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10.1371/journal.pcbi.1005087 | A Parsimonious Model of the Rabbit Action Potential Elucidates the Minimal Physiological Requirements for Alternans and Spiral Wave Breakup | Elucidating the underlying mechanisms of fatal cardiac arrhythmias requires a tight integration of electrophysiological experiments, models, and theory. Existing models of transmembrane action potential (AP) are complex (resulting in over parameterization) and varied (leading to dissimilar predictions). Thus, simpler m... | Understanding and preventing life-threatening irregular electrical heart rhythms includes basic experimental, numerical, and theoretical research. Computer models of the electrical dynamics of cardiac cells and impulse propagation throughout the heart are essential tools of this research. For example, simulations of el... | The simulation of action potentials (APs) and their propagation has been an integral part of the field of electrophysiology for over half a century.[1] Over a hundred cellular AP models from many regions of the heart encompassing a variety of species have been published. These “ionic” models have been derived almost ex... |
10.1371/journal.pmed.1002675 | Climate change and African trypanosomiasis vector populations in Zimbabwe's Zambezi Valley: A mathematical modelling study | Quantifying the effects of climate change on the entomological and epidemiological components of vector-borne diseases is an essential part of climate change research, but evidence for such effects remains scant, and predictions rely largely on extrapolation of statistical correlations. We aimed to develop a mechanisti... | Tsetse flies are blood-feeding insects that transmit pathogens causing fatal diseases of humans and livestock across sub-Saharan Africa.
The birth and death rates of tsetse are influenced by environmental conditions, particularly temperature.
Since 1975, mean daily temperatures at Rekomitjie, a research station in the ... | Tsetse flies (Glossina spp.) transmit protozoa of the genus Trypanosoma that cause sleeping sickness—human African trypanosomiasis (HAT)—in humans. The initial phase of HAT is characterised by intermittent fever and joint pains; thereafter, there are sleeping difficulties and confusion. Without treatment, the disease i... |
10.1371/journal.pcbi.1005032 | Structure Prediction of RNA Loops with a Probabilistic Approach | The knowledge of the tertiary structure of RNA loops is important for understanding their functions. In this work we develop an efficient approach named RNApps, specifically designed for predicting the tertiary structure of RNA loops, including hairpin loops, internal loops, and multi-way junction loops. It includes a ... | RNA is an important and versatile macromolecule participating in a variety of biological processes. In addition to experimental approaches, computational prediction of 3D structure of RNAs and loops is an alternative and important source of gaining structure information and insights into their functions. The prediction... | RNAs are a type of macromolecule of crucial and versatile biological importance. In addition to their long-discovered functions of carrying genetic information and acting as a part of translation machinery, recently they were found to be able to participate in the regulation of gene expressions and protein synthesis, a... |
10.1371/journal.pntd.0005504 | Knockdown resistance mutations predict DDT resistance and pyrethroid tolerance in the visceral leishmaniasis vector Phlebotomus argentipes | Indoor residual spraying (IRS) with DDT has been the primary strategy for control of the visceral leishmaniasis (VL) vector Phlebotomus argentipes in India but efficacy may be compromised by resistance. Synthetic pyrethroids are now being introduced for IRS, but with a shared target site, the para voltage-gated sodium ... | Visceral leishmaniasis is a fatal disease transmitted solely by the sandfly Phlebotomus argentipes in India. For decades, indoor residual spraying targeting sandflies with DDT has been the main control tool in the region. Emergence of DDT resistance has compromised this strategy and pyrethroids are now being implemente... | Visceral leishmaniasis (VL) causes over 20,000 deaths annually [1]. In the Indian subcontinent VL, also known as Kala-azar, is caused by the obligate intracellular protozoan Leishmania donovani that exhibits a continuous cycle comprising of humans, as the only known vertebrate host in the region, and females of the san... |
10.1371/journal.pgen.1005071 | Inhibition of Telomere Recombination by Inactivation of KEOPS Subunit Cgi121 Promotes Cell Longevity | DNA double strand break (DSB) is one of the major damages that cause genome instability and cellular aging. The homologous recombination (HR)-mediated repair of DSBs plays an essential role in assurance of genome stability and cell longevity. Telomeres resemble DSBs and are competent for HR. Here we show that in buddin... | Aging is a general biological process among the living organisms which is affected by environmental stimuli but also genetically controlled. Genome instability is one of the aging hallmarks and has long been implicated as one of the main causal factors in aging. DNA double strand breaks (DSBs) are the most deleterious ... | Aging is generally defined as the time-dependent functional decline and increased mortality in most living organisms. Although aging appears to be a natural process, increasing evidence indicates that aging is genetically controlled. In order to elucidate how aging is influenced by intrinsic cellular traits, researcher... |
10.1371/journal.pgen.1002742 | Genome-Wide Analysis of GLD-1–Mediated mRNA Regulation Suggests a Role in mRNA Storage | Translational repression is often accompanied by mRNA degradation. In contrast, many mRNAs in germ cells and neurons are “stored" in the cytoplasm in a repressed but stable form. Unlike repression, the stabilization of these mRNAs is surprisingly little understood. A key player in Caenorhabditis elegans germ cell devel... | One of the most striking developmental events is the oocyte-to-embryo transition that, in the absence of Pol II–dependent transcription, depends on regulated translation of maternal mRNAs. Prior to their activation, these maternal mRNAs need to be “stored" in the egg cytoplasm in a repressed but stable form. Surprising... | The oocyte-to-embryo transition (OET), which encompasses oocyte maturation, ovulation, fertilization, and early embryogenesis, occurs while Pol II dependent transcription is globally repressed. This is why OET is largely driven by maternal mRNAs that are stored in the egg cytoplasm in a repressed but, importantly, also... |
10.1371/journal.ppat.1006476 | Innate immunity restricts Citrobacter rodentium A/E pathogenesis initiation to an early window of opportunity | Citrobacter rodentium infection is a mouse model for the important human diarrheal infection caused by enteropathogenic E. coli (EPEC). The pathogenesis of both species is very similar and depends on their unique ability to form intimately epithelium-adherent microcolonies, also known as “attachment/effacement” (A/E) l... | The so-called “attaching and effacing” (A/E) pathogens enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC) cause serious human diarrheal infections by adhering to and damaging the intestinal epithelium. Previous work on the mouse A/E pathogen Citrobacter rodentium has established that host adaptive imm... | Enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) serotype O157:H7 remain important causes of human diarrhea and mortality worldwide [1,2]. Citrobacter rodentium is a natural pathogen of mice which is used to model human EPEC and EHEC infection, as it shares the pathogenic mechanism of epith... |
10.1371/journal.ppat.1002583 | Preferential Entry of Botulinum Neurotoxin A Hc Domain through Intestinal Crypt Cells and Targeting to Cholinergic Neurons of the Mouse Intestine | Botulism, characterized by flaccid paralysis, commonly results from botulinum neurotoxin (BoNT) absorption across the epithelial barrier from the digestive tract and then dissemination through the blood circulation to target autonomic and motor nerve terminals. The trafficking pathway of BoNT/A passage through the inte... | Botulism is a severe and often fatal disease in man and animals characterized by flaccid paralysis. Clostridium botulinum produces a potent neurotoxin (botulinum neurotoxin) responsible for all the symptoms of botulism. Botulism is most often acquired by ingesting preformed botulinum neurotoxin in contaminated food or ... | Botulinum neurotoxins (BoNTs) are responsible for a severe nervous disease in man and animals known as botulism, characterized by skeletal muscle flaccid paralysis and respiratory arrest, resulting from inhibition of acetylcholine (ACh) release in peripheral cholinergic nerve terminals. BoNTs are produced by Clostridiu... |
10.1371/journal.pcbi.1001118 | Multi-Scaled Explorations of Binding-Induced Folding of Intrinsically Disordered Protein Inhibitor IA3 to its Target Enzyme | Biomolecular function is realized by recognition, and increasing evidence shows that recognition is determined not only by structure but also by flexibility and dynamics. We explored a biomolecular recognition process that involves a major conformational change – protein folding. In particular, we explore the binding-i... | The intrinsically disordered peptide IA3 is the endogenous inhibitor for the enzyme named yeast aspartic proteinase saccharopepsin (YPrA). In the presence of YPrA, IA3 folds itself into an amphipathic helix that blocks the active site cleft of the enzyme. We developed a multi-scaled approach to explore the underlying m... | “Intrinsically Disordered Proteins” (IDPs) are proteins that are disordered either in whole or in part. They play important roles in various cellular functions, including regulation, signaling and control processes [1]. Bioinformatic and statistical studies show that many proteins are intrinsically disordered: Of the c... |
10.1371/journal.ppat.1003912 | Viral MicroRNA Effects on Pathogenesis of Polyomavirus SV40 Infections in Syrian Golden Hamsters | Effects of polyomavirus SV40 microRNA on pathogenesis of viral infections in vivo are not known. Syrian golden hamsters are the small animal model for studies of SV40. We report here effects of SV40 microRNA and influence of the structure of the regulatory region on dynamics of SV40 DNA levels in vivo. Outbred young ad... | The recent discovery of virally encoded microRNAs (miRNAs) raises the possibility of additional regulatory processes being involved in viral replication, immune recognition, and host cell survival. In this study, we sought to characterize the effect of SV40-encoded miRNAs and the structure of the viral regulatory regio... | Definition of steps in the pathogenesis of a viral infection and of the response of the host to the viral assault is important to understanding the genesis of associated diseases and to guiding the development of viral diagnostics, therapeutics, and preventative measures. Viral microRNAs (miRNAs) are predicted to be in... |
10.1371/journal.pntd.0005953 | Estimating sensitivity of the Kato-Katz technique for the diagnosis of Schistosoma mansoni and hookworm in relation to infection intensity | The Kato-Katz technique is the most widely used diagnostic method in epidemiologic surveys and drug efficacy trials pertaining to intestinal schistosomiasis and soil-transmitted helminthiasis. However, the sensitivity of the technique is low, particularly for the detection of light-intensity helminth infections. Examin... | The World Health Organization (WHO) has defined a roadmap for schistosomiasis and soil-transmitted helminthiasis morbidity control and interruption of transmission with targets to be reached by 2025. Control efforts require reliable estimates of at-risk populations, number of infections, and disease burden estimates in... | Soil-transmitted helminthiasis (STH) and schistosomiasis are two of the most prevalent neglected tropical diseases with more than 1 billion and over 250 million people affected worldwide, respectively [1, 2]. Their collective global burden is 6 million disability-adjusted life years [3], with school-aged children at th... |
10.1371/journal.pcbi.1005736 | Differential temperature sensitivity of synaptic and firing processes in a neural mass model of epileptic discharges explains heterogeneous response of experimental epilepsy to focal brain cooling | Experiments with drug-induced epilepsy in rat brains and epileptic human brain region reveal that focal cooling can suppress epileptic discharges without affecting the brain’s normal neurological function. Findings suggest a viable treatment for intractable epilepsy cases via an implantable cooling device. However, pre... | Focal cooling of the epileptic brain region has been shown to consistently suppress epileptic activity and it is hoped that this treatment can be developed in the future into an implantable cooling device. However, it is still not clearly understood how cooling suppresses epileptic activity. This study uses a computati... | The World Health Organization identifies epilepsy as one of the most common neurological diseases affecting approximately 50 million people across all ages across the world [1]. According to the International League Against Epilepsy, a patient has epilepsy if he has had a seizure and his brain activity demonstrates a p... |
10.1371/journal.pcbi.1005173 | MD/DPD Multiscale Framework for Predicting Morphology and Stresses of Red Blood Cells in Health and Disease | Healthy red blood cells (RBCs) have remarkable deformability, squeezing through narrow capillaries as small as 3 microns in diameter without any damage. However, in many hematological disorders the spectrin network and lipid bilayer of diseased RBCs may be significantly altered, leading to impaired functionality includ... | Red blood cells (RBCs) and their mechanical properties play a crucial role in the dynamic and rheological behavior of blood in normal and disease states. However, the precise determination of RBC membrane properties is hard to be achieved experimentally. To this end, accurate numerical modeling can be used to provide v... | Blood is a biological fluid that delivers nutrients and oxygen to living cells and removes their waste products. Due to its particulate nature, blood is considered as a complex non-Newtonian fluid exhibiting intriguing dynamic and rheological behavior depending mainly on flow rate, vessel geometry, and volume fraction ... |
10.1371/journal.pcbi.1004601 | Lévy Walks Suboptimal under Predation Risk | A key challenge in movement ecology is to understand how animals move in nature. Previous studies have predicted that animals should perform a special class of random walks, called Lévy walk, to obtain more targets. However, some empirical studies did not support this hypothesis, and the relationship between search str... | Moving agents should efficiently search for targets (e.g., food, prey, or specific locations) when lacking information about the location of the targets. For this random search problem, the Lévy walk hypothesis claims that Lévy walk movement patterns (i.e., each step length follows a distribution that is heavy-tailed) ... | How should we move to search for targets when we have no information about their location? This is called the random search problem, which has attracted the attention of researchers in various fields [1]. The problem can be applied to various phenomena, including molecular-level movements within an organism, cell movem... |
10.1371/journal.ppat.1006632 | Rewiring monocyte glucose metabolism via C-type lectin signaling protects against disseminated candidiasis | Monocytes are innate immune cells that play a pivotal role in antifungal immunity, but little is known regarding the cellular metabolic events that regulate their function during infection. Using complementary transcriptomic and immunological studies in human primary monocytes, we show that activation of monocytes by C... | Fungal infections are a major health concern for immunocompromised individuals due to the lack of success of the currently available antifungal therapies. Unveiling the metabolic processes involved in the immune function offers a promising opportunity for the development of new therapeutic approaches against these infe... | The immune system is constantly challenged by pathogens, and this requires immune cells to optimize the management of metabolic resources in order to exert their crucial role in host defense. A number of studies have shown how different stimuli induce metabolic reprogramming in immune cells, required for the response a... |
10.1371/journal.pntd.0000495 | Preclinical Assessment of the Treatment of Second-Stage African Trypanosomiasis with Cordycepin and Deoxycoformycin | There is an urgent need to substitute the highly toxic compounds still in use for treatment of the encephalitic stage of human African trypanosomiasis (HAT). We here assessed the treatment with the doublet cordycepin and the deaminase inhibitor deoxycoformycin for this stage of infection with Trypanosoma brucei (T.b.).... | There is an urgent need to substitute the highly toxic arsenic compounds still in use for treatment of the encephalitic stage of African trypanosomiasis, a disease caused by infection with Trypanosoma brucei. We exploited the inability of trypanosomes to engage in de novo purine synthesis as a therapeutic target. Cordy... | Human African trypanosomiasis (HAT), also known as sleeping sickness, is a neglected tropical infectious disease that has re-emerged in sub-Saharan Africa in the late 1900ties [1],[2]. The disease is caused by subspecies of the protozoan parasite Trypanosoma brucei and is transmitted by the blood-sucking tsetse fly. Fo... |
10.1371/journal.pntd.0002402 | Sex-Biased Expression of MicroRNAs in Schistosoma mansoni | Schistosomiasis is an important neglected tropical disease caused by digenean helminth parasites of the genus Schistosoma. Schistosomes are unusual in that they are dioecious and the adult worms live in the blood system. MicroRNAs play crucial roles during gene regulation and are likely to be important in sex different... | Schistosomiasis is the second most common disease caused by a parasite, affecting over 200 million people. The parasites involved are flatworms of the genus Schistosoma. Unlike most non-parasitic flatworms, Schistosoma species have separate sexes, and the emergence of sex has been associated with the development of a p... | Human schistosomiasis is a neglected tropical disease (NTD) caused by blood flukes of the genus Schistosoma. Schistosomiasis is estimated to affect over 200 million people in developing tropical and subtropical countries, with over 90% of cases being confined to Africa [1], [2]. Schistosoma mansoni is primarily respons... |
10.1371/journal.ppat.1006413 | Genomic fossils reveal adaptation of non-autonomous pararetroviruses driven by concerted evolution of noncoding regulatory sequences | The interplay of different virus species in a host cell after infection can affect the adaptation of each virus. Endogenous viral elements, such as endogenous pararetroviruses (PRVs), have arisen from vertical inheritance of viral sequences integrated into host germline genomes. As viral genomic fossils, these sequence... | This paper addresses the adaptive strategies of ancient defective viruses recorded in grass genomes. We mined numerous virus segments from various grass genomes and assembled several defective pararetrovirus (non-autonomous PRV) species. We attempted to understand how these non-autonomous PRVs can complete parasitic li... | Similar to virus–host interactions, virus–virus interactions, especially those occurring during mixed plant virus infections in nature, have complex outcomes ranging from antagonism to synergism [1, 2]. Such interactions between different virus species affect their adaptation [1, 2]. Numerous virus-derived sequences, r... |
10.1371/journal.pmed.1002617 | Heat-related mortality trends under recent climate warming in Spain: A 36-year observational study | Anthropogenic greenhouse gas emissions have increased summer temperatures in Spain by nearly one degree Celsius on average between 1980 and 2015. However, little is known about the extent to which the association between heat and human mortality has been modified. We here investigate whether the observed warming has be... | The Euro-Mediterranean region arises as a major climatic hot spot because of global warming.
Warmer temperatures should in principle contribute to an increase in the number of deaths because of heat.
We do not know yet if and to what extent societal adaptation and/or socioeconomic development is modifying this expected... | Anthropogenic climate change represents a major threat for human health and a challenge for public health services [1]. One of its most important effects is the potential increase in heat-related mortality resulting from rising temperatures and the associated increase in the frequency, intensity, and duration of extrem... |
10.1371/journal.pbio.0050230 | Insights into the Genome of Large Sulfur Bacteria Revealed by Analysis of Single Filaments | Marine sediments are frequently covered by mats of the filamentous Beggiatoa and other large nitrate-storing bacteria that oxidize hydrogen sulfide using either oxygen or nitrate, which they store in intracellular vacuoles. Despite their conspicuous metabolic properties and their biogeochemical importance, little is kn... | In 1888 Winogradsky proposed the concept of chemolithotrophy—growth using inorganic compounds as an energy source—after studying the sulfur bacterium Beggiatoa. These filamentous bacteria and related organisms inhabit the surface of marine and freshwater sediments, where they oxidize hydrogen sulfide using either oxyge... | Mats of conspicuously large sulfur-oxidizing bacteria often cover the seafloor in organicly rich coastal areas, at hydrate ridge methane seeps, at hydrothermal vents, on whale falls, and in coastal upwelling regions [1–5]. The closely related genera Beggiatoa, Thioploca, and Thiomargarita are among the largest prokaryo... |
10.1371/journal.pcbi.1006180 | Atomic resolution mechanism of ligand binding to a solvent inaccessible cavity in T4 lysozyme | Ligand binding sites in proteins are often localized to deeply buried cavities, inaccessible to bulk solvent. Yet, in many cases binding of cognate ligands occurs rapidly. An intriguing system is presented by the L99A cavity mutant of T4 Lysozyme (T4L L99A) that rapidly binds benzene (~106 M-1s-1). Although the protein... | Proteins often bind ligands in buried cavities that appear to be inaccessible based on static structures. The mechanisms and pathways by which ligands reach their binding sites in such cases are, thus, often unknown. Yet, ligand recognition by occluded cavities can happen rapidly. A central question remains: How does s... | Measurements of affinities of small molecules to specific binding sites in proteins have become routine, especially in the context of drug discovery studies where such experiments are often among the first to be performed. These thermodynamic measurements are routinely supplemented by kinetic studies of drug-receptor i... |
10.1371/journal.pcbi.1005135 | Large-Scale Off-Target Identification Using Fast and Accurate Dual Regularized One-Class Collaborative Filtering and Its Application to Drug Repurposing | Target-based screening is one of the major approaches in drug discovery. Besides the intended target, unexpected drug off-target interactions often occur, and many of them have not been recognized and characterized. The off-target interactions can be responsible for either therapeutic or side effects. Thus, identifying... | High-throughput techniques have generated vast amounts of diverse omics and phenotypic data. However, these sets of data have not yet been fully explored to improve the effectiveness and efficiency of drug discovery, a process which has traditionally adopted a one-drug-one-gene paradigm. Consequently, the cost of bring... | Conventional one-drug-one-gene drug discovery and drug development is a time-consuming and expensive process. It suffers from high attrition rate and possible unexpected post-market withdrawal [1]. It has been recognized that a drug rarely only binds to its intended target, and off-target interactions (i.e. interaction... |
10.1371/journal.pcbi.1000709 | Comparing Families of Dynamic Causal Models | Mathematical models of scientific data can be formally compared using Bayesian model evidence. Previous applications in the biological sciences have mainly focussed on model selection in which one first selects the model with the highest evidence and then makes inferences based on the parameters of that model. This “be... | Bayesian model comparison provides a formal method for evaluating different computational models in the biological sciences. Emerging application domains include dynamical models of neuronal and biochemical networks based on differential equations. Much previous work in this area has focussed on selecting the single be... | Mathematical models of scientific data can be formally compared using Bayesian model evidence [1]–[3], an approach that is now widely used in statistics [4], signal processing [5], machine learning [6], natural language processing [7], and neuroimaging [8]–[10]. An emerging area of application is the evaluation of dyna... |
10.1371/journal.ppat.1004669 | Essential Domains of Anaplasma phagocytophilum Invasins Utilized to Infect Mammalian Host Cells | Anaplasma phagocytophilum causes granulocytic anaplasmosis, an emerging disease of humans and domestic animals. The obligate intracellular bacterium uses its invasins OmpA, Asp14, and AipA to infect myeloid and non-phagocytic cells. Identifying the domains of these proteins that mediate binding and entry, and determini... | Anaplasma phagocytophilum causes the potentially deadly bacterial disease granulocytic anaplasmosis. The pathogen replicates inside white blood cells and, like all other obligate intracellular organisms, must enter host cells to survive. Multiple A. phagocytophilum surface proteins called invasins cooperatively orchest... | Human granulocytic anaplasmosis (HGA) is an emerging tick-borne zoonosis in the United States, Europe, and Asia [1]. The number of HGA cases reported to the U. S. Centers for Disease Control and Prevention rose nearly seven-fold between 2003 and 2012 [2,3]. Seroprevalence data indicate that the disease is underreported... |
10.1371/journal.pntd.0003646 | Trypanosoma cruzi, Etiological Agent of Chagas Disease, Is Virulent to Its Triatomine Vector Rhodnius prolixus in a Temperature-Dependent Manner | It is often assumed that parasites are not virulent to their vectors. Nevertheless, parasites commonly exploit their vectors (nutritionally for example) so these can be considered a form of host. Trypanosoma cruzi, a protozoan found in mammals and triatomine bugs in the Americas, is the etiological agent of Chagas dise... | Parasites are often assumed to cause little harm to their arthropod vectors, even though they commonly reproduce inside the arthropods and exploit their nutrients, even causing lesions when crossing internal barriers. Thus, the interests of parasite and vector may well not be aligned and we can expect the parasite to e... | A long-standing implicit assumption in the literature on vector-borne diseases is that the parasite does little or no harm to its vector (see [1] for a review). This makes considerable intuitive sense as the parasite relies on the vector for its transmission, so negative effects on the vectors’ fitness could be expecte... |
10.1371/journal.pcbi.1003650 | Model Selection in Systems Biology Depends on Experimental Design | Experimental design attempts to maximise the information available for modelling tasks. An optimal experiment allows the inferred models or parameters to be chosen with the highest expected degree of confidence. If the true system is faithfully reproduced by one of the models, the merit of this approach is clear - we s... | Different models of the same process represent distinct hypotheses about reality. These can be decided between within the framework of model selection, where the evidence for each is given by their ability to reproduce a set of experimental data. Even if one of the models is correct, the chances of identifying it can b... | Mathematical models provide a rich framework for biological investigation. Depending upon the questions posed, the relevant existing knowledge and alternative hypotheses may be combined and conveniently encoded, ready for analysis via a wealth of computational techniques. The consequences of each hypothesis can be unde... |
10.1371/journal.pcbi.1002906 | Pairwise Analysis Can Account for Network Structures Arising from Spike-Timing Dependent Plasticity | Spike timing-dependent plasticity (STDP) modifies synaptic strengths based on timing information available locally at each synapse. Despite this, it induces global structures within a recurrently connected network. We study such structures both through simulations and by analyzing the effects of STDP on pair-wise inter... | The connectivity structure in neural networks reflects, at least in part, the long-term effects of synaptic plasticity mechanisms that underlie learning and memory. In one of the most widespread such mechanisms, spike-timing dependent plasticity (STDP), the temporal order of pre- and postsynaptic spiking across a synap... | Spike timing-dependent plasticity (STDP) is a widespread mechanism that modifies synapses on the basis of the intervals between ensembles of pre- and postsynaptic spikes [1], [2]. The most prevalent form of STDP involves potentiation of the synapse when presynaptic spikes precede postsynaptic spikes, and depression for... |
10.1371/journal.pgen.1008202 | Exploring various polygenic risk scores for skin cancer in the phenomes of the Michigan genomics initiative and the UK Biobank with a visual catalog: PRSWeb | Polygenic risk scores (PRS) are designed to serve as single summary measures that are easy to construct, condensing information from a large number of genetic variants associated with a disease. They have been used for stratification and prediction of disease risk. The primary focus of this paper is to demonstrate how ... | In the study of genetically complex diseases, polygenic risk scores (PRS) synthesize information from multiple genetic risk factors to provide insight into a patient’s inherited risk of developing a disease based on his/her genetic profile. These risk scores can be explored in conjunction with health and disease inform... | The underlying risk factors of genetically complex diseases are numerous. Genome-wide association studies (GWAS) on thousands of diseases and traits have made great strides in uncovering a vast array of genetic variants that contribute to genetic predispositions to disease [1]. In order to harness the information from ... |
10.1371/journal.pntd.0005349 | Distinct antibody responses of patients with mild and severe leptospirosis determined by whole proteome microarray analysis | Leptospirosis is an important zoonotic disease worldwide. Humans usually present a mild non-specific febrile illness, but a proportion of them develop more severe outcomes, such as multi-organ failure, lung hemorrhage and death. Such complications are thought to depend on several factors, including the host immunity. P... | Leptospirosis is zoonotic disease of global importance, with over a million cases and nearly 60,000 deaths annually. Symptomatic disease presentation ranges from a mild febrile disease with non-specific symptoms to severe forms, characterized by multi-organ failure, lung hemorrhage, and death. Factors driving severe ou... | Leptospirosis causes over one million cases and nearly 60,000 deaths annually, with the greatest disease burden in urban slums in tropical and subtropical countries [1–3]. Ten pathogenic Leptospira species, over 200 serovars, and a large number of mammalian reservoirs, including rats, have facilitated the emergence of ... |
10.1371/journal.pgen.1004464 | Arabidopsis DELLA Protein Degradation Is Controlled by a Type-One Protein Phosphatase, TOPP4 | Gibberellins (GAs) are a class of important phytohormones regulating a variety of physiological processes during normal plant growth and development. One of the major events during GA-mediated growth is the degradation of DELLA proteins, key negative regulators of GA signaling pathway. The stability of DELLA proteins i... | Gibberellins (GAs) are essential regulators of plant growth and development. They are tightly related to crop productivity in the first “green revolution.” GA triggers its responses by targeting DELLA proteins, the important repressors, for degradation. This process is believed to be regulated by protein phosphorylatio... | Gibberellins (GAs) are a class of major plant hormones mediating almost all physiological events during normal plant lifespan, including seed germination, leaf formation, cell elongation and flowering time control, etc [1]–[3]. In recent decades, several molecular components essential for GA signal transduction have be... |
10.1371/journal.pntd.0005659 | Challenges in developing methods for quantifying the effects of weather and climate on water-associated diseases: A systematic review | Infectious diseases attributable to unsafe water supply, sanitation and hygiene (e.g. Cholera, Leptospirosis, Giardiasis) remain an important cause of morbidity and mortality, especially in low-income countries. Climate and weather factors are known to affect the transmission and distribution of infectious diseases and... | Unsafe water supplies, limited sanitation and poor hygiene are still important causes of infectious disease (e.g. Cholera, Leptospirosis, Giardiasis), especially in low-income countries. Climate and weather affect the transmission and distribution of infectious diseases. Therefore, scientists are continuously developin... | The seasonal and geographic distributions of infectious diseases are currently among the best indications of an association with weather and climate. The literature on climate effects is expanding in response to concerns about global climate change. The significance of the methods and data available is not only confine... |
10.1371/journal.pntd.0005858 | Assessment of risk of dengue and yellow fever virus transmission in three major Kenyan cities based on Stegomyia indices | Dengue (DEN) and yellow fever (YF) are re-emerging in East Africa, with contributing drivers to this trend being unplanned urbanization and increasingly adaptable anthropophilic Aedes (Stegomyia) vectors. Entomological risk assessment of these diseases remains scarce for much of East Africa and Kenya even in the dengue... | Despite the growing problem of dengue (DEN) and yellow fever (YF) evidenced from recent outbreaks in East Africa, risk assessment for their transmission and establishment through surveys of populations of the Aedes mosquito vectors, remain scarce. By estimating standard indices for the potential vectors, Aedes aegypti ... | Dengue (DEN) and yellow fever (YF) are re-emerging diseases of public health importance caused by arboviral pathogens [1–4]. Both diseases share a common ecological niche including non-human primates as reservoir hosts and are vectored primarily by Aedes (Stegomyia) species [5]. Dengue fever is caused by one of the fou... |
10.1371/journal.pgen.1003723 | Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis | Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understan... | Genetic studies of common diseases have seen tremendous progress in the last half-decade primarily due to recent technologies that enable a systematic examination of genetic markers across the entire genome in large numbers of patients and healthy controls. The studies, while identifying genomic regions that influence ... | Inflammatory bowel diseases (IBDs) are classified as chronic relapsing inflammatory diseases of the gastrointestinal tract. The two major forms of IBDs are Crohn's disease (CD, OMIM 266600) and ulcerative colitis (UC, OMIM 191390). Both genetic and environment factors play a central role in the pathogenesis of the infl... |
10.1371/journal.pbio.1000047 | Two Separate Interfaces between the Voltage Sensor and Pore Are Required for the Function of Voltage-Dependent K+ Channels | Voltage-dependent K+ (Kv) channels gate open in response to the membrane voltage. To further our understanding of how cell membrane voltage regulates the opening of a Kv channel, we have studied the protein interfaces that attach the voltage-sensor domains to the pore. In the crystal structure, three physical interface... | Voltage-dependent ion channels open with a voltage dependence that is remarkably steep. This steep voltage dependence, which is essential to the propagation of nerve impulses, originates in the interaction between voltage-sensor domains of the ion channel and its pore. The voltage-sensor domains transmit voltage-driven... | Voltage-dependent ion channels mediate electrical impulses and thus enable the rapid transfer of information along the cell surface. These impulses underlie information processing by the nervous system, muscle contraction, and many other important biological processes [1]. Members of the large family of voltage-depende... |
10.1371/journal.pgen.1003843 | A Novel Role for Ecdysone in Drosophila Conditioned Behavior: Linking GPCR-Mediated Non-canonical Steroid Action to cAMP Signaling in the Adult Brain | The biological actions of steroid hormones are mediated primarily by their cognate nuclear receptors, which serve as steroid-dependent transcription factors. However, steroids can also execute their functions by modulating intracellular signaling cascades rapidly and independently of transcriptional regulation. Despite... | The brain is a prominent target of steroid hormones, which control a variety of neurobiological processes and are critical to the regulation of behavior. Some effects of these hormones involve changes in gene expression and thus emerge slowly, over the course of hours or even days. Other responses to steroids occur rap... | Steroid hormones are essential modulators of a broad range of biological processes in a diversity of organisms across phyla. In the adult nervous system, the functions of steroids such as estrogens and glucocorticoids are of particular interest because they have significant effects on the resilience and adaptability of... |
10.1371/journal.pgen.1002291 | Essential Roles of BCCIP in Mouse Embryonic Development and Structural Stability of Chromosomes | BCCIP is a BRCA2- and CDKN1A(p21)-interacting protein that has been implicated in the maintenance of genomic integrity. To understand the in vivo functions of BCCIP, we generated a conditional BCCIP knockdown transgenic mouse model using Cre-LoxP mediated RNA interference. The BCCIP knockdown embryos displayed impaired... | BCCIP is a BRCA2- and p21-interacting protein. Studies with cell culture systems have suggested an essential role of BCCIP gene in homologous recombination and suppression of replication stress and have suggested that BCCIP defects causes mitotic errors. However, the in vivo function(s) of BCCIP and the mechanistic lin... | Loss of genomic integrity is a hallmark for tumorigenesis. Mammalian cells maintain genomic integrity by ensuring DNA replication fidelity in S-phase, equal chromosome distribution into daughter cells during mitosis, error-free repair of sporadic DNA damage throughout the cell cycle, and a coordinated cell cycle progre... |
10.1371/journal.pntd.0003306 | Approaches to Refining Estimates of Global Burden and Economics of Dengue | Dengue presents a formidable and growing global economic and disease burden, with around half the world's population estimated to be at risk of infection. There is wide variation and substantial uncertainty in current estimates of dengue disease burden and, consequently, on economic burden estimates. Dengue disease var... | Dengue is the most common mosquito-transmitted viral disease. It represents a formidable public health problem that is expanding in both infection rates and geographical range. Fortunately, vaccines, improved diagnostics, innovative vector control approaches, and other disease control methods are under development. Des... | Dengue presents a formidable global economic and disease burden with around half the world's population estimated to be at risk of infection [1], [2]. Dengue transmission has intensified in the past decades, with outbreaks increasing in frequency, magnitude, and countries involved [3], [4]. Dengue disease varies across... |
10.1371/journal.pgen.1000366 | A Gene-Based Linkage Map for Bicyclus anynana Butterflies Allows for a Comprehensive Analysis of Synteny with the Lepidopteran Reference Genome | Lepidopterans (butterflies and moths) are a rich and diverse order of insects, which, despite their economic impact and unusual biological properties, are relatively underrepresented in terms of genomic resources. The genome of the silkworm Bombyx mori has been fully sequenced, but comparative lepidopteran genomics has... | Butterflies and moths (called the Lepidoptera) are a large and diverse group of insects that has long captured the attention of biologists and laymen. The colorful patterns on the wings of butterflies, in particular, offer an ideal system to investigate which genes and developmental mechanisms contribute to evolutionar... | With the need for a wider sampling of biological diversity [1]–[3], the availability of tools for large-scale genetic and genomic analysis is rapidly being extended beyond a handful of classical model systems. Gene collections are growing for various species and with them, the need for methods to assign genes to geneti... |
10.1371/journal.ppat.1002873 | Listeria monocytogenes Cytoplasmic Entry Induces Fetal Wastage by Disrupting Maternal Foxp3+ Regulatory T Cell-Sustained Fetal Tolerance | Although the intracellular bacterium Listeria monocytogenes has an established predilection for disseminated infection during pregnancy that often results in spontaneous abortion or stillbirth, the specific host-pathogen interaction that dictates these disastrous complications remain incompletely defined. Herein, we de... | Pregnant women are uniquely susceptible to the bacterium Listeria monocytogenes that preferentially lives inside infected cells. Since infection during pregnancy often triggers prematurity, abortion, or stillbirth, we propose that understanding how these complications occur represent important prerequisites for improvi... | Listeria monocytogenes (Lm) is a ubiquitous human pathogen with a unique predisposition for invasive disseminated infection during pregnancy that represents a significant etiology of spontaneous abortion, stillbirth, and neonatal infection [1], [2]. Although many Lm-specific proteins required for cell entry and maintai... |
10.1371/journal.pgen.1005896 | Inferring Phylogenetic Networks with Maximum Pseudolikelihood under Incomplete Lineage Sorting | Phylogenetic networks are necessary to represent the tree of life expanded by edges to represent events such as horizontal gene transfers, hybridizations or gene flow. Not all species follow the paradigm of vertical inheritance of their genetic material. While a great deal of research has flourished into the inference ... | Phylogenetic networks display the evolutionary history of groups of individuals (species or populations) including reticulation events such as hybridization, horizontal gene transfer or migration. Here, we present a likelihood method to learn networks from molecular sequences at multiple genes. Our model accounts for s... | Evolutionary relationships are typically visualized in a tree, which implicitly assumes vertical transfer of genetic material from ancestors to descendants. However, not all species follow this paradigm. If genes can be horizontally transferred between some organisms, a tree is not a good representation of their histor... |
10.1371/journal.pntd.0005338 | Unusual pattern of chikungunya virus epidemic in the Americas, the Panamanian experience | Chikungunya virus (CHIKV) typically causes explosive epidemics of fever, rash and polyarthralgia after its introduction into naïve populations. Since its introduction in Panama in May of 2014, few autochthonous cases have been reported; most of them were found within limited outbreaks in Panama City in 2014 and Puerto ... | Chikungunya virus (CHIKV) is a mosquito borne pathogen that causes fever with rash and arthralgia, which are often confused with Dengue virus (DENV) infections. It has been reported that when CHIKV colonizes regions without previous circulation, it generally results in explosive human epidemics. In Panama, the first CH... | The chikungunya virus (CHIKV, Alphavirus, Togaviridae) is an RNA single-stranded arthropod-borne pathogen that was first recognized in 1952–1953 in southeast Tanzania and northern Mozambique [1]. In Africa, CHIKV was associated with small outbreaks in rural areas, however, in Asia between 1960–1970, the virus was assoc... |
10.1371/journal.pcbi.1005573 | NetNorM: Capturing cancer-relevant information in somatic exome mutation data with gene networks for cancer stratification and prognosis | Genome-wide somatic mutation profiles of tumours can now be assessed efficiently and promise to move precision medicine forward. Statistical analysis of mutation profiles is however challenging due to the low frequency of most mutations, the varying mutation rates across tumours, and the presence of a majority of passe... | The transition from a normal cell to a cancer cell is driven by genetic alterations, such as mutations, that induce uncontrolled cell proliferation. With the advent of next-generation sequencing technologies (NGS) in the last decade, thousands of tumours have been sequenced and their mutation profiles determined. Howev... | Tumourigenesis and cancer growth involve somatic mutations which appear and accumulate during cancer progression. These mutations impair the normal behaviour of various cancer genes, and give cancer cells an often devastating advantage to proliferate over normal cells [1–3]. Systematically assessing and monitoring soma... |
10.1371/journal.pgen.1006525 | Functional Requirements for Heparan Sulfate Biosynthesis in Morphogenesis and Nervous System Development in C. elegans | The regulation of cell migration is essential to animal development and physiology. Heparan sulfate proteoglycans shape the interactions of morphogens and guidance cues with their respective receptors to elicit appropriate cellular responses. Heparan sulfate proteoglycans consist of a protein core with attached heparan... | During animal development, cells and neurons navigate long distances to reach their final target destinations. Migrating cells are guided by extracellular molecular cues, and cellular responses to these cues are regulated by heparan sulfate proteoglycans. Heparan sulfate proteoglycans are proteins with long heparan sul... | Cell migration is key to animal development and physiology. To reach their targets, migrating cells rely on guidance factors and morphogens, which can be regulated by heparan sulfate proteoglycans (HSPGs) [1]. HSPGs are cell-surface or extracellular proteins characterized by the attachment of heparan sulfate (HS) polys... |
10.1371/journal.ppat.1000377 | Elite Suppressor–Derived HIV-1 Envelope Glycoproteins Exhibit Reduced Entry Efficiency and Kinetics | Elite suppressors (ES) are a rare subset of HIV-1–infected individuals who are able to maintain HIV-1 viral loads below the limit of detection by ultra-sensitive clinical assays in the absence of antiretroviral therapy. Mechanism(s) responsible for this elite control are poorly understood but likely involve both host a... | The majority of HIV-1–infected individuals experience high plasma viral loads and CD4+ T cells loss in the absence of antiretroviral therapy. However, a very rare and important subset of individuals termed elite suppressors is able to maintain HIV-1 plasma viral loads below the limit of viral detection in the absence o... | A minor subset of HIV-1–infected individuals maintains stable CD4+ T cell counts in the absence of antiretroviral therapy. A small proportion of these long-term nonprogressors (LTNPs), termed elite suppressors (ES), control plasma viral loads to <50 copies/ml [1]. Mechanism(s) responsible for this elite control are poo... |
10.1371/journal.pgen.1005874 | Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies | Vascular endothelial growth factor (VEGF) is an angiogenic and neurotrophic factor, secreted by endothelial cells, known to impact various physiological and disease processes from cancer to cardiovascular disease and to be pharmacologically modifiable. We sought to identify novel loci associated with circulating VEGF l... | Vascular Endothelial Growth Factor (VEGF) is a protein with a fundamental role in development of vascular system. The protein, produced by many types of cells, is released in the blood. High levels of VEGF have been observed in different pathological conditions especially in cancer, cardiovascular, and inflammatory dis... | Vascular Endothelial Growth Factor (VEGF) is secreted largely by endothelial cells and plays a key role in several physiological and pathological conditions. During growth, development, and maintenance of the circulatory system, VEGF is the principal pro-angiogenic factor and it has additionally, a neurotrophic role. H... |
10.1371/journal.pntd.0007041 | Mechanisms underpinning the permanent muscle damage induced by snake venom metalloprotease | Snakebite is a major neglected tropical health issue that affects over 5 million people worldwide resulting in around 1.8 million envenomations and 100,000 deaths each year. Snakebite envenomation also causes innumerable morbidities, specifically loss of limbs as a result of excessive tissue/muscle damage. Snake venom ... | Snakebite is a major neglected tropical disease that affects thousands of people in the rural areas of developing countries. As well as the deaths, snakebites result in a significant number of disabilities including permanent loss of limbs that alter the lifestyle of the victims. Snake venom is a mixture of different p... | Snakebite envenomation is a recently reinstated neglected tropical disease [1] that causes around 100,000 deaths annually [2, 3] and innumerable permanent disabilities predominantly on the rural population living in the lower income regions of the world [4–6]. The significant rate of mortality and morbidity occurs due ... |
10.1371/journal.pgen.1003411 | The Role of the Arabidopsis Exosome in siRNA–Independent Silencing of Heterochromatic Loci | The exosome functions throughout eukaryotic RNA metabolism and has a prominent role in gene silencing in yeast. In Arabidopsis, exosome regulates expression of a “hidden” transcriptome layer from centromeric, pericentromeric, and other heterochromatic loci that are also controlled by small (sm)RNA-based de novo DNA met... | To maintain genomic stability and prevent expansion of invasive genomic sequences such as transposable elements (TEs), eukaryotes have evolved defensive mechanisms to control them. Here, we examine the role of the Arabidopsis exosome complex in such mechanisms. Evolutionarily conserved from archaea to humans, the exoso... | High-throughput analyses have revealed that eukaryotic genomes are pervasively transcribed [1]–[4], and the majority of the transcriptional activity takes place outside of protein-coding genes, producing non-coding RNAs (ncRNAs) derived from genome regions once thought to be transcriptionally silent, including intergen... |
10.1371/journal.pcbi.1002303 | A Hierarchical Neuronal Model for Generation and Online Recognition of Birdsongs | The neuronal system underlying learning, generation and recognition of song in birds is one of the best-studied systems in the neurosciences. Here, we use these experimental findings to derive a neurobiologically plausible, dynamic, hierarchical model of birdsong generation and transform it into a functional model of b... | How do birds communicate via their songs? Investigating this question may not only lead to a better understanding of communication via birdsong, but many believe that the answer will also give us hints about how humans decode speech from complex sound wave modulations. In birds, the output and neuronal responses of the... | Songbirds are able to repeat the same, often complex songs with amazing precision. When male birds sing to a female repeatedly, there is on average a 1% temporal deviation across the whole song [1], [2]. This combination of complexity and precision is remarkable. Studying the neuronal basis of birdsong generation may l... |
10.1371/journal.pgen.1003600 | Latent Effects of Hsp90 Mutants Revealed at Reduced Expression Levels | In natural systems, selection acts on both protein sequence and expression level, but it is unclear how selection integrates over these two dimensions. We recently developed the EMPIRIC approach to systematically determine the fitness effects of all possible point mutants for important regions of essential genes in yea... | Changes in protein sequence or expression strength can both lead to adaptation in natural systems. While many studies have focused individually on either expression strength or protein sequence, in principle the fitness effects of these two protein properties are interdependent. We systematically investigated the fitne... | Genetic changes that alter protein sequence or expression level can lead to adaptation, suggesting these protein properties are central to evolutionary processes. Many studies have individually investigated the effects of changes to either protein sequence or expression level. For example, protein sequences have been o... |
10.1371/journal.pcbi.1000777 | A Differentiation-Based Phylogeny of Cancer Subtypes | Histopathological classification of human tumors relies in part on the degree of differentiation of the tumor sample. To date, there is no objective systematic method to categorize tumor subtypes by maturation. In this paper, we introduce a novel computational algorithm to rank tumor subtypes according to the dissimila... | Gene expression profiling of malignancies is often held to demonstrate genes that are “up-regulated” or “down-regulated”, but the appropriate frame of reference against which observations should be compared has not been determined. Fully differentiated somatic cells arise from stem cells, with changes in gene expressio... | Cancer research has traditionally focused on the identification of oncogenes and tumor suppressor genes, but in the last decades it has become increasingly apparent that disruption of normal differentiation is an important component of tumorigenesis. Lack of cellular maturation is now recognized as a hallmark of human ... |
10.1371/journal.pntd.0005065 | Immune Modulation as an Effective Adjunct Post-exposure Therapeutic for B. pseudomallei | Melioidosis is caused by the facultative intracellular bacterium Burkholderia pseudomallei and is potentially fatal. Despite a growing global burden and high fatality rate, little is known about the disease. Recent studies demonstrate that cyclooxygenase-2 (COX-2) inhibition is an effective post-exposure therapeutic fo... | Burkholderia pseudomallei is the causative agent of melioidosis, a fatal tropical disease endemic in parts of Southwest Asia and Northern Australia. While it was once believed to be isolated to these areas, recent research indicates the global burden on melioidosis is growing. Furthermore, treatment of melioidosis is d... | Melioidosis is a tropical and often fatal disease caused by the aerobic, Gram-negative facultative intracellular bacterium Burkholderia pseudomallei [1]. Traditional B. pseudomallei infection is associated with environmental exposures during the monsoon season in the tropics. It has also been identified as a Tier 1 sel... |
10.1371/journal.pgen.1004469 | A Novel MMP12 Locus Is Associated with Large Artery Atherosclerotic Stroke Using a Genome-Wide Age-at-Onset Informed Approach | Genome-wide association studies (GWAS) have begun to identify the common genetic component to ischaemic stroke (IS). However, IS has considerable phenotypic heterogeneity. Where clinical covariates explain a large fraction of disease risk, covariate informed designs can increase power to detect associations. As prevale... | Ischaemic stroke places an enormous burden on global healthcare. However, the disease processes that lead to stroke are not fully understood. Genome-wide association studies have recently established that common genetic variants can increase risk of ischaemic stroke and its subtypes. In this study, we aimed to identify... | Genome-wide association studies (GWAS) in ischaemic stroke have begun to identify the common genetic variants that confer risk of the disease. However, there is considerable heterogeneity present in stroke phenotypes: GWAS analyses have primarily looked at the three main subtypes; cardioembolic (CE), large artery ather... |
10.1371/journal.pbio.1002028 | Evolution of RNA-Protein Interactions: Non-Specific Binding Led to RNA Splicing Activity of Fungal Mitochondrial Tyrosyl-tRNA Synthetases | The Neurospora crassa mitochondrial tyrosyl-tRNA synthetase (mtTyrRS; CYT-18 protein) evolved a new function as a group I intron splicing factor by acquiring the ability to bind group I intron RNAs and stabilize their catalytically active RNA structure. Previous studies showed: (i) CYT-18 binds group I introns by using... | The acquisition of new modes of post-transcriptional gene regulation played an important role in the evolution of eukaryotes and was achieved by an increase in the number of RNA-binding proteins with new functions. RNA-binding proteins bind directly to double- or single-stranded RNA and regulate many cellular processes... | RNA-binding proteins play critical roles in post-transcriptional regulation of gene expression in all domains of life [1]. However, the complexity of this regulation is far greater in eukaryotes than in prokaryotes, reflecting both the larger number of RNAs requiring regulation and the evolution of new RNA processing a... |
10.1371/journal.ppat.1007763 | On the evolutionary ecology of multidrug resistance in bacteria | Resistance against different antibiotics appears on the same bacterial strains more often than expected by chance, leading to high frequencies of multidrug resistance. There are multiple explanations for this observation, but these tend to be specific to subsets of antibiotics and/or bacterial species, whereas the tren... | Antibiotic resistance is a serious public health concern, yet the ecology and evolution of drug resistance are not fully understood. This impacts our ability to design effective interventions to combat resistance. From a public health point of view, multidrug resistance is particularly problematic because resistance to... | Antibiotic resistance and, in particular, multidrug resistance (MDR) are public health threats. Multidrug resistant infections are associated with poorer clinical outcomes and higher cost of treatment than other infections [1, 2] and there is concern that the emergence of pan-resistant strains (pathogens resistant to a... |
10.1371/journal.pgen.1000119 | The Recombinational Anatomy of a Mouse Chromosome | Among mammals, genetic recombination occurs at highly delimited sites known as recombination hotspots. They are typically 1–2 kb long and vary as much as a 1,000-fold or more in recombination activity. Although much is known about the molecular details of the recombination process itself, the factors determining the lo... | In most eukaryotic organisms, recombination—the exchange of genetic information between homologous chromosomes—ensures the proper recognition and segregation of chromosomes during meiosis. Recombination events in mammals are not randomly positioned along the chromosomes but occur in preferential 1–2-kilobase sequences ... | Genetic recombination is a fundamental process common to all eukaryotic organisms, which ensures proper chromosomal segregation of homologous chromosomes in meiosis and increases genetic diversity by creating new combinations of parental alleles at each generation. The process begins in the leptotene stage of meiosis I... |
10.1371/journal.pgen.1007797 | Genome-wide identification of RETINOBLASTOMA RELATED 1 binding sites in Arabidopsis reveals novel DNA damage regulators | Retinoblastoma (pRb) is a multifunctional regulator, which was likely present in the last common ancestor of all eukaryotes. The Arabidopsis pRb homolog RETINOBLASTOMA RELATED 1 (RBR1), similar to its animal counterparts, controls not only cell proliferation but is also implicated in developmental decisions, stress res... | The Retinoblastoma (pRb) tumor suppressor is a master regulator of the cell cycle and its inactivation is associated with many types of cancer. Since pRb’s first description as a transcriptional repressor of genes important for cell cycle progression, many more functions have been elucidated, e.g. in developmental deci... | The first molecular function assigned to the human tumor suppressor Retinoblastoma (pRb) was that of a transcriptional repressor controlling entry into S-phase. It was shown that pRb binds and inhibits the function of E2F-DP transcription factors and that phosphorylation of pRb by CDK-cyclin complexes disrupts this int... |
10.1371/journal.pgen.1002991 | Muscle-Specific Splicing Factors ASD-2 and SUP-12 Cooperatively Switch Alternative Pre-mRNA Processing Patterns of the ADF/Cofilin Gene in Caenorhabditis elegans | Pre–mRNAs are often processed in complex patterns in tissue-specific manners to produce a variety of protein isoforms from single genes. However, mechanisms orchestrating the processing of the entire transcript are not well understood. Muscle-specific alternative pre–mRNA processing of the unc-60 gene in Caenorhabditis... | Muscle is a specialized organ with specialized contractile apparatuses. A number of genes encoding contractile apparatus-related proteins undergo muscle-specific pre–mRNA processing. However, the molecular mechanisms and consequences of muscle-specific alternative pre–mRNA processing remain largely unknown. In this stu... | Alternative pre-mRNA processing is a major way to produce a number of different mRNAs and proteins from one gene [1], [2]. Recent transcriptome analyses by deep sequencing estimated that more than 90% of human multi-exon genes undergo alternative processing and most alternative processing events are regulated in tissue... |
10.1371/journal.pgen.1005952 | Evolution of Social Insect Polyphenism Facilitated by the Sex Differentiation Cascade | The major transition to eusociality required the evolution of a switch to canalize development into either a reproductive or a helper, the nature of which is currently unknown. Following predictions from the ‘theory of facilitated variation’, we identify sex differentiation pathways as promising candidates because of t... | Division of labor into reproductive queens and helper workers in the societies of ants, bees and wasps is achieved by phenotypic plasticity, which allows individuals to embark on discrete developmental trajectories in response to variable signals. These signals can be genetic, epigenetic or environmental, thereby resem... | The mechanisms underlying the evolution of phenotypic novelty are hotly debated [1–4]. A fundamental question is how small genetic or epigenetic changes can produce a set of simultaneous, complementary phenotypic changes required to generate new adaptive trait combinations. A key prediction of the ‘theory of facilitate... |
10.1371/journal.pgen.1001055 | Multivesicular Body Formation Requires OSBP–Related Proteins and Cholesterol | In eukaryotes, different subcellular organelles have distinct cholesterol concentrations, which is thought to be critical for biological functions. Oxysterol-binding protein-related proteins (ORPs) have been assumed to mediate nonvesicular cholesterol trafficking in cells; however, their in vivo functions and therefore... | The multivesicular body (MVB) sorting pathway provides a mechanism for the lysosomal degradation of membrane proteins, such as growth factor receptors. The formation of MVBs is unique in that the curvature is directed toward the lumen of the compartment rather than the cytosol. During MVB formation, the curvature-induc... | The multivesicular body (MVB) sorting pathway provides a mechanism for the lysosomal degradation of membrane proteins and has a role in many processes, including growth factor receptor down-regulation [1], antigen presentation [2], developmental signaling [3], [4], the budding of enveloped viruses [5], and cytokinesis ... |
10.1371/journal.pgen.1006222 | KdmB, a Jumonji Histone H3 Demethylase, Regulates Genome-Wide H3K4 Trimethylation and Is Required for Normal Induction of Secondary Metabolism in Aspergillus nidulans | Histone posttranslational modifications (HPTMs) are involved in chromatin-based regulation of fungal secondary metabolite biosynthesis (SMB) in which the corresponding genes—usually physically linked in co-regulated clusters—are silenced under optimal physiological conditions (nutrient-rich) but are activated when nutr... | In this work we monitored by proteomic analysis and ChIP-seq the genome-wide distribution of several key modifications on histone H3 in the model fungus Aspergillus nidulans cultivated either under optimal physiological conditions (active growth) or less favourable conditions which are known to promote the production o... | Chromatin is the natural substrate for all eukaryotic nuclear processes such as transcription, replication, recombination or DNA repair. Chromatin structure is necessarily dynamic and the underlying mechanisms involve remodeling of nucleosomes as well as depositing and removing posttranslational modifications on N-term... |
10.1371/journal.ppat.1005065 | IL-27 Signaling Is Crucial for Survival of Mice Infected with African Trypanosomes via Preventing Lethal Effects of CD4+ T Cells and IFN-γ | African trypanosomes are extracellular protozoan parasites causing a chronic debilitating disease associated with a persistent inflammatory response. Maintaining the balance of the inflammatory response via downregulation of activation of M1-type myeloid cells was previously shown to be crucial to allow prolonged survi... | Infection with extracellular protozoan parasites, African trypanosomes, is characterized by a persistent inflammatory immune response. It has been recently shown that maintaining the balance of the inflammatory responses via dampening M1-type myeloid cell activation is critical to guarantee control of the parasites and... | African trypanosomiasis is a vector-borne parasitic disease of medical and veterinary importance. It is estimated that 170,000 people contract the disease every year, and that approximately 70 million people mainly in sub-Saharan Africa are at the risk of contracting the disease [1,2]. In addition, this disease severel... |
10.1371/journal.pgen.1000868 | Derepression of the Plant Chromovirus LORE1 Induces Germline Transposition in Regenerated Plants | Transposable elements represent a large proportion of the eukaryotic genomes. Long Terminal Repeat (LTR) retrotransposons are very abundant and constitute the predominant family of transposable elements in plants. Recent studies have identified chromoviruses to be a widely distributed lineage of Gypsy elements. These e... | In contrast to animals, where germline differentiation initiates early in embryogenesis, germline differentiation in plants starts in the adult phase during reproductive development. Transpositions of transposable elements in both somatic and gametic cells can be transmitted to the next generation. As a result, plant g... | A large proportion of the eukaryotic genome is composed of transposable elements (TEs). In flowering plants, Long Terminal Repeat (LTR) retrotransposons have been regarded as the largest order of TEs [1],[2] and it has been suggested that the ratio between propagation and exclusion of LTR retrotransposons may have affe... |
10.1371/journal.pgen.1008065 | Floral regulators FLC and SOC1 directly regulate expression of the B3-type transcription factor TARGET OF FLC AND SVP 1 at the Arabidopsis shoot apex via antagonistic chromatin modifications | Integration of environmental and endogenous cues at plant shoot meristems determines the timing of flowering and reproductive development. The MADS box transcription factor FLOWERING LOCUS C (FLC) of Arabidopsis thaliana is an important repressor of floral transition, which blocks flowering until plants are exposed to ... | The initiation of flowering in plants is exquisitely sensitive to environmental signals, ensuring that reproduction occurs at the appropriate time of year. The sensitivity of these responses depends upon strong repression of flowering under inappropriate conditions. FLOWERING LOCUS C (FLC) and SHORT VEGETATIVE PHASE (S... | The transition from vegetative to reproductive development in plants is controlled by a complex transcriptional network that responds both to environmental cues and endogenous hormonal signals [1, 2]. In Arabidopsis thaliana, the MADS-box transcription factor FLOWERING LOCUS C (FLC) plays a major role in this network a... |
10.1371/journal.ppat.1006736 | Progesterone impairs antigen-non-specific immune protection by CD8 T memory cells via interferon-γ gene hypermethylation | Pregnant women and animals have increased susceptibility to a variety of intracellular pathogens including Listeria monocytogenes (LM), which has been associated with significantly increased level of sex hormones such as progesterone. CD8 T memory(Tm) cell-mediated antigen-non-specific IFN-γ responses are critically re... | Increased female sex hormones during pregnancy generate a temporary immune suppression status in the pregnant that protect the developing fetus from maternal rejection but renders the pregnant highly susceptible to various pathogens. However, molecular mechanisms underlying such an increased maternal susceptibility to ... | Increased susceptibility to a variety of pathogens during pregnancy has been related to a temporary status of immune suppression induced by increased female sex hormones such as progesterone and estrogen[1–5]. Indeed, previous studies showed that female sex hormones play regulatory roles in various human immune cells e... |
10.1371/journal.ppat.1006733 | Inhibition of group-I metabotropic glutamate receptors protects against prion toxicity | Prion infections cause inexorable, progressive neurological dysfunction and neurodegeneration. Expression of the cellular prion protein PrPC is required for toxicity, suggesting the existence of deleterious PrPC-dependent signaling cascades. Because group-I metabotropic glutamate receptors (mGluR1 and mGluR5) can form ... | Prion diseases are a result of ordered accumulation of the misfolded conformer of cellular prion protein (PrPC), a GPI anchored protein expressed on the cell surface. Similar pathogenetic principles operate in several other neurodegenerative diseases. Currently no disease-modifying therapies exist and the situation is ... | The decisive event in the pathogenesis of prion diseases is the conversion of the normal cellular prion protein (PrPC) into an aggregated conformational variant called PrPSc [1]. Expression of PrPC at the cell surface is not only required for the self-propagation of prions, but also for mediating the toxicity induced b... |
10.1371/journal.pgen.1003279 | Autophagy Induction Is a Tor- and Tp53-Independent Cell Survival Response in a Zebrafish Model of Disrupted Ribosome Biogenesis | Ribosome biogenesis underpins cell growth and division. Disruptions in ribosome biogenesis and translation initiation are deleterious to development and underlie a spectrum of diseases known collectively as ribosomopathies. Here, we describe a novel zebrafish mutant, titania (ttis450), which harbours a recessive lethal... | Autophagy is an act of self-preservation whereby a cell responds to stressful conditions such as nutrient depletion and intense muscular activity by digesting its own cytoplasmic organelles and proteins to fuel its longer-term survival. An understanding of the wide spectrum of physiological stimuli that can trigger thi... | The generation of new ribosomes is the most energy-consuming process in the cell [1]. It requires the coordinated transcription and maturation of 4 different ribosomal RNA (rRNA) molecules and 70 small nucleolar RNAs (snoRNAs) together with the synthesis of approximately 80 ribosomal proteins (RPs) and an additional 17... |
10.1371/journal.pcbi.1002263 | Computational Modeling and Analysis of Insulin Induced Eukaryotic Translation Initiation | Insulin, the primary hormone regulating the level of glucose in the bloodstream, modulates a variety of cellular and enzymatic processes in normal and diseased cells. Insulin signals are processed by a complex network of biochemical interactions which ultimately induce gene expression programs or other processes such a... | Insulin is a hormone produced by the body that regulates uptake of glucose from the bloodstream. The cellular response to insulin is governed by a complex network of intracellular interactions that ultimately influence cell growth and metabolism. Because of its central role in physiology, insulin signaling has been ext... | Insulin, the primary hormone regulating the level of glucose in the bloodstream, modulates a variety of cellular and enzymatic processes in normal and diseased cells [1]–[7]. The regulation of cellular function by insulin and insulin-like growth factors I/II (IGF-I/II) is a highly complex process [8]–[14]. Insulin and ... |
10.1371/journal.pntd.0005694 | Increasing airline travel may facilitate co-circulation of multiple dengue virus serotypes in Asia | The incidence of dengue has grown dramatically in recent decades worldwide, especially in Southeast Asia and the Americas with substantial transmission in 2014–2015. Yet the mechanisms underlying the spatio-temporal circulation of dengue virus (DENV) serotypes at large geographical scales remain elusive. Here we invest... | In the past half century the incidence of dengue fever worldwide has increased 30-fold, with an estimated ~390 million infections per year. The years 2014 and 2015 were characterized by large dengue outbreaks worldwide, which are a threat to public health, especially in Asian countries. Here we use a phylogeographic ap... | Dengue virus (DENV) is a growing threat to public health, with nearly 390 million infections every year worldwide, of which ~96 million are symptomatic [1,2]. An estimated 2.5 billion people are at risk of dengue infection [3]. Dengue is regarded as the world’s most important mosquito-borne viral disease and is endemic... |
10.1371/journal.pntd.0001207 | Community Participation in Chagas Disease Vector Surveillance: Systematic Review | Vector control has substantially reduced Chagas disease (ChD) incidence. However, transmission by household-reinfesting triatomines persists, suggesting that entomological surveillance should play a crucial role in the long-term interruption of transmission. Yet, infestation foci become smaller and harder to detect as ... | Blood-sucking triatomine bugs are the vectors of Chagas disease, a potentially fatal illness that affects millions in Latin America. With no vaccines available, prevention heavily depends on controlling household-infesting triatomines. Insecticide-spraying campaigns have effectively reduced incidence, but persistent ho... | Chagas disease still imposes a heavy burden on most Latin American countries, with about 10–12 million people infected by Trypanosoma cruzi [1], [2]. Multinational control initiatives have since the early 1990s drastically reduced prevalence and incidence, mainly through insecticide-based elimination of domestic vector... |
10.1371/journal.ppat.1006814 | The potent effect of mycolactone on lipid membranes | Mycolactone is a lipid-like endotoxin synthesized by an environmental human pathogen, Mycobacterium ulcerans, the causal agent of Buruli ulcer disease. Mycolactone has pleiotropic effects on fundamental cellular processes (cell adhesion, cell death and inflammation). Various cellular targets of mycolactone have been id... | Buruli ulcer is a necrotizing skin disease caused by an environmental mycobacterial pathogen. The pathogenesis of this neglected tropical disease involves the production of a toxin, mycolactone, which spreads through the tissues, away from the infecting organisms. Mycolactone has pleiotropic effects on fundamental cell... | Buruli ulcer (BU) is the third most common human mycobacterial infection in the world, after tuberculosis and leprosy [1,2]. BU is a neglected tropical disease of the skin and subcutaneous tissue caused by an environmental pathogen, Mycobacterium ulcerans (M. ulcerans). This disease, which can affect all age groups and... |
10.1371/journal.pgen.1005288 | In Vivo Senescence in the Sbds-Deficient Murine Pancreas: Cell-Type Specific Consequences of Translation Insufficiency | Genetic models of ribosome dysfunction show selective organ failure, highlighting a gap in our understanding of cell-type specific responses to translation insufficiency. Translation defects underlie a growing list of inherited and acquired cancer-predisposition syndromes referred to as ribosomopathies. We sought to id... | Growth of all living things relies on protein synthesis. Failure of components of the complex protein synthesis machinery underlies a growing list of inherited and acquired multi—organ syndromes referred to as ribosomopathies. While ribosomes, the critical working components of the protein synthesis machinery, are requ... | The protein translation machinery encompasses interrelated processes of ribosome biogenesis [1] as well as protein synthesis [2]. Mutations in genes that encode components of this machinery are implicated in a growing list of inherited and acquired disorders termed ribosomopathies. All aspects of cell growth require pr... |
10.1371/journal.pcbi.1000291 | Accurate Path Integration in Continuous Attractor Network Models of
Grid Cells | Grid cells in the rat entorhinal cortex display strikingly regular firing
responses to the animal's position in 2-D space and have been
hypothesized to form the neural substrate for dead-reckoning. However, errors
accumulate rapidly when velocity inputs are in... | Even in the absence of external sensory cues, foraging rodents maintain an
estimate of their position, allowing them to return home in a roughly straight
line. This computation is known as dead reckoning or path integration. A
discovery made three years ago in... | Since the discovery of grid cells in the dorsolateral band of the medial entorhinal
cortex (dMEC) [1], several ideas have been put forth on how
grid-cell activity might emerge [2]–[7]. The theoretical ideas
suggested so far fall into two categories. In continuous attracto... |
10.1371/journal.pntd.0005838 | Estimating the burden of scrub typhus: A systematic review | Scrub typhus is a vector-borne zoonotic disease that can be life-threatening. There are no licensed vaccines, or vector control efforts in place. Despite increasing awareness in endemic regions, the public health burden and global distribution of scrub typhus remains poorly known.
We systematically reviewed all literat... | Scrub typhus is a mite-transmitted infectious disease that can be life-threatening. Diagnosing this disease is difficult, requiring special techniques that are often not readily available. As the actual impact of scrub typhus on the population and its geographical distribution remains unknown, we searched systematicall... | Scrub typhus is an infectious disease caused by Orientia tsutsugamushi, an obligate intracellular bacteria, transmitted by the bites of chigger mites [1]. In Southeast Asia, scrub typhus is a leading cause of treatable non-malarial febrile illness [2]. The first accounts linking febrile illness with the appearance of “... |
10.1371/journal.pcbi.1005714 | A computational model of spatio-temporal cardiac intracellular calcium handling with realistic structure and spatial flux distribution from sarcoplasmic reticulum and t-tubule reconstructions | Intracellular calcium cycling is a vital component of cardiac excitation-contraction coupling. The key structures responsible for controlling calcium dynamics are the cell membrane (comprising the surface sarcolemma and transverse-tubules), the intracellular calcium store (the sarcoplasmic reticulum), and the co-locali... | The organisation of the membrane and sub-cellular structures of cells in the heart closely controls the coupling between its electrical and mechanical function. Computational models of the cellular calcium handling system, which is responsible for this electro-mechanical coupling, have been developed in recent years to... | The cardiac intracellular calcium (Ca2+) handling system is responsible for the control of cellular and organ contraction associated with the heartbeat [1]. Malfunction of this system can directly affect the ability of the heart to work effectively as a pump–reducing cardiac output and potentially leading to mortality.... |
10.1371/journal.pgen.1005514 | Basolateral Endocytic Recycling Requires RAB-10 and AMPH-1 Mediated Recruitment of RAB-5 GAP TBC-2 to Endosomes | The small GTPase RAB-5/Rab5 is a master regulator of the early endosome, required for a myriad of coordinated activities, including the degradation and recycling of internalized cargo. Here we focused on the recycling function of the early endosome and the regulation of RAB-5 by GAP protein TBC-2 in the basolateral C. ... | When cargo is internalized from the cell surface by endocytosis, it enters a series of intracellular organelles called endosomes. Endosomes sort cargo, such that some cargos are sent to the lysosome for degradation, while others are recycled to the plasma membrane. Small GTPase proteins of the Rabs family are master re... | Endocytic recycling, the return of proteins and lipids from endosomes to the plasma membrane, plays a key role in many essential cellular processes including nutrient uptake, cell migration, cytokinesis, synaptic plasticity, immune response, and growth factor receptor modulation [1]. In polarized epithelial cells an ad... |
10.1371/journal.ppat.1004680 | Coordinated Function of Cellular DEAD-Box Helicases in Suppression of Viral RNA Recombination and Maintenance of Viral Genome Integrity | The intricate interactions between viruses and hosts include an evolutionary arms race and adaptation that is facilitated by the ability of RNA viruses to evolve rapidly due to high frequency mutations and genetic RNA recombination. In this paper, we show evidence that the co-opted cellular DDX3-like Ded1 DEAD-box heli... | A major force in virus evolution is the ability of viruses to recombine and change their genomes rapidly. Similar to viral replication that greatly depends on subverted cellular proteins, viral genetic recombination is also affected by host factors based on genome-wide screens with tomato bushy stunt virus (TBSV) in ye... | RNA viruses replicate inside cells and they require many cellular factors to complete their infection cycle. The intricate interactions between viruses and hosts include evolutionary arms race and adaptation that is facilitated by the ability of RNA viruses to evolve rapidly due to high frequency mutations and genetic ... |
10.1371/journal.pntd.0002226 | Dual Targeting of Insulin and Venus Kinase Receptors of Schistosoma mansoni for Novel Anti-schistosome Therapy | Chemotherapy of schistosomiasis relies on a single drug, Praziquantel (PZQ) and mass-use of this compound has led to emergence of resistant strains of Schistosoma mansoni, therefore pointing out the necessity to find alternative drugs. Through their essential functions in development and metabolism, receptor tyrosine k... | Schistosomiasis is a chronic, debilitating disease that affects over 200 million people in the world. The pathology of schistosomiasis is caused mainly by host immune responses to parasite eggs and due to the formation of granulomas in liver and other tissues. There is no vaccine for schistosomiasis and treatment relie... | Schistosomiasis is the second important parasitic disease in the world. This water-borne disease occurs in over 70 tropical and subtropical countries, mainly in sub-Saharan Africa, with 200 million individuals infected, and a number of deaths estimated to be more than 200 thousands annually [1], [2]. Diverse programs a... |
10.1371/journal.ppat.1002671 | Macrophage Activation Associated with Chronic Murine Cytomegalovirus Infection Results in More Severe Experimental Choroidal Neovascularization | The neovascular (wet) form of age-related macular degeneration (AMD) leads to vision loss due to choroidal neovascularization (CNV). Since macrophages are important in CNV development, and cytomegalovirus (CMV)-specific IgG serum titers in patients with wet AMD are elevated, we hypothesized that chronic CMV infection c... | Neovascular age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly. Onset of AMD is due to local production of vascular endothelial growth factor (VEGF) that promotes formation of new blood vessels in the retina, thereby leading to retinal tissue destruction and blindness. Since a cli... | Angiogenesis, the formation of blood vessels, plays a critical role in embryonic development, wound healing, and normal physiologic processes associated with natural growth and development. On the other hand, new blood vessel growth (neovascularization) contributes to a number of pathologic conditions that include athe... |
10.1371/journal.pcbi.1004687 | A Boolean Function for Neural Induction Reveals a Critical Role of Direct Intercellular Interactions in Patterning the Ectoderm of the Ascidian Embryo | A complex system of multiple signaling molecules often produce differential gene expression patterns in animal embryos. In the ascidian embryo, four signaling ligands, Ephrin-A.d (Efna.d), Fgf9/16/20, Admp, and Gdf1/3-r, coordinately induce Otx expression in the neural lineage at the 32-cell stage. However, it has not ... | It is often difficult to understand a complex system of multiple signaling molecules in animal embryos only with experimental procedures. Although theoretical analysis might solve this problem, it is often difficult to precisely determine parameters for signaling gradients and kinetics of signaling molecules. In the pr... | In animal embryos, cell-cell interactions directed by secreted and membrane-bound signaling ligands play an important role in establishing specific gene expression patterns. There are 16 ectodermal cells in the animal hemisphere of the 32-cell embryo of the ascidian, Ciona intestinalis, and all 16 have the potential to... |
10.1371/journal.pbio.0060285 | Specialization Does Not Predict Individual Efficiency in an Ant | The ecological success of social insects is often attributed to an increase in efficiency achieved through division of labor between workers in a colony. Much research has therefore focused on the mechanism by which a division of labor is implemented, i.e., on how tasks are allocated to workers. However, the important ... | Social insects, including ants, bees, and termites, may make up 75% of the world's insect biomass. This success is often attributed to their complex colony organization. Each individual is thought to specialize in a particular task and thus become an “expert” for this task. Researchers have long assumed that the ecolog... | Social insects are enormously successful ecologically. Ants, social bees, social wasps, and termites may make up 75% of the world's insect biomass, they play a major role in soil turnover and nutrient cycling, and they often surpass vertebrates in their biomass in a habitat [1]. Division of labor is often cited as the ... |
10.1371/journal.pgen.1000557 | Pch2 Links Chromosome Axis Remodeling at Future Crossover Sites and Crossover Distribution during Yeast Meiosis | Segregation of homologous chromosomes during meiosis I depends on appropriately positioned crossovers/chiasmata. Crossover assurance ensures at least one crossover per homolog pair, while interference reduces double crossovers. Here, we have investigated the interplay between chromosome axis morphogenesis and non-rando... | In the germ line of sexually reproducing organisms, haploid gametes are generated from diploid precursor cells by a specialized cell division called meiosis. Reduction by half of chromosome numbers during the first meiotic division depends on genetic exchange, resulting in the formation of crossovers. Without crossover... | During meiosis, a single round of DNA replication is followed by two rounds of chromosome separation, with homologous chromosomes (homologs) segregating during meiosis I and sister chromatids during meiosis II. Homolog segregation critically depends on formation of crossovers (COs) between homologs. COs, cytologically ... |
10.1371/journal.pntd.0000925 | Ecology and Geography of Plague Transmission Areas in Northeastern Brazil | Plague in Brazil is poorly known and now rarely seen, so studies of its ecology are difficult. We used ecological niche models of historical (1966-present) records of human plague cases across northeastern Brazil to assess hypotheses regarding environmental correlates of plague occurrences across the region. Results in... | We analyzed the spatial and environmental distributions of human plague cases across northeastern Brazil from 1966-present, where the disease is now only rarely transmitted to humans, but persists as a zoonosis of native rodent populations. We elucidated environmental correlates of plague occurrences by way of ecologic... | Plague arrived in Brazil during the Third Pandemic, in October 1899, imported by ship traffic to Santos, in São Paulo state, and was rapidly diffused to other coastal cities. By 1906, it had dispersed by means of land and sea commerce more broadly, and had become established in native rodent populations, particularly i... |
10.1371/journal.pntd.0001257 | Improving the Cost-Effectiveness of Visual Devices for the Control of Riverine Tsetse Flies, the Major Vectors of Human African Trypanosomiasis | Control of the Riverine (Palpalis) group of tsetse flies is normally achieved with stationary artificial devices such as traps or insecticide-treated targets. The efficiency of biconical traps (the standard control device), 1×1 m black targets and small 25×25 cm targets with flanking nets was compared using electrocuti... | Sleeping Sickness (Human African Trypanosomiasis) is a serious threat to health and development in sub-Saharan Africa. Currently there are no vaccines or prophylactic drugs available to prevent contraction of the disease. Consequently vector control is the only method of disease prevention. In many areas, especially th... | African sleeping sickness or Human African Trypanosomiasis (HAT) is endemic to 36 countries in sub-Saharan Africa covering 9 million km2 with 60 million of the 400 million inhabitants at risk of the disease. Africa has emerged from a recent sleeping sickness epidemic. In 1997 about 450,000 people were afflicted [1] whi... |
10.1371/journal.pmed.1002136 | Clonal Evolutionary Analysis during HER2 Blockade in HER2-Positive Inflammatory Breast Cancer: A Phase II Open-Label Clinical Trial of Afatinib +/- Vinorelbine | Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer associated with HER2 amplification, with high risk of metastasis and an estimated median survival of 2.9 y. We performed an open-label, single-arm phase II clinical trial (ClinicalTrials.gov NCT01325428) to investigate the efficacy and safety ... | Inflammatory breast cancer (IBC) is a rare and poorly understood form of breast cancer that grows and spreads very quickly. Fifty percent of IBC cases are HER2-positive.
Afatinib is an investigational drug that showed promise in early-stage trials in the setting of HER2-positive metastatic breast cancer.
Our study was ... | Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer that accounts for around 1%–6% of breast cancers [1–4]. IBC tends to affect younger women and has a high risk of local and distant metastasis. Prognosis is poor, with median survival estimated at 2.9 y in IBC patients versus 6.4 y in those wit... |
10.1371/journal.pcbi.1004226 | Sparse and Compositionally Robust Inference of Microbial Ecological Networks | 16S ribosomal RNA (rRNA) gene and other environmental sequencing techniques provide snapshots of microbial communities, revealing phylogeny and the abundances of microbial populations across diverse ecosystems. While changes in microbial community structure are demonstrably associated with certain environmental conditi... | Genomic survey of microbes by 16S rRNA gene sequencing and metagenomics has inspired appreciation for the role of complex communities in diverse ecosystems. However, due to the unique properties of community composition data, standard data analysis tools are likely to produce statistical artifacts. For a typical experi... | Low-cost metagenomic and amplicon-based sequencing promises to make the resolution of complex interactions between microbial populations and their surrounding environment a routine component of observational ecology and experimental biology. Indeed, large-scale data collection efforts (such as Earth Microbiome Project ... |
10.1371/journal.pbio.1001290 | Mediator Acts Upstream of the Transcriptional Activator Gal4 | The proteasome inhibitor MG132 had been shown to prevent galactose induction of the S. cerevisiae GAL1 gene, demonstrating that ubiquitin proteasome-dependent degradation of transcription factors plays an important role in the regulation of gene expression. The deletion of the gene encoding the F-box protein Mdm30 had ... | The expression levels of proteins are tightly regulated, not only via their production but also via their degradation. Genes are transcribed only if their encoded proteins are required by the environmental or developmental conditions of a cell, and once a certain protein is no longer needed, it is rapidly degraded by t... | Cells regulate the expression of their genes according to requirement [1]. Activators recruit chromatin-remodeling or chromatin-modifying complexes that change the structure of chromatin to promote transcription [2],[3], while repressors recruit chromatin-modifying complexes that change the structure of chromatin to pr... |
10.1371/journal.pgen.1000421 | A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci | There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD). The only known genetic risk factor is severe deficiency of α1-antitrypsin, which is present in 1–2% of individuals with COPD. We conducted a genome-wide association study (GWAS) in a homogenous ca... | There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD), which is a heritable multi-factorial trait. Identifying the genetic determinants of COPD risk will have tremendous public health importance. This study describes the first genome-wide association ... | COPD is expected to be the third leading cause of worldwide mortality and the fifth leading cause of morbidity by the year 2020 [1]. Cigarette smoking is the major risk factor for COPD but smokers show considerable variation in their risk of developing airflow obstruction. Familial aggregation studies suggest a strong ... |
10.1371/journal.ppat.1003464 | Structure and Function of a Fungal Adhesin that Binds Heparin and Mimics Thrombospondin-1 by Blocking T Cell Activation and Effector Function | Blastomyces adhesin-1 (BAD-1) is a 120-kD surface protein on B. dermatitidis yeast. We show here that BAD-1 contains 41 tandem repeats and that deleting even half of them impairs fungal pathogenicity. According to NMR, the repeats form tightly folded 17-amino acid loops constrained by a disulfide bond linking conserved... | Work on fungi is of worldwide importance due to the increasing burden of diseases caused by these agents in humans, plants and animals globally and throughout our ecosystem. The human pathogen Blastomyces dermatitidis harbors an essential virulence factor BAD-1. We describe new structural and functional features of BAD... | The dimorphic fungus Blastomyces dermatitidis is endemic to the Ohio and Mississippi river valleys, where it is the causative agent of blastomycosis. Blastomycosis is one of the principal systemic mycoses of humans and animals worldwide, and results from the inhalation of spores and/or hyphal fragments released into th... |
10.1371/journal.ppat.1003565 | Coronaviruses Lacking Exoribonuclease Activity Are Susceptible to Lethal Mutagenesis: Evidence for Proofreading and Potential Therapeutics | No therapeutics or vaccines currently exist for human coronaviruses (HCoVs). The Severe Acute Respiratory Syndrome-associated coronavirus (SARS-CoV) epidemic in 2002–2003, and the recent emergence of Middle East Respiratory Syndrome coronavirus (MERS-CoV) in April 2012, emphasize the high probability of future zoonotic... | RNA viruses have high mutation rates (10−3 to 10−5 mutations/nucleotide/round of replication), allowing for rapid viral adaptation in response to selective pressure. While RNA viruses have long been considered unable to correct mistakes during replication, CoVs such as SARS-CoV and the recently emerged MERS-CoV are imp... | The potential for CoVs to cause significant human disease is well demonstrated, with six known HCoVs—HKU1, OC43, NL63, 229E, SARS-CoV and MERS-CoV—causing colds, pneumonia, systemic infection, and severe or lethal disease [1]–[5]. Four of these viruses have been identified in just the last 10 years, with two, SARS-CoV ... |
10.1371/journal.ppat.1005284 | Influenza Virus Induces Cholesterol-Enriched Endocytic Recycling Compartments for Budozone Formation via Cell Cycle-Independent Centrosome Maturation | Influenza virus particles are assembled at the plasma membrane in concert with incorporation of the virus genome, but the details of its spatio-temporal regulation are not understood. Here we showed that influenza virus infection induces the assembly of pericentrosomal endocytic recycling compartment (ERC) through the ... | Influenza virus particles are assembled at the plasma membrane in concert with incorporation of the virus genome, but the details of its spatiotemporal regulation are unknown. We found that the virus genome is transported to the plasma membrane using cholesterol-enriched recycling endosomes through cell cycle-independe... | Endocytic transport pathways are important to arrange the plasma membrane components for diversified cellular processes at the plasma membrane including virus budding. Endocytosed proteins are first delivered to the early/sorting endosomes, from where proteins are either recycled back to the plasma membrane or transpor... |
10.1371/journal.pntd.0003198 | Leishmania Specific CD4 T Cells Release IFNγ That Limits Parasite Replication in Patients with Visceral Leishmaniasis | Visceral leishmaniasis (VL) is associated with increased circulating levels of multiple pro-inflammatory cytokines and chemokines, including IL-12, IFNγ, and TNFα, and elevated expression of IFNγ mRNA in lesional tissue such as the spleen and bone marrow. However, an immunological feature of VL patients is that their p... | Our research aims to understand the immune failure underlying progression of human visceral leishmaniasis (VL). A key immunological feature of VL patients is that their peripheral blood mononuclear cells (PBMCs) do not respond to stimulation with leishmanial antigen. Surprisingly, when employing a whole blood assay we ... | Visceral leishmaniasis is a chronic disease caused by the protozoan parasites Leishmania donovani and Leishmania infantum/chagasi. Leishmania are transmitted by the bite of phlebotomine sand flies, and replicate within macrophages of their mammalian hosts. In VL, the target organs are chiefly the liver and the spleen. ... |
10.1371/journal.pbio.2000731 | Lung Basal Stem Cells Rapidly Repair DNA Damage Using the Error-Prone Nonhomologous End-Joining Pathway | Lung squamous cell carcinoma (SqCC), the second most common subtype of lung cancer, is strongly associated with tobacco smoking and exhibits genomic instability. The cellular origins and molecular processes that contribute to SqCC formation are largely unexplored. Here we show that human basal stem cells (BSCs) isolate... | Human lungs are constantly exposed to inhaled chemicals that have the potential to damage cellular DNA. Lung stem cells must therefore have the ability to repair DNA damage to survive and achieve tissue homeostasis. Lung airways are composed of different types of cells, including basal cells, which have been proposed t... | Human lungs are constantly exposed to inhaled environmental and chemical insults that have the potential to damage cellular DNA. Lung stem and progenitor cells must be capable of repairing their DNA to maintain healthy survival. The failure of stem cells to repair DNA damage can contribute to tissue loss through damage... |
10.1371/journal.pcbi.1005923 | Modeling the genetic relatedness of Plasmodium falciparum parasites following meiotic recombination and cotransmission | Unlike in most pathogens, multiple-strain (polygenomic) infections of P. falciparum are frequently composed of genetic siblings. These genetic siblings are the result of sexual reproduction and can coinfect the same host when cotransmitted by the same mosquito. The degree with which coinfecting strains are related vari... | Genomic studies of P. falciparum reveal that multi-strain infections can include genetically related strains. P. falciparum must reproduce sexually in the mosquito vector. One consequence of sexual reproduction is that parasites cotransmitted by the same mosquito are related to one another. The degree of genetic relate... | Unlike most bacterial and viral pathogens, the malaria parasite P. falciparum, while predominantly haploid, must sexually reproduce in a mosquito vector before infecting a new human host. Sexual recombination has a significant impact on the population genomics of the parasite, and its effects depend on epidemiological ... |
10.1371/journal.pgen.1003350 | A Novel Mutation in the Upstream Open Reading Frame of the CDKN1B Gene Causes a MEN4 Phenotype | The CDKN1B gene encodes the cyclin-dependent kinase inhibitor p27KIP1, an atypical tumor suppressor playing a key role in cell cycle regulation, cell proliferation, and differentiation. Impaired p27KIP1 expression and/or localization are often observed in tumor cells, further confirming its central role in regulating t... | Gene expression can be modulated at different steps on the way from DNA to protein including control of transcription, translation, and post-translational modifications. An abnormality in the regulation of mRNA and protein expression is a hallmark of many human diseases, including cancer. In some eukaryotic genes trans... | CDKN1B encodes the cyclin-dependent kinase (CDK) inhibitor, p27KIP1, which negatively regulates the Cdk2/cyclin E and Cdk2/cyclin A protein complexes, thereby preventing the progression from the G1 to the S phase of the cell cycle [1]. In G0 and early G1, p27KIP1 expression and stability are maximal. During the G1 phas... |
10.1371/journal.pntd.0001365 | Hidden Sylvatic Foci of the Main Vector of Chagas Disease Triatoma infestans: Threats to the Vector Elimination Campaign? | Establishing the sources of reinfestation after residual insecticide spraying is crucial for vector elimination programs. Triatoma infestans, traditionally considered to be limited to domestic or peridomestic (abbreviated as D/PD) habitats throughout most of its range, is the target of an elimination program that has a... | Triatoma infestans, a highly domesticated species and historically the main vector of Trypanosoma cruzi, is the target of an insecticide-based elimination program in the southern cone countries of South America since 1991. Only limited success has been achieved in the Gran Chaco region due to repeated reinfestations. W... | Disease eradication or elimination programs depend on time-limited intensive campaigns and are likely to fail if resistance to insecticides or drugs (i.e., malaria) or sylvatic transmission cycles (i.e., yellow fever) occur. Chagas disease is the most important vector-borne disease in Latin America in terms of disabili... |
10.1371/journal.pntd.0006488 | Cost-benefit analysis of intervention policies for prevention and control of brucellosis in India | Brucellosis is endemic in the bovine population in India and causes a loss of US$ 3·4 billion to the livestock industry besides having a significant human health impact.
We developed a stochastic simulation model to estimate the impact of three alternative vaccination strategies on the prevalence of Brucella infection ... | Brucellosis is an endemic zoonosis in India and recent studies demonstrate that the disease results in a median loss of US$ 3.43 billion in livestock populations. Lack of resources to compensate farmers and a ban on cow slaughter means that test and slaughter policy to control brucellosis cannot be implemented in India... | Brucellosis is an important zoonotic disease causing infertility, repeat breeding, retention of placenta and abortion in cattle. Humans in contact with animals usually get infected by coming in direct or indirect contact with reproductive secretions and excretions from infected animals. The disease is quite painful amo... |
10.1371/journal.pcbi.1006055 | Computational analysis of the oscillatory behavior at the translation level induced by mRNA levels oscillations due to finite intracellular resources | Recent studies have demonstrated how the competition for the finite pool of available gene expression factors has important effect on fundamental gene expression aspects. In this study, based on a whole-cell model simulation of translation in S. cerevisiae, we evaluate for the first time the expected effect of mRNA lev... | Each cell contains a limited number of macromolecules and factors that participate in the gene expression process. These expression resources are shared between the different molecules that encode the genetic code, resulting in non-trivial couplings and competitions between the different gene expression stages. Such co... | During the gene expression process various macromolecules (e.g. ribosomes, RNA polymerase (RNAP), transcription factors, elongation factors, spliceosome, transfer RNA (tRNA) molecules, etc.) process the genetic material (DNA, mRNA, pre-mRNA) in order to generate proteins [1]. The number of gene expression macromolecule... |
10.1371/journal.pcbi.1005045 | The Computational Properties of a Simplified Cortical Column Model | The mammalian neocortex has a repetitious, laminar structure and performs functions integral to higher cognitive processes, including sensory perception, memory, and coordinated motor output. What computations does this circuitry subserve that link these unique structural elements to their function? Potjans and Diesman... | What computations do existing biophysically-plausible models of cortex perform on their inputs, and how do these computations relate to theories of cortical processing? We begin with a computational model of cortical tissue and seek to understand its input/output transformations. Our approach limits confirmation bias, ... | For more than a century, neuroscientists have worked to refine descriptions of cortical anatomy, either differentiating or consolidating models of cortical circuits [1]. The notion that a fundamental neuronal circuit performs a canonical computation in neocortex, that can be generalized across species and areas, is of ... |
10.1371/journal.pgen.1003732 | Meiotic Recombination Initiation in and around Retrotransposable Elements in Saccharomyces cerevisiae | Meiotic recombination is initiated by large numbers of developmentally programmed DNA double-strand breaks (DSBs), ranging from dozens to hundreds per cell depending on the organism. DSBs formed in single-copy sequences provoke recombination between allelic positions on homologous chromosomes, but DSBs can also form in... | Meiosis is the cell division that generates gametes for sexual reproduction. During meiosis, homologous recombination occurs frequently, initiated by DNA double-strand breaks (DSBs) made by Spo11. Meiotic recombination usually occurs between sequences at allelic positions on homologous chromosomes, but a DSB within a r... | Meiosis is the specialized cell division that halves the genome complement to produce gametes for sexual reproduction. During meiosis, homologous recombination is induced by programmed DNA double-strand breaks (DSBs) made by the topoisomerase-like Spo11 protein in a reaction in which Spo11 attaches covalently to 5′ str... |
10.1371/journal.pcbi.1000158 | Modeling ChIP Sequencing In Silico with Applications | ChIP sequencing (ChIP-seq) is a new method for genomewide mapping of protein binding sites on DNA. It has generated much excitement in functional genomics. To score data and determine adequate sequencing depth, both the genomic background and the binding sites must be properly modeled. To develop a computational founda... | ChIP-seq is an apt combination of chromosome immunoprecipitation and next-generation sequencing to identify transcription factor binding sites in vivo on the whole-genome scale. Since its advent, this new method has generated much excitement in the field of functional genomics. Proper computational modeling of the ChIP... | Gene expression is carefully regulated in all living cells. Only a fraction of the genes in a genome are expressed to various degrees under a given condition or in a particular cell type. The main control of such regulation occurs at the transcription level: the RNA polymerases transcribe genes following binding of tra... |
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