for the management of diarrheal diseases, which may overwhelm health facilities amid outbreaks or seasona... |
10.1371/journal.pntd.0000638 | Discovery of Markers of Exposure Specific to Bites of Lutzomyia longipalpis, the Vector of Leishmania infantum chagasi in Latin America | Sand flies deliver Leishmania parasites to a host alongside salivary molecules that affect infection outcomes. Though some proteins are immunogenic and have potential as markers of vector exposure, their identity and vector specificity remain elusive.
We screened human, dog, and fox sera from endemic areas of visceral ... | Leishmania parasites are transmitted by the bite of an infected vector sand fly that injects salivary molecules into the host skin during feeding. Certain salivary molecules can produce antibodies and can be used as an indicator of exposure to a vector sand fly and potentially the disease it transmits. Here we identifi... | Sand fly salivary proteins play a major role in blood feeding and Leishmania transmission [1]–[3]. Exposure to sand fly salivary proteins induces both cellular immunity and specific antibodies [3],[4]. A relationship between the level of specific antibodies to saliva, vector exposure and risk of contracting disease has... |
10.1371/journal.pntd.0005723 | Implementation of a study to examine the persistence of Ebola virus in the body fluids of Ebola virus disease survivors in Sierra Leone: Methodology and lessons learned | The 2013–2016 West African Ebola virus disease epidemic was unprecedented in terms of the number of cases and survivors. Prior to this epidemic there was limited data available on the persistence of Ebola virus in survivors’ body fluids and the potential risk of transmission, including sexual transmission.
Given the ur... | The 2013–2016 West African Ebola virus disease epidemic was unprecedented in the numbers of cases, deaths and survivors. Prior to this epidemic, limited data were available about the persistence of Ebola virus in body fluids of Ebola virus disease survivors and the related risk of transmission, including sexual transmi... | The 2013–2016 West African Ebola virus disease (EVD) epidemic was unprecedented in terms of the number of cases, deaths [1] and socio-economic consequences across the three most affected countries: Guinea, Liberia and Sierra Leone [2, 3]. As of 10 June 2016, 28,616 confirmed, probable and suspected cases of EVD and 11,... |
10.1371/journal.pgen.1006011 | Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD | Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large ... | Precision medicine is an emerging approach that takes into account variability in genes, gene and protein expression, environment and lifestyle. Recent advances in high-throughput genome-wide genotyping, genomics, and proteomics coupled with the creation of large, highly-phenotyped clinical cohorts now allows for integ... | Implementing precision medicine will require extensive use of biomarkers and in-depth understanding of the contributions of genetic, epigenetic, and environmental variation to phenotypic diversity and disease progression. Genome-wide association studies (GWAS) linking disease phenotypes to single nucleotide polymorphic... |
10.1371/journal.pbio.2003853 | Protein aggregates encode epigenetic memory of stressful encounters in individual Escherichia coli cells | Protein misfolding and aggregation are typically perceived as inevitable and detrimental processes tied to a stress- or age-associated decline in cellular proteostasis. A careful reassessment of this paradigm in the E. coli model bacterium revealed that the emergence of intracellular protein aggregates (PAs) was not re... | Since accurate protein folding is crucial for cellular viability, misfolded and aggregated proteins have typically been thought of as detrimental structures with potentially harmful physiological effects. In this report, we show that this general paradigm does not appear to hold in the model bacterium Escherichia coli.... | Proper protein folding and maintenance of proteome integrity are essential for cell function and viability [1,2]. Nevertheless, the generation of nonnative protein conformations is inevitable to some extent because of the inherent stochastic nature of protein folding [3,4] and is often even aggravated by genetic (e.g.,... |
10.1371/journal.pgen.1002853 | Mutations in a P-Type ATPase Gene Cause Axonal Degeneration | Neuronal loss and axonal degeneration are important pathological features of many neurodegenerative diseases. The molecular mechanisms underlying the majority of axonal degeneration conditions remain unknown. To better understand axonal degeneration, we studied a mouse mutant wabbler-lethal (wl). Wabbler-lethal (wl) mu... | Axonal degeneration is an important pathological feature of many neurodegenerative diseases, such as Alzheimer disease, Parkinson's disease, and amyotrophic lateral sclerosis. In most of these disease conditions, molecular mechanisms of axonal degeneration remain largely unknown. Spontaneous mouse mutants are important... | Neuronal loss and axonal degeneration are important pathological features of neurodegenerative diseases, such as Alzheimer disease, Parkinson's disease, amyotrophic lateral sclerosis and glaucoma. Axonopathies, conditions in which axon injury occurs first during disease progression, have been extensively studied, but t... |
10.1371/journal.pntd.0007706 | Multiplex profiling of inflammation-related bioactive lipid mediators in Toxocara canis- and Toxocara cati-induced neurotoxocarosis | Somatic migration of Toxocara canis- and T. cati-larvae in humans may cause neurotoxocarosis (NT) when larvae accumulate and persist in the central nervous system (CNS). Host- or parasite-induced immunoregulatory processes contribute to the pathogenesis; however, detailed data on involvement of bioactive lipid mediator... | Neurotoxocarosis (NT) is induced by larvae of the zoonotic roundworms Toxocara canis and T. cati migrating and persisting in the central nervous system of paratenic hosts, and may be accompanied by severe neurological symptoms. Toxocara spp. are known to modulate the hosts’ immune response, but data concerning involvem... | Toxocara canis (Werner, 1782) and T. cati (Schrank, 1788) are globally distributed, intestinal helminth parasites with canids and felids as definitive hosts [1]. Humans and a wide range of other species can act as paratenic hosts after accidental ingestion of infective stages (L3) of Toxocara spp., resulting in persist... |
10.1371/journal.pgen.1003163 | Increased Maternal Genome Dosage Bypasses the Requirement of the FIS Polycomb Repressive Complex 2 in Arabidopsis Seed Development | Seed development in flowering plants is initiated after a double fertilization event with two sperm cells fertilizing two female gametes, the egg cell and the central cell, leading to the formation of embryo and endosperm, respectively. In most species the endosperm is a polyploid tissue inheriting two maternal genomes... | Flowering plants reproduce by forming seeds that contain an embryo surrounded by a nourishing endosperm tissue that, similar to the mammalian placenta, supports embryo growth. Normal endosperm development requires the FERTILIZATION INDEPENDENT SEED (FIS) Polycomb Repressive Complex2 (PRC2). In most flowering plants the... | Seed development in flowering plants is initiated by double fertilization of the female gametophyte. Within the female gametophyte there are two distinct gametic cells that have divergent fates after fertilization. The haploid egg cell will give rise to the diploid embryo, while the homodiploid central cell will form t... |
10.1371/journal.pgen.1000960 | GC-Biased Evolution Near Human Accelerated Regions | Regions of the genome that have been the target of positive selection specifically along the human lineage are of special importance in human biology. We used high throughput sequencing combined with methods to enrich human genomic samples for particular targets to obtain the sequence of 22 chromosomal samples at high ... | The search for functional regions in the human genome, beyond the protein-coding portion, often relies on signals of conservation across species. The Human Accelerated Regions (HARs) are strongly conserved elements, ranging in size from 100–400 bp, that show an unexpected number of human-specific changes. This pattern ... | Understanding the forces that have shaped the evolution of the human genome is one of the most exciting problems in modern genomics. Two approaches to this problem are focused on identification and characterization of those genomic regions that have evolved the slowest and fastest along the human lineage [1]–[5]. The s... |
10.1371/journal.pbio.1002593 | Brain–Computer Interface–Based Communication in the Completely Locked-In State | Despite partial success, communication has remained impossible for persons suffering from complete motor paralysis but intact cognitive and emotional processing, a state called complete locked-in state (CLIS). Based on a motor learning theoretical context and on the failure of neuroelectric brain–computer interface (BC... | Despite scientific and technological advances, communication has remained impossible for persons suffering from complete motor paralysis but intact cognitive and emotional processing, a condition that is called completely locked-in state. Brain–computer interfaces based on neuroelectrical technology (like an electroenc... | Communication is the process of expressing and sharing feelings, thoughts, and intentions with one another by verbal and various nonverbal means. Communication skills appear automatic but can pose severe challenges to individuals suffering from motor neuron disorders. The most devastating of motor neuron diseases is am... |
10.1371/journal.pcbi.1002058 | Impact of Microscopic Motility on the Swimming Behavior of Parasites: Straighter Trypanosomes are More Directional | Microorganisms, particularly parasites, have developed sophisticated swimming mechanisms to cope with a varied range of environments. African Trypanosomes, causative agents of fatal illness in humans and animals, use an insect vector (the Tsetse fly) to infect mammals, involving many developmental changes in which cell... | Single cell motility is essential for many physiological functions. We seek to further our understanding of the swimming mechanism of trypanosomes - parasites responsible for deadly disease in humans and cattle. Trypanosomes are found both in the blood stream and invading tissue spaces. The swimming mechanisms used by ... | Eukaryotic cell motility plays a key role in many physiological functions including cell division, development, survival, as well as disease pathogenesis [1]–[4]. Studies of single cell motility have not only uncovered different aspects of these functions, but also provide great biophysical insight into life at low Rey... |
10.1371/journal.pcbi.1006143 | Latent environment allocation of microbial community data | As data for microbial community structures found in various environments has increased, studies have examined the relationship between environmental labels given to retrieved microbial samples and their community structures. However, because environments continuously change over time and space, mixed states of some env... | In the past decade, microbiomes from various natural and human symbiotic environments have been thoroughly studied. However, our knowledge is limited as to what types of environments affect the structure of a microbial community. In the first place, how can we define “environments”, in particular, the environmental ent... | Microbial communities are present worldwide in almost all possible environments. Because the composition (structure) of a microbial community and its surrounding environment are closely related to each other, it is important to understand what kinds of structural patterns are possible and how environmental factors affe... |
10.1371/journal.pgen.1002640 | Population Structure of Hispanics in the United States: The Multi-Ethnic Study of Atherosclerosis | Using ∼60,000 SNPs selected for minimal linkage disequilibrium, we perform population structure analysis of 1,374 unrelated Hispanic individuals from the Multi-Ethnic Study of Atherosclerosis (MESA), with self-identification corresponding to Central America (n = 93), Cuba (n = 50), the Dominican Republic (n = 203), Mex... | Using genotype data from about 60,000 distinct genetic markers, we examined population structure in 1,374 unrelated Hispanic individuals from the Multi-Ethnic Study of Atherosclerosis (MESA), with self-identification corresponding to Central America (n = 93), Cuba (n = 50), the Dominican Republic (n = 203), Mexico (n =... | Although epidemiologic studies often regard Hispanics in the United States as a homogenous group, U.S. Hispanics have a complex population structure comprised of many overlapping subgroups, and also vary markedly in environmental and cultural factors linked to country of origin and history of immigration to the United ... |
10.1371/journal.pbio.1002580 | ADAMTS5 Is a Critical Regulator of Virus-Specific T Cell Immunity | The extracellular matrix (ECM) provides physical scaffolding for cellular constituents and initiates biochemical and biomechanical cues that are required for physiological activity of living tissues. The ECM enzyme ADAMTS5, a member of the ADAMTS (A Disintegrin-like and Metalloproteinase with Thrombospondin-1 motifs) p... | Movement of immune cells is critical for effective clearance of pathogens. The response to influenza virus infection requires immune cell trafficking between the lung, mediastinal lymph node and other peripheral lymphoid organs such as the spleen. We set out to assess the contribution of a specific extracellular matrix... | Influenza A virus infection is responsible for substantial global morbidity and mortality (>500,000 deaths each year [1]) and largely afflicts high-risk groups, including the very young and elderly. There are currently two countermeasures employed to control influenza virus infection: vaccines and antivirals. Although ... |
10.1371/journal.pcbi.1000883 | Computational Models of HIV-1 Resistance to Gene Therapy Elucidate Therapy Design Principles | Gene therapy is an emerging alternative to conventional anti-HIV-1 drugs, and can potentially control the virus while alleviating major limitations of current approaches. Yet, HIV-1's ability to rapidly acquire mutations and escape therapy presents a critical challenge to any novel treatment paradigm. Viral escape is t... | A primary obstacle to the success of any anti-HIV treatment is HIV's ability to rapidly resist it by generating new viral strains whose vulnerability to the treatment is reduced. Gene therapies represent a novel class of treatments for HIV infection that may supplement or replace present therapies, as they alleviate so... | With no HIV-1 vaccine or cure in sight, treating and controlling the virus continues to be a major global health concern [1], [2]. The advent of highly active antiretroviral therapy (HAART) has remarkably prolonged patients' survival, but has failed to eradicate the virus or to control the epidemic. In particular, HAAR... |
10.1371/journal.pntd.0004843 | Rickettsial Disease in the Peruvian Amazon Basin | Using a large, passive, clinic-based surveillance program in Iquitos, Peru, we characterized the prevalence of rickettsial infections among undifferentiated febrile cases and obtained evidence of pathogen transmission in potential domestic reservoir contacts and their ectoparasites. Blood specimens from humans and anim... | Rickettsial infection remains relatively unexplored in South America compared to other regions of the world. For most regions of Peru (including the Amazon Basin), nothing more than broad serological characterization is available about circulating rickettsiae. Even less is known about the animal reservoirs and insect v... | Rickettsiae and rickettsia-like organisms are a diverse group of obligate intracellular bacteria within the order Rickettsiales that include members of the genera Rickettsia, Orientia, Ehrlichia, Anaplasma, Neorickettsia and Wolbachia. Based on whole-genome analysis, species within the genus Rickettsia are divided into... |
10.1371/journal.pbio.0050179 | Rb-Mediated Neuronal Differentiation through Cell-Cycle–Independent Regulation of E2f3a | It has long been known that loss of the retinoblastoma protein (Rb) perturbs neural differentiation, but the underlying mechanism has never been solved. Rb absence impairs cell cycle exit and triggers death of some neurons, so differentiation defects may well be indirect. Indeed, we show that abnormalities in both diff... | The retinoblastoma protein (Rb), an important tumor suppressor, blocks division and death by inhibiting the E2f transcription factor family. In contrast, Rb is thought to promote differentiation by potentiating tissue-specific transcription factors, although differentiation defects in Rb null cells could be an indirect... | The simplicity of the retina makes it an ideal tissue to study neurogenesis. Its development proceeds through three overlapping steps starting with retinal progenitor cell (RPC) proliferation, followed by birth of post-mitotic retinal transition cells (RTCs, also referred to as precursors), and ending with terminal dif... |
10.1371/journal.ppat.1007871 | The lectin-specific activity of Toxoplasma gondii microneme proteins 1 and 4 binds Toll-like receptor 2 and 4 N-glycans to regulate innate immune priming | Infection of host cells by Toxoplasma gondii is an active process, which is regulated by secretion of microneme (MICs) and rhoptry proteins (ROPs and RONs) from specialized organelles in the apical pole of the parasite. MIC1, MIC4 and MIC6 assemble into an adhesin complex secreted on the parasite surface that functions... | Toxoplasmosis is caused by the protozoan Toxoplasma gondii, belonging to the Apicomplexa phylum. This phylum comprises important parasites able to infect a broad diversity of animals, including humans. A particularity of T. gondii is its ability to invade virtually any nucleated cell of all warm-blooded animals through... | Toxoplasma gondii is a coccidian parasite belonging to the phylum Apicomplexa and is the causative agent of toxoplasmosis. This protozoan parasite infects a variety of vertebrate hosts, including humans with about one-third of the global population being chronically infected [1]. Toxoplasmosis can be fatal in immunocom... |
10.1371/journal.pntd.0002819 | A Thrombomodulin Mutation that Impairs Active Protein C Generation Is Detrimental in Severe Pneumonia-Derived Gram-Negative Sepsis (Melioidosis) | During severe (pneumo)sepsis inflammatory and coagulation pathways become activated as part of the host immune response. Thrombomodulin (TM) is involved in a range of host defense mechanisms during infection and plays a pivotal role in activation of protein C (PC) into active protein C (APC). APC has both anticoagulant... | Pneumonia and sepsis are conditions in which a procoagulant state is observed, with activation of coagulation and downregulation of anticoagulant pathways, both closely interrelated with inflammation. The protein C (PC) system is an important anticoagulant pathway implicated in the pathogenesis of sepsis. After binding... | Thrombomodulin (TM, CD141) is a multifunctional transmembrane glycoprotein receptor expressed on the surface of all vascular cells and various hematopoietic cells involved in activation of various parameters of inflammation and coagulation including protein C (PC), thrombin-activatable fibrinolysis inhibitor (TAFI), co... |
10.1371/journal.ppat.1003362 | IL-21 Restricts Virus-driven Treg Cell Expansion in Chronic LCMV Infection | Foxp3+ regulatory T (Treg) cells are essential for the maintenance of immune homeostasis and tolerance. During viral infections, Treg cells can limit the immunopathology resulting from excessive inflammation, yet potentially inhibit effective antiviral T cell responses and promote virus persistence. We report here that... | T cell exhaustion represents a state of T cell dysfunction associated with clinically relevant diseases, such as persistent viral infections or cancer. Although the molecular signature of exhausted T cells has been characterized in detail at the functional and transcriptional level, the immunological mechanisms that le... | The immune system has to efficiently eliminate pathogens but simultaneously needs to avoid the potential self-damage and immunopathology caused by excessive immune activation. Therefore, a tight regulation of immune responses is critical for host survival. The subset of CD4+CD25+ regulatory T (Treg) cells exerts key ne... |
10.1371/journal.ppat.1006226 | The transcriptome of HIV-1 infected intestinal CD4+ T cells exposed to enteric bacteria | Global transcriptome studies can help pinpoint key cellular pathways exploited by viruses to replicate and cause pathogenesis. Previous data showed that laboratory-adapted HIV-1 triggers significant gene expression changes in CD4+ T cell lines and mitogen-activated CD4+ T cells from peripheral blood. However, HIV-1 pri... | The gastrointestinal (GI) tract is a major site of early HIV-1 replication and death of CD4+ T cells. As HIV-1 replicates in the gut, the protective epithelial barrier gets disrupted, causing the entry of bacteria into the underlying tissue and the bloodstream, leading to inflammation and clinical complications even in... | CD4+ T cells are the major targets of HIV-1 infection, and their preferential depletion during the course of infection is the hallmark feature of progression to AIDS [1]. Thus, major efforts have been made to understand the molecular events that occur following HIV-1 infection of CD4+ T cells. Insights on the cellular ... |
10.1371/journal.pntd.0006684 | Ecological niche modelling and predicted geographic distribution of Lutzomyia cruzi, vector of Leishmania infantum in South America | In some transmission foci of Leishmania infantum in Brazil, Lutzomyia cruzi could be considered the main vector of this pathogen. In addition, L. cruzi is a permissive vector of L. amazonensis. Its geographical distribution seems to be restricted and limited to Cerrado and Pantanal biomes, which includes some areas in ... | Leishmaniases are vector-borne diseases caused by Leishmania parasites which are transmitted to humans by the bites of infected female sand flies. The sand fly Lutzomyia cruzi is the vector of Leishmania infantum, the causative agent of visceral leishmaniasis (VL), in some specific areas of Brazil. The transmission of ... | World Health Organization data show that vector-borne diseases represent more than 17% of the global burden of all infectious diseases, causing more than 1 million deaths per year [1]. The dynamics and intensity of transmission of pathogens exhibit significant spatial and temporal heterogeneity, especially in vector-bo... |
10.1371/journal.ppat.1000171 | B Cell Recognition of the Conserved HIV-1 Co-Receptor Binding Site Is Altered by Endogenous Primate CD4 | The surface HIV-1 exterior envelope glycoprotein, gp120, binds to CD4 on the target cell surface to induce the co-receptor binding site on gp120 as the initial step in the entry process. The binding site is comprised of a highly conserved region on the gp120 core, as well as elements of the third variable region (V3). ... | A major goal of HIV-1 vaccine research is to design novel candidates capable of neutralizing the vast array of viruses circulating in the human population. One approach is to base the vaccine upon the HIV-1 outer surface envelope glycoproteins to generate antibodies. However, during persistent infection in humans, the ... | The human immunodeficiency virus (HIV-1) exterior envelope glycoprotein, gp120, and the transmembrane glycoprotein, gp41, are non-covalently associated to comprise the trimeric, functional viral spike. These glycoproteins mediate entry and represent the sole virally encoded targets for neutralizing antibodies (nAbs) on... |
10.1371/journal.pntd.0006616 | Dengue virus serotype distribution based on serological evidence in pediatric urban population in Indonesia | Dengue is a febrile illness transmitted by mosquitoes, causing disease across the tropical and sub-tropical world. Antibody prevalence data and serotype distributions describe population-level risk and inform public health decision-making.
In this cross-sectional study we used data from a pediatric dengue seroprevalenc... | Dengue is a febrile illness transmitted by mosquitoes, causing disease across the tropical and sub-tropical world. Antibody prevalence data and serotype distribution describe population-level risk and inform public health decision-making. We present data from a dengue seroprevalence study in children in Indonesia; circ... | Dengue is a febrile illness caused by dengue virus (DENV) infection. The clinical manifestations of dengue occur on a spectrum, ranging from asymptomatic or a mild flu-like syndrome known as classic dengue fever (DF), to a more severe form known as dengue hemorrhagic fever (DHF) and the potentially fatal dengue shock s... |
10.1371/journal.ppat.1004816 | Prospective Large-Scale Field Study Generates Predictive Model Identifying Major Contributors to Colony Losses | Over the last decade, unusually high losses of colonies have been reported by beekeepers across the USA. Multiple factors such as Varroa destructor, bee viruses, Nosema ceranae, weather, beekeeping practices, nutrition, and pesticides have been shown to contribute to colony losses. Here we describe a large-scale contro... | Roughly one third of the food supply relies on pollinating insects. The number of colony losses of the domesticated Honey Bee (Apis mellifera) has grown significantly in the past eight years, endangering pollination of crops like almonds. Recent research indicates that colony losses are influenced by a combination of s... | Pollination by wild or managed species of pollinators is essential to agricultural productivity. Honey Bees (Apis mellifera) play an essential role in this process by pollinating many important crops such as apples, almonds, and alfalfa [1,2]. In the United States (USA), almond-bearing acres have grown by 130% since 19... |
10.1371/journal.pntd.0004254 | The Impact of Trachomatous Trichiasis on Quality of Life: A Case Control Study | Trachomatous trichiasis is thought to have a profound effect on quality of life (QoL), however, there is little research in this area. We measured vision and health-related QoL in a case-control study in Amhara Region, Ethiopia.
We recruited 1000 adult trichiasis cases and 200 trichiasis-free controls, matched to every... | There is clear evidence that visual impairment generally reduces quality of life. However, relatively little is known about the impact that trachomatous trichiasis (TT) has on the lives of affected people with and without the presence of visual impairment. We measured the impact of TT on vision and health-related quali... | Trachoma is the leading infectious cause of blindness worldwide [1]. About 229 million people live in trachoma endemic areas [2]. The disease starts in early childhood with repeated episodes of Chlamydia trachomatis infection. This triggers conjunctival inflammation of the upper eyelid, which leads to scarring. The sca... |
10.1371/journal.ppat.1005323 | Dual Requirement of Cytokine and Activation Receptor Triggering for Cytotoxic Control of Murine Cytomegalovirus by NK Cells | Natural killer (NK) cells play a critical role in controlling murine cytomegalovirus (MCMV) and can mediate both cytokine production and direct cytotoxicity. The NK cell activation receptor, Ly49H, is responsible for genetic resistance to MCMV in C57BL/6 mice. Recognition of the viral m157 protein by Ly49H is sufficien... | Natural killer (NK) cells play a crucial role in the protection of the host against viruses and in particular herpesvirus infections. Through their activation receptors which recognize surface ligands on target cells, NK cells can mediate direct killing (cytotoxicity) of virus-infected cells and produce their signature... | Natural killer (NK) cells are a critical component of the innate immune system. They play essential roles in controlling viral infections as illustrated in patients with selective NK cell defects who are susceptible to recurrent herpesvirus infections [1]. These clinical responses are recapitulated in animal studies, p... |
10.1371/journal.pcbi.1005285 | Dynamic Maternal Gradients Control Timing and Shift-Rates for Drosophila Gap Gene Expression | Pattern formation during development is a highly dynamic process. In spite of this, few experimental and modelling approaches take into account the explicit time-dependence of the rules governing regulatory systems. We address this problem by studying dynamic morphogen interpretation by the gap gene network in Drosophi... | Animal development is a highly dynamic process. Biochemical or environmental signals can cause the rules that shape it to change over time. We know little about the effects of such changes. For the sake of simplicity, we usually leave them out of our models and experimental assays. Here, we do exactly the opposite. We ... | Biological systems depend on time. Like everything else that persists for more than an instant, there is a temporal dimension to their existence. This much is obvious. What is less obvious, however, is the active role that time plays in altering the rules governing biological processes. For instance, fluctuating enviro... |
10.1371/journal.ppat.1000579 | The Chlamydia Type III Secretion System C-ring Engages a Chaperone-Effector Protein Complex | In Gram-negative bacterial pathogens, specialized chaperones bind to secreted effector proteins and maintain them in a partially unfolded form competent for translocation by type III secretion systems/injectisomes. How diverse sets of effector-chaperone complexes are recognized by injectisomes is unclear. Here we descr... | The obligate intracellular bacteria Chlamydia trachomatis is a common sexually transmitted pathogen and the leading cause of preventable blindness worldwide. Chlamydia co-opts host cells by secreting virulence factors directly into target cells through a multi-protein complex termed a type III secretion system or “inje... | The obligate, intracellular bacterium Chlamydia trachomatis infects the epithelium of the genital tract and conjunctivae, causing a wide range of ailments including the blinding disease trachoma, conjunctivitis, salpingitis, pelvic inflammatory disease and infertility [1]. Chlamydiae display an elaborate life cycle beg... |
10.1371/journal.pntd.0004000 | Short-term Forecasting of the Prevalence of Trachoma: Expert Opinion, Statistical Regression, versus Transmission Models | Trachoma programs rely on guidelines made in large part using expert opinion of what will happen with and without intervention. Large community-randomized trials offer an opportunity to actually compare forecasting methods in a masked fashion.
The Program for the Rapid Elimination of Trachoma trials estimated longitudi... | Forecasts of infectious diseases are rarely made in a falsifiable manner. Trachoma trials offer an opportunity to actually compare forecasting methods in a masked fashion. The World Health Organization recommends at least three annual antibiotic mass drug administrations where the prevalence of trachoma is greater than... | The World Health Organization (WHO), the International Trachoma Initiative, Ministries of Health, and their partners aim to control blinding trachoma by 2020, implementing surgical campaigns, antibiotic distributions, hygiene initiatives, and environmental improvements [1]. Trachoma control is a massive undertaking: 50... |
10.1371/journal.pgen.1001247 | A Quantitative Systems Approach Reveals Dynamic Control of tRNA Modifications during Cellular Stress | Decades of study have revealed more than 100 ribonucleoside structures incorporated as post-transcriptional modifications mainly in tRNA and rRNA, yet the larger functional dynamics of this conserved system are unclear. To this end, we developed a highly precise mass spectrometric method to quantify tRNA modifications ... | While the genetic code in DNA is read from four nucleobase structures, there are more than 100 ribonucleoside structures incorporated as post-transcriptional modifications mainly in tRNA and rRNA. These structures and their biosynthetic machinery are highly conserved, with 20–30 present in any one organism, yet the lar... | The complexity of the transfer RNA (tRNA) system confers great potential for its use in cellular regulatory programs. There are hundreds of tRNA-encoding genes in S. cerevisiae and human genomes, with extensive post-transcriptional processing that includes enzyme-mediated ribonucleoside modifications [1]. Considering b... |
10.1371/journal.pgen.1007723 | Capitalizing on the heterogeneous effects of CFTR nonsense and frameshift variants to inform therapeutic strategy for cystic fibrosis | CFTR modulators have revolutionized the treatment of individuals with cystic fibrosis (CF) by improving the function of existing protein. Unfortunately, almost half of the disease-causing variants in CFTR are predicted to introduce premature termination codons (PTC) thereby causing absence of full-length CFTR protein. ... | The development of variant specific modulators that correct dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein is an excellent example of precision medicine. Currently there is no molecular treatment available for individuals with cystic fibrosis (CF) carrying nonsense or frameshift varian... | The development of variant-specific modulators that correct dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein is an excellent model for precision medicine [1–4]. Cystic fibrosis (CF) is a progressive, multi-organ, life-threating, autosomal recessive disease caused by variants in CFTR gene... |
10.1371/journal.pcbi.1003323 | Linking Transcriptional Changes over Time in Stimulated Dendritic Cells to Identify Gene Networks Activated during the Innate Immune Response | The innate immune response is primarily mediated by the Toll-like receptors functioning through the MyD88-dependent and TRIF-dependent pathways. Despite being widely studied, it is not yet completely understood and systems-level analyses have been lacking. In this study, we identified a high-probability network of gene... | The innate immune response is the first level of protection in organisms against invading pathogens. It consists of a large number of proteins functioning in signaling cascades triggered by the binding of fragments from microbes to specific cellular receptors. Disruptions in these pathways can lead to numerous diseases... | The innate immune system is the primary host response to invading pathogens. The innate immune response is characterized by germline-encoded pattern-recognition receptors (PRRs) that detect and bind to specific microbial components, also known as pathogen-associated molecular patterns (PAMPs). Toll-like receptors (TLRs... |
10.1371/journal.pmed.1002476 | Life course socioeconomic position, alcohol drinking patterns in midlife, and cardiovascular mortality: Analysis of Norwegian population-based health surveys | Socioeconomically disadvantaged groups tend to experience more harm from the same level of exposure to alcohol as advantaged groups. Alcohol has multiple biological effects on the cardiovascular system, both potentially harmful and protective. We investigated whether the diverging relationships between alcohol drinking... | Individuals with low socioeconomic position tend to consume alcohol less frequently than individuals with middle or high socioeconomic position but experience more alcohol-related hospitalisations and deaths.
The study was performed to assess whether the relation between drinking patterns and cardiovascular disease dif... | Socioeconomic position (SEP) is relevant to behaviours, exposures, and susceptibilities that may influence health [1], such as social support, financial resources, or the knowledge, awareness, and determination required to actively follow a healthy lifestyle or consult a physician if needed. There is an inverse socioec... |
10.1371/journal.pntd.0002524 | Identification of Strain-Specific B-cell Epitopes in Trypanosoma cruzi Using Genome-Scale Epitope Prediction and High-Throughput Immunoscreening with Peptide Arrays | The factors influencing variation in the clinical forms of Chagas disease have not been elucidated; however, it is likely that the genetics of both the host and the parasite are involved. Several studies have attempted to correlate the T. cruzi strains involved in infection with the clinical forms of the disease by usi... | Serological tests are preferentially used for the diagnosis of Chagas disease during the chronic phase because of the low parasitemia and high anti-T. cruzi antibody titers. However, contradictory or inconclusive results, mainly related to the characteristics of the antigens used, are often observed. Additionally, the ... | Chagas disease, a zoonosis caused by the protozoan parasite Trypanosoma cruzi, affects approximately 10 million people in the Americas. Approximately 14,000 deaths occur annually, and 50,000–200,000 new cases are diagnosed each year [1]. During the acute phase of infection, diagnosis is based on parasitological methods... |
10.1371/journal.pcbi.1004948 | Neuroprosthetic Decoder Training as Imitation Learning | Neuroprosthetic brain-computer interfaces function via an algorithm which decodes neural activity of the user into movements of an end effector, such as a cursor or robotic arm. In practice, the decoder is often learned by updating its parameters while the user performs a task. When the user’s intention is not directly... | There are various existing methods for rapidly learning a decoder during closed-loop brain computer interface (BCI) tasks. While many of these methods work well in practice, there is no clear theoretical foundation for parameter learning. We offer a unification of closed-loop decoder learning setting as an imitation le... | Brain-computer interfaces (BCI, or brain-machine interfaces) translate noisy neural activity into commands for controlling an effector via a decoding algorithm [1–4]. While there are various proposed and debated encoding mechanisms describing how motor-relevant variables actually relate to neural activity [5–9], in pra... |
10.1371/journal.pntd.0000707 | Decreased Prevalence of Lymphatic Filariasis among Diabetic Subjects Associated with a Diminished Pro-Inflammatory Cytokine Response (CURES 83) | Epidemiological studies have shown an inverse correlation between the incidence of lymphatic filariasis (LF) and the incidence of allergies and autoimmunity. However, the interrelationship between LF and type-2 diabetes is not known and hence, a cross sectional study to assess the baseline prevalence and the correlates... | Childhood helminth infections can reduce the risk and severity of allergies and autoimmune diseases, by means of immunomodulation, and a decrease in helminth infections could potentially account for the increased prevalence of these diseases in the western world (hygiene hypothesis). We hypothesized that the same immun... | Global epidemiological studies have shown a marked increase in the incidence of diabetes worldwide. India leads the world in absolute numbers of diabetic subjects [1]. Type-2 diabetes mellitus constitutes about ∼90% of the entire diabetic population. The association between diabetes mellitus and increased susceptibilit... |
10.1371/journal.ppat.1003984 | ChIP-Seq and RNA-Seq Reveal an AmrZ-Mediated Mechanism for Cyclic di-GMP Synthesis and Biofilm Development by Pseudomonas aeruginosa | The transcription factor AmrZ regulates genes important for P. aeruginosa virulence, including type IV pili, extracellular polysaccharides, and the flagellum; however, the global effect of AmrZ on gene expression remains unknown, and therefore, AmrZ may directly regulate many additional genes that are crucial for infec... | Pathogenic bacteria such as Pseudomonas aeruginosa utilize a wide variety of systems to sense and respond to the changing conditions during an infection. When a stress is sensed, signals are transmitted to impact expression of many genes that allow the bacterium to adapt to the changing conditions. AmrZ is a protein th... | Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen that is a major burden on the health care industry. Up to 10% of all nosocomial infections are attributed to P. aeruginosa, with mortality rates approaching 40% in patients with bacteremia [1], [2]. This bacterium is often a causative agent of sepsis, as ... |
10.1371/journal.pcbi.1004542 | Bridging between NMA and Elastic Network Models: Preserving All-Atom Accuracy in Coarse-Grained Models | Dynamics can provide deep insights into the functional mechanisms of proteins and protein complexes. For large protein complexes such as GroEL/GroES with more than 8,000 residues, obtaining a fine-grained all-atom description of its normal mode motions can be computationally prohibitive and is often unnecessary. For th... | Proteins and other biomolecules are not static but are constantly in motion. Moreover, they possess intrinsic collective motion patterns that are tightly linked to their functions. Thus, an accurate and detailed description of their motions can provide deep insights into their functional mechanisms. For large protein c... | Protein dynamics plays a key role in describing the function of most proteins and protein complexes. The importance of protein dynamics studies has been increasingly recognized alongside the importance of the structures themselves. Experimentally, protein dynamics can be studied using nuclear magnetic resonance (NMR) [... |
10.1371/journal.pntd.0004801 | Impact of the Mycobaterium africanum West Africa 2 Lineage on TB Diagnostics in West Africa: Decreased Sensitivity of Rapid Identification Tests in The Gambia | MPT64 rapid speciation tests are increasingly being used in diagnosis of tuberculosis (TB). Mycobacterium africanum West Africa 2 (Maf 2) remains an important cause of TB in West Africa and causes one third of disease in The Gambia. Since the introduction of MPT64 antigen tests, a higher than expected rate of suspected... | Diagnostics for rapid confirmation of positive liquid cultures presumptive of Mycobacterium tuberculosis bacteria, based on the detection of the MPT64 antigen, are being used in many TB diagnostic laboratories worldwide. Of note, diagnostic performance of these tests in West Africa, where TB is uniquely caused by the g... | Tuberculosis remains a significant public health problem in Africa. Key to interrupting transmission, which is an essential step to reduce the incidence of TB, is timely identification and treatment of diseased individuals. This objective has fueled research into new generations of diagnostics and drugs. MPT64 is a 24k... |
10.1371/journal.ppat.1002512 | Mechanisms of Pathogenesis, Infective Dose and Virulence in Human Parasites | The number of pathogens that are required to infect a host, termed infective dose, varies dramatically across pathogen species. It has recently been predicted that infective dose will depend upon the mode of action of the molecules that pathogens use to facilitate their infection. Specifically, pathogens which use loca... | We found that mechanisms used by parasites to infect hosts are able to explain variation in two key pathogen traits: infective dose and virulence. In pathogens where the molecules secreted to facilitate infection acted locally, the number of cells required to start an infection (infective dose), was lower than in patho... | There is huge variation across pathogen species in the number of cells required to successfully infect a host. This number is known as the ‘infective dose’. At one end of the scale, species such as Shigella and Giardia lamblia require about 10 cells to start an infection. In contrast, species such as Vibrio cholera and... |
10.1371/journal.pbio.2005756 | BRAF and AXL oncogenes drive RIPK3 expression loss in cancer | Necroptosis is a lytic programmed cell death mediated by the RIPK1-RIPK3-MLKL pathway. The loss of Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) expression and necroptotic potential have been previously reported in several cancer cell lines; however, the extent of this loss across cancer types, as well... | Necroptosis is a regulated process that triggers cell death, resulting in necrosis and inflammation. Cancer cells have been shown to lose their ability to die via necroptosis, but the genetic factors that drive this resistance remain unknown. Here, we have analyzed 941 different cancer cell types and found that 83% of ... | Necroptosis is a necrotic programmed cell death pathway mediated by the RIPK1-RIPK3-MLKL signaling cascade [1–4]. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) can be activated when cells are stimulated by Tumor necrosis factor alpha (TNFα), Fas, or TRAIL ligands as well as downstream of Toll-like rece... |
10.1371/journal.ppat.1007263 | Structure of the Cladosporium fulvum Avr4 effector in complex with (GlcNAc)6 reveals the ligand-binding mechanism and uncouples its intrinsic function from recognition by the Cf-4 resistance protein | Effectors are microbial-derived secreted proteins with an essential function in modulating host immunity during infections. CfAvr4, an effector protein from the tomato pathogen Cladosporium fulvum and the founding member of a fungal effector family, promotes parasitism through binding fungal chitin and protecting it fr... | Microbes mobilize an array of secreted effectors to manipulate their hosts during infections, whereas in response, hosts utilize cognate immune receptors to perceive effectors and mount a defense. To date, the structural basis of effector function and recognition by immune receptors are still poorly understood. Here we... | Effectors are intriguing and enigmatic proteins deployed by microbes during host-pathogen interactions [1, 2]. Although inhibition of plant immunity during host infection is the main function of these proteins, the manner by which individual effectors perform this task is poorly understood [2]. One of the better unders... |
10.1371/journal.pmed.1002912 | Simplified clinical algorithm for identifying patients eligible for same-day HIV treatment initiation (SLATE): Results from an individually randomized trial in South Africa and Kenya | The World Health Organization recommends "same-day" initiation of antiretroviral therapy (ART) for HIV patients who are eligible and ready. Identifying efficient, safe, and feasible procedures for determining same-day eligibility and readiness is now a priority. The Simplified Algorithm for Treatment Eligibility (SLATE... | Both the World Health Organization and many national governments in sub-Saharan Africa now recommend that patients diagnosed with HIV start antiretroviral treatment (ART) as quickly as they can and, if possible, on the same day as their HIV diagnosis, known as “same-day initiation.”
Despite the recommendations, initiat... | In July 2017, the World Health Organization (WHO) revised its guidelines for antiretroviral therapy (ART) for HIV to recommend “same-day” treatment initiation (on day of diagnosis) whenever possible and “rapid” initiation (within 7 days of diagnosis) for all HIV-positive patients [1]. The guidelines cited evidence from... |
10.1371/journal.ppat.1004598 | In Vivo Approaches Reveal a Key Role for DCs in CD4+ T Cell Activation and Parasite Clearance during the Acute Phase of Experimental Blood-Stage Malaria | Dendritic cells (DCs) are phagocytes that are highly specialized for antigen presentation. Heterogeneous populations of macrophages and DCs form a phagocyte network inside the red pulp (RP) of the spleen, which is a major site for the control of blood-borne infections such as malaria. However, the dynamics of splenic D... | Malaria is a significant health issue, particularly in the tropical and subtropical regions of the world. The red pulp (RP) of the spleen is a major site for the control of blood-borne infections such as malaria. Macrophages and dendritic cells (DCs) form a complex phagocyte network inside the splenic RP. DCs are usual... | The spleen is a primary site for the control of blood-borne infectious diseases in humans and rodents [1], [2]. Although splenic phagocytic activity has been well documented in vitro[3]-[5] and ex vivo [3], [6]-[8], few studies have reported on the in vivo three-dimensional (3D) interactions between splenic phagocytes ... |
10.1371/journal.pntd.0000414 | Marriage, Sex, and Hydrocele: An Ethnographic Study on the Effect of Filarial Hydrocele on Conjugal Life and Marriageability from Orissa, India | Lymphatic filariasis (LF), a leading cause of permanent and long-term disability, affects 120 million people globally. Hydrocele, one of the chronic manifestations of LF among 27 million people worldwide, causes economic and psychological burdens on patients and their families. The present study explores and describes ... | Lymphatic filariasis, the second leading cause of permanent and long-term disability, affects 120 million people globally. Hydrocele, an accumulation of fluid in the scrotum that causes it to swell, is one of the chronic manifestations of LF among men and there are about 27 million men with hydrocele worldwide. We cond... | Lymphatic filariasis (LF), the second leading cause of permanent and long-term disability [1], affects 120 million people globally [2]. It is a mosquito-borne parasitic disease caused by Wuchereria bancrofti, which accounts for approximately 90% of all LF cases, followed by Brugia malayi and Brugia timoti. India contri... |
10.1371/journal.pgen.1007936 | Spatial soft sweeps: Patterns of adaptation in populations with long-range dispersal | Adaptation in extended populations often occurs through multiple independent mutations responding in parallel to a common selection pressure. As the mutations spread concurrently through the population, they leave behind characteristic patterns of polymorphism near selected loci—so-called soft sweeps—which remain visib... | When a species is spread out over a large geographic range, different regions may adapt to the same selection pressure by acquiring distinct beneficial mutations. The resulting pattern of genetic variation in the population is called a soft sweep. Dispersal strongly influences soft sweep patterns, as it determines how ... | Rare beneficial alleles can rapidly increase their frequency in a population in response to a new selective pressure. When adaptation is limited by the availability of mutations, a single beneficial mutation may sweep through the entire population in the classical scenario of a “hard sweep”. However, populations may ex... |
10.1371/journal.pntd.0000722 | The Global Burden of Alveolar Echinococcosis | Human alveolar echinococcosis (AE) is known to be common in certain rural communities in China whilst it is generally rare and sporadic elsewhere. The objective of this study was to provide a first estimate of the global incidence of this disease by country. The second objective was to estimate the global disease burde... | Human alveolar echinococcosis (AE), caused by the larval stage of the fox tapeworm Echinococcus multilocularis, is amongst the world's most dangerous zoonoses. Transmission to humans is by consumption of parasite eggs which are excreted in the faeces of the definitive hosts: foxes and, increasingly, dogs. Transmission ... | Human alveolar echinococcosis (AE) is caused by the larval stage of the fox tapeworm Echinococcus multilocularis. It is amongst the world's most dangerous zoonoses. Transmission of AE to humans is by consumption of parasite eggs which are excreted in the faeces of the definitive hosts: foxes and, increasingly, dogs. Na... |
10.1371/journal.pcbi.1003925 | A Comparative Study and a Phylogenetic Exploration of the Compositional Architectures of Mammalian Nuclear Genomes | For the past four decades the compositional organization of the mammalian genome posed a formidable challenge to molecular evolutionists attempting to explain it from an evolutionary perspective. Unfortunately, most of the explanations adhered to the “isochore theory,” which has long been rebutted. Recently, an alterna... | The non-uniformity of DNA composition in mammalian genomes has been known for over four decades. Many attempts have been made to provide a concise description of this heterogeneity and to identify the evolutionary driving forces behind this compositional phenomenology. The first concise description of the genome sugges... | Human and cow genomes have been shown to possess a complex architecture, in which compositionally homogeneous and nonhomogeneous domains of varying lengths and nucleotide composition are interspersed with one another [1], [2]. These empirically derived compositional architectures are mostly incompatible with the “isoch... |
10.1371/journal.pgen.1004002 | Phosphate Flow between Hybrid Histidine Kinases CheA3 and CheS3 Controls Rhodospirillum centenum Cyst Formation | Genomic and genetic analyses have demonstrated that many species contain multiple chemotaxis-like signal transduction cascades that likely control processes other than chemotaxis. The Che3 signal transduction cascade from Rhodospirillum centenum is one such example that regulates development of dormant cysts. This Che-... | Bacteria use chemotaxis and chemotaxis-like signal transduction pathways to quickly sense and adapt to a constantly changing environment. The purple photosynthetic bacterium Rhodospirillum centenum is able to withstand long periods of desiccation by forming metabolically dormant cyst cells, the development of which is ... | Rhodospirillum centenum is a photosynthetic member of the Azospirillum clade, members of which associate with root rhizospheres in a broad range of plants. These aerobic nitrogen fixating organisms are capable of promoting plant growth by the donation of both fixed nitrogen and plant hormones [1]. Inoculating fields an... |
10.1371/journal.pntd.0002856 | Hemoglobin Uptake by Paracoccidioides spp. Is Receptor-Mediated | Iron is essential for the proliferation of fungal pathogens during infection. The availability of iron is limited due to its association with host proteins. Fungal pathogens have evolved different mechanisms to acquire iron from host; however, little is known regarding how Paracoccidioides species incorporate and metab... | Fungal infections contribute substantially to human morbidity and mortality. During infectious processes, fungi have evolved mechanisms to obtain iron from high-affinity iron-binding proteins. In the current study, we demonstrated that hemoglobin is the preferential host iron source for the thermodimorphic fungus Parac... | Iron is an essential micronutrient for almost all organisms, including fungi. Because iron is a transition element, iron can participate as a cofactor in a series of biological processes, such as respiration and amino acid metabolism, as well as DNA and sterol biosynthesis [1]. However, at high levels, iron can be toxi... |
10.1371/journal.pntd.0002965 | Wolbachia Enhances West Nile Virus (WNV) Infection in the Mosquito Culex tarsalis | Novel strategies are required to control mosquitoes and the pathogens they transmit. One attractive approach involves maternally inherited endosymbiotic Wolbachia bacteria. After artificial infection with Wolbachia, many mosquitoes become refractory to infection and transmission of diverse pathogens. We evaluated the e... | Current methods to control mosquitoes and the pathogens they transmit are ineffective, partly due to insecticide and drug resistance. One novel control method involves exploiting naturally occurring Wolbachia bacteria in insects. Wolbachia are bacterial symbionts that are attractive candidates for mosquito-borne diseas... | Efforts to control vector-borne pathogens have been hindered by evolution of insecticide resistance and failing drug therapies. Evidence suggests bed nets and indoor residual spraying with insecticides are losing efficacy in developing countries [1], [2]. To improve the sustainability and efficacy of control efforts, a... |
10.1371/journal.pntd.0000702 | The Sudden Dominance of blaCTX–M Harbouring Plasmids in Shigella spp. Circulating in Southern Vietnam | Plasmid mediated antimicrobial resistance in the Enterobacteriaceae is a global problem. The rise of CTX-M class extended spectrum beta lactamases (ESBLs) has been well documented in industrialized countries. Vietnam is representative of a typical transitional middle income country where the spectrum of infectious dise... | Shigellosis is a disease caused by bacteria belonging to Shigella spp. and is a leading cause of bacterial gastrointestinal infections in infants in unindustrialized countries. The Shigellae are dynamic and capable of rapid change when placed under selective pressure in a human population. Extended spectrum beta lactam... | Enterobacteriaceae that have the capability to express CTX-M (so named because of their hydrolytic activity against cefotaxime) family extended spectrum beta lactamases (ESBLs) have emerged as a major health threat worldwide [1], [2]. Most of the research in this area is conducted in industrialized countries, where org... |
10.1371/journal.ppat.1002280 | Evolutionarily Divergent, Unstable Filamentous Actin Is Essential for Gliding Motility in Apicomplexan Parasites | Apicomplexan parasites rely on a novel form of actin-based motility called gliding, which depends on parasite actin polymerization, to migrate through their hosts and invade cells. However, parasite actins are divergent both in sequence and function and only form short, unstable filaments in contrast to the stability o... | Cellular movement is key to life and in the case of intracellular parasites, provides a vital mechanism to gain access to the protected niche they require. The parasite Toxoplasma gondii is a model for a group of parasites called apicomplexans, which move by an actin-dependent process referred to as gliding motility. T... | Actin is an essential protein that is highly conserved in sequence and function in eukaryotic cells. Despite this conservation, parasites within the phylum Apicomplexa encode divergent actins that remain largely in an unpolymerized state in vivo and only form short, unstable filaments in vitro, in contrast to conventio... |
10.1371/journal.pgen.1000909 | Whole-Genome SNP Association in the Horse: Identification of a Deletion in Myosin Va Responsible for Lavender Foal Syndrome | Lavender Foal Syndrome (LFS) is a lethal inherited disease of horses with a suspected autosomal recessive mode of inheritance. LFS has been primarily diagnosed in a subgroup of the Arabian breed, the Egyptian Arabian horse. The condition is characterized by multiple neurological abnormalities and a dilute coat color. C... | Genetic disorders affect many domesticated species, including the horse. In this study we have focused on Lavender Foal Syndrome, a seizure disorder that leads to suffering and death in foals soon after birth. A recessively inherited disorder, its occurrence is often unpredictable and difficult for horse breeders to av... | Heritable disorders affect many domestic species, including the horse. In the Arabian breed of horse a neurological disorder has been reported that is lethal soon after birth [1]. Affected foals can display an array of neurological signs including tetanic-like seizures, opisthotonus, stiff or paddling leg movements and... |
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