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10.1371/journal.pcbi.1003511 | STDP Installs in Winner-Take-All Circuits an Online Approximation to Hidden Markov Model Learning | In order to cross a street without being run over, we need to be able to extract very fast hidden causes of dynamically changing multi-modal sensory stimuli, and to predict their future evolution. We show here that a generic cortical microcircuit motif, pyramidal cells with lateral excitation and inhibition, provides t... | It has recently been shown that STDP installs in ensembles of pyramidal cells with lateral inhibition networks for Bayesian inference that are theoretically optimal for the case of stationary spike input patterns. We show here that if the experimentally found lateral excitatory connections between pyramidal cells are t... | An ubiquitous motif of cortical microcircuits is ensembles of pyramidal cells (in layers 2/3 and in layer 5) with lateral inhibition [1]–[3]. This network motif is called a winner-take-all (WTA) circuit, since inhibition induces competition between pyramidal neurons [4]. We investigate in this article which computation... |
10.1371/journal.pntd.0006013 | A recombinase polymerase amplification assay for rapid detection of Crimean-Congo Haemorrhagic fever Virus infection | Crimean-Congo Haemorrhagic fever Virus (CCHFV) is a rapidly emerging vector-borne pathogen and the cause of a virulent haemorrhagic fever affecting large parts of Europe, Africa, the Middle East and Asia.
An isothermal recombinase polymerase amplification (RPA) assay was successfully developed for molecular detection o... | The Crimean-Congo Haemorrhagic fever (CCHF) recombinase polymerase amplification assay is a new, rapid and portable diagnostic method. It has been developed for the detection of infection with CCHF virus (CCHFV), the cause of a deadly haemorrhagic disease in humans and an emerging global health threat. As a rapid diagn... | CCHFV is an RNA virus classified in the Orthonairovirus genus, of the family Nairoviridae, within the order Bunyavirales (International Committee on Taxonomy of Viruses 2016). It displays a high degree of sequence variability [1] with the S-segments of CCHF viruses being phylogenetically grouped into 7 clades (Europe 1... |
10.1371/journal.pmed.1002501 | Multimorbidity and survival for patients with acute myocardial infarction in England and Wales: Latent class analysis of a nationwide population-based cohort | There is limited knowledge of the scale and impact of multimorbidity for patients who have had an acute myocardial infarction (AMI). Therefore, this study aimed to determine the extent to which multimorbidity is associated with long-term survival following AMI.
This national observational study included 693,388 patient... | Survival following a heart attack (acute myocardial infarction) has improved over recent decades.
The population is ageing, and there are more patients living longer with multiple long-term health conditions (multimorbidity).
Previous studies have looked at the associations between individual long-term health condition... | The increasing prevalence of long-term health conditions, and consequent growing prevalence of multimorbidity (the presence of multiple co-morbidities), is a major global challenge facing healthcare systems [1,2]. Presently, around two-thirds of patients with cardiovascular disease are estimated to have at least 1 long... |
10.1371/journal.ppat.1005566 | The Rewiring of Ubiquitination Targets in a Pathogenic Yeast Promotes Metabolic Flexibility, Host Colonization and Virulence | Efficient carbon assimilation is critical for microbial growth and pathogenesis. The environmental yeast Saccharomyces cerevisiae is “Crabtree positive”, displaying a rapid metabolic switch from the assimilation of alternative carbon sources to sugars. Following exposure to sugars, this switch is mediated by the transc... | Most yeast species occupy environmental niches, but some infect humans. All species must assimilate carbon to grow and colonize their niche, but carbon source availability differs significantly between niches. The environmental yeast Saccharomyces cerevisiae is thought to have evolved under conditions of sugar feast an... | Microbes must acquire nutrients efficiently if they are to compete effectively in complex microenvironments. A common microbial strategy is to focus resources on the utilization of energetically favourable carbon sources when they are available, and then, once they become exhausted, switch to alternative, less favourab... |
10.1371/journal.pntd.0004325 | Development of Equine IgG Antivenoms against Major Snake Groups in Mozambique | Snake envenoming is a significant public health problem in underdeveloped and developing countries. In sub-Saharan Africa, it is estimated that 90,000–400,000 envenomations occur each year, resulting in 3,500–32,000 deaths. Envenomings are caused by snakes from the Viperidae (Bitis spp. and Echis spp.) and Elapidae (Na... | Snake envenoming has long been a serious public health problem in underdeveloped and developing countries. In sub-Saharan Africa, the number of bites can be as high as 400,000 and result in up to 32,000 deaths. As accidents involving snakes are most common among young men in rural areas, complications and amputations c... | Snake envenoming prevention and treatment has been a worldwide effort in underdeveloped and developing countries in Africa, Asia and South America. In sub-Saharan Africa, it is estimated that 90,000–400,000 envenomations occur per year, resulting in 3,500–32,000 fatalities [1]. Amputations and complications caused by s... |
10.1371/journal.pcbi.1000832 | RNAcontext: A New Method for Learning the Sequence and Structure Binding Preferences of RNA-Binding Proteins | Metazoan genomes encode hundreds of RNA-binding proteins (RBPs). These proteins regulate post-transcriptional gene expression and have critical roles in numerous cellular processes including mRNA splicing, export, stability and translation. Despite their ubiquity and importance, the binding preferences for most RBPs ar... | Many disease-associated mutations do not change the protein sequence of genes; instead they change the instructions on how a gene's mRNA transcript should be processed. Translating these instructions allows us to better understand the connection between these mutations and disease. RNA-binding proteins (RBP) perform th... | RBPs act in the post-transcriptional regulation (PTR) of gene expression by binding to target RNAs to control splicing, stability, localization and translation. Recent draft networks of RBP-transcript physical interaction in yeast [1], fruit flies [2], and humans [3] reveal a complex and combinatorial pattern of RBP ta... |
10.1371/journal.pbio.0060273 | Phase Coupling of a Circadian Neuropeptide With Rest/Activity Rhythms Detected Using a Membrane-Tethered Spider Toxin | Drosophila clock neurons are self-sustaining cellular oscillators that rely on negative transcriptional feedback to keep circadian time. Proper regulation of organismal rhythms of physiology and behavior requires coordination of the oscillations of individual clock neurons within the circadian control network. Over the... | The regulation of the daily fluctuations that characterize an organism's physiology and behavior requires coordination of the cellular oscillations of individual “clock” neurons within the circadian control network. Clock neurons that secrete a neuropeptide called pigment dispersing factor (PDF) calibrate, or entrain, ... | Drosophila clock neurons are self-sustaining cellular oscillators that rely on negative transcriptional feedback and cellular signaling pathways to keep circadian time. PERIOD (PER) and TIMELESS (TIM) clock proteins constitute the core of a negative transcriptional feedback loop, in which these clock proteins inhibit t... |
10.1371/journal.pgen.1005079 | Escape from X Inactivation Varies in Mouse Tissues | X chromosome inactivation (XCI) silences most genes on one X chromosome in female mammals, but some genes escape XCI. To identify escape genes in vivo and to explore molecular mechanisms that regulate this process we analyzed the allele-specific expression and chromatin structure of X-linked genes in mouse tissues and ... | X inactivation is a female-specific phenomenon that occurs during early development and results in the silencing of one X chromosome in female mammals. However, some genes escape inactivation and remain expressed from both X chromosomes. To date, the identity of escape genes and the molecular mechanisms of this process... | Dosage compensation in mammals is achieved by upregulation of the X chromosome in both sexes and random inactivation of one of the two X chromosomes in females [1]. Initially, the future inactive X (Xi) is coated by the long non-coding RNA Xist (X inactive specific transcript), a process essential for the onset of sile... |
10.1371/journal.pntd.0006047 | Ecological niche modeling and distribution of Ornithodoros hermsi associated with tick-borne relapsing fever in western North America | Tick-borne relapsing fever in western North America is a zoonosis caused by the spirochete bacterium, Borrelia hermsii, which is transmitted by the bite of infected Ornithodoros hermsi ticks. The pathogen is maintained in natural cycles involving small rodent hosts such as chipmunks and tree squirrels, as well as the t... | The model presented here provides valuable epidemiological information on tick-borne relapsing fever in western North America. The inference gleaned from these models represents areas where human infection with B. hermsii is likely to occur. The predicted distribution of O. hermsi and B. hermsii may allow health offici... | Tick-borne relapsing fever (TBRF) is a zoonosis endemic to the Americas, Africa, and Asia, and caused by spirochetes transmitted by soft ticks (Family: Argasidae) in the genus Ornithodoros [1]. The disease is caused by a diversity of regionally specific bacterial species in the genus Borrelia [2]. Although of low incid... |
10.1371/journal.pgen.1002250 | Natural Polymorphism in BUL2 Links Cellular Amino Acid Availability with Chronological Aging and Telomere Maintenance in Yeast | Aging and longevity are considered to be highly complex genetic traits. In order to gain insight into aging as a polygenic trait, we employed an outbred Saccharomyces cerevisiae model, generated by crossing a vineyard strain RM11 and a laboratory strain S288c, to identify quantitative trait loci that control chronologi... | Dietary restriction promotes longevity in many species, ranging from yeast to primates, and delays aging-related pathologies including cancer in rodent models. There is considerable interest in understanding how nutrient limitation mediates these beneficial effects. Much of what we have learned about the genetics of ag... | The observation that dietary restriction promotes longevity in organisms ranging from yeast to primates raises the expectation that molecular mechanisms mediating this lifespan extension may also be shared among species. In support of the idea that related genetic circuitry controls aging in different species are the f... |
10.1371/journal.pbio.1001674 | TGF-β Signalling Is Required for CD4+ T Cell Homeostasis But Dispensable for Regulatory T Cell Function | TGF-β is widely held to be critical for the maintenance and function of regulatory T (Treg) cells and thus peripheral tolerance. This is highlighted by constitutive ablation of TGF-β receptor (TR) during thymic development in mice, which leads to a lethal autoimmune syndrome. Here we describe that TGF-β–driven peripher... | TGF-β is a cytokine thought to be critical for the maintenance and function of tolerance in the immune system. In many studies the disruption of TGF-β signalling in CD4+ T cells (a type of white blood cell that coordinates immune responses) has resulted in autoimmune syndromes. We show here that the induced removal of ... | Transforming growth factor β (TGF-β1) is a cytokine that is expressed throughout the hematopoietic system. It was initially described to suppress T cell proliferation [1], but later found to also support differentiation of T cells into specialized subsets. Mice deficient in TGF-β1 show hyperactivation and uncontrolled ... |
10.1371/journal.pcbi.1002020 | Molecular Mechanism of Cyclodextrin Mediated Cholesterol Extraction | The depletion of cholesterol from membranes, mediated by β-cyclodextrin (β-CD) is well known and documented, but the molecular details of this process are largely unknown. Using molecular dynamics simulations, we have been able to study the CD mediated extraction of cholesterol from model membranes, in particular from ... | The ability of certain molecules to capture other molecules forming so-called inclusion complexes has a range of potential important applications in e.g. drug delivery and chemical sensing. Here we study the complexation of cholesterol by small oligosaccharide rings named cyclodextrins (CDs). Cholesterol is an essentia... | Among all cyclodextrins (CDs), the most abundant are -, -, and -CDs with six, seven and eight glucopyranose monomers, respectively. They have a rigid conical molecular structure with a hydrophobic interior and a hydrophilic exterior. The internal cavity of these molecules is able to include a wide range of guest molecu... |
10.1371/journal.pcbi.1002496 | Modeling Meiotic Chromosomes Indicates a Size Dependent Contribution of Telomere Clustering and Chromosome Rigidity to Homologue Juxtaposition | Meiosis is the cell division that halves the genetic component of diploid cells to form gametes or spores. To achieve this, meiotic cells undergo a radical spatial reorganisation of chromosomes. This reorganisation is a prerequisite for the pairing of parental homologous chromosomes and the reductional division, which ... | Organisms store their genetic material in the form of chromosomes that must be replicated and shared out during cell division. In sexual reproduction the cell division, called meiosis, halves the number of chromosomes to form gametes. This halving requires a complex reorganisation of chromosomes. Each gamete receives o... | There are two major forms of cell division among eukaryotes. Mitosis is used for cell duplication and meiosis is used to produce gametes and spores (Fig. 1). Meiosis is preceded, like mitosis, with a round of DNA synthesis that replicates all chromosomes. A major difference between these methods of cell division reside... |
10.1371/journal.pcbi.0030131 | Global and Local Architecture of the Mammalian microRNA–Transcription Factor Regulatory Network | microRNAs (miRs) are small RNAs that regulate gene expression at the posttranscriptional level. It is anticipated that, in combination with transcription factors (TFs), they span a regulatory network that controls thousands of mammalian genes. Here we set out to uncover local and global architectural features of the ma... | It is becoming increasingly appreciated that a new type of gene which does not code for proteins, the regulatory RNAs, constitutes a considerable portion of mammalian genomes, and these genes serve as key players in the regulatory network of living cells. Among these regulatory RNAs are the microRNAs (miRs), small RNAs... | microRNAs (miRs) are short RNAs that post transcriptionally regulate messenger RNAs. Two main mechanisms for such effects are degradation of the target mRNA, and inhibition of its translation [1]. In recent years considerable progress within multiple genomes was obtained in the experimental identification of genes enco... |
10.1371/journal.pgen.1003923 | Systematic Unraveling of the Unsolved Pathway of Nicotine Degradation in Pseudomonas | Microorganisms such as Pseudomonas putida play important roles in the mineralization of organic wastes and toxic compounds. To comprehensively and accurately elucidate key processes of nicotine degradation in Pseudomonas putida, we measured differential protein abundance levels with MS-based spectral counting in P. put... | Pseudomonas putida strains are among the microorganisms that have acquired the capability to use toxic and xenobiotic compounds, such as nicotine, for growth. Although nicotine degradation by Pseudomonas was first discovered more than 50 years ago, the underlying molecular mechanisms remain unclear. In the last few yea... | Strains belonging to Pseudomonas putida, a non-pathogenic member of the genus Pseudomonas, are able to metabolize a variety of organic material [1], [2]. According to their metabolic and physiologic versatility, these strains are thought to play a pivotal role in the recycling of organic wastes in the environment, incl... |
10.1371/journal.pntd.0006928 | Molecular genotyping, diversity studies and high-resolution molecular markers unveiled by microsatellites in Giardia duodenalis | Giardia duodenalis (synonyms G. lamblia and G. intestinalis) is an enteric protozoan parasite of a wide range of mammalian hosts, including humans and various domestic and wild animals. There is considerable genetic variability in G. duodenalis and isolates of this parasite have been divided into eight genetic assembla... | Giardia duodenalis is a protozoan parasite that causes giardiasis, a disease that affects millions of people worldwide and a wide range of mammalian hosts. G. duodenalis presents considerable genetic variability and there is an increasing demand for the development of new molecular markers. This study aimed to identify... | Giardia duodenalis (synonyms G. lamblia and G. intestinalis) is an enteric protozoan that parasitizes a wide range of mammalian hosts, including humans and various domestic and wild animals [1,2]. This parasite causes giardiasis, which is one of the most prevalent parasitic waterborne diseases in the world, accounting ... |
10.1371/journal.ppat.1002388 | A Kinase Chaperones Hepatitis B Virus Capsid Assembly and Captures Capsid Dynamics in vitro | The C-terminal domain (CTD) of Hepatitis B virus (HBV) core protein is involved in regulating multiple stages of the HBV lifecycle. CTD phosphorylation correlates with pregenomic-RNA encapsidation during capsid assembly, reverse transcription, and viral transport, although the mechanisms remain unknown. In vitro, purif... | A virus particle is a molecular machine that has evolved to self-assemble within the confines of a living cell. For hepatitis B virus (HBV), outside of a cell, the self-assembly process is very aggressive and consequently not specific for viral RNA. Here we show that HBV takes advantage of a host protein, SRPK, which a... | Hepatitis B virus (HBV) is an enveloped DNA virus that causes liver damage and can lead to cirrhosis and liver cancer [1]. It has infected 2 billion people worldwide including 350 million chronic carriers [2], making it a major health concern, and also leading to social problems due to discrimination against the virus ... |
10.1371/journal.ppat.1002283 | Targeting of a Chlamydial Protease Impedes Intracellular Bacterial Growth | Chlamydiae are obligate intracellular bacteria that propagate in a cytosolic vacuole. Recent work has shown that growth of Chlamydia induces the fragmentation of the Golgi apparatus (GA) into ministacks, which facilitates the acquisition of host lipids into the growing inclusion. GA fragmentation results from infection... | Chlamydiae are bacteria that replicate only inside host (for instance human) cells and that are frequent agents of human disease, in particular sexually transmitted disease. Chlamydia lives in a vacuole inside the cell, surrounded by a lipid membrane, and must acquire nutrients and other factors from the host cell for ... | Chlamydiae are a group of obligate intracellular bacteria that infect humans and animals. Chlamydia trachomatis is the most common bacterial agent of sexually transmitted disease with a prevalence of up to about 5% in young women as well as a common cause of eye infections. Clinically, the most relevant aspect of infec... |
10.1371/journal.pgen.1004783 | HAM-5 Functions As a MAP Kinase Scaffold during Cell Fusion in Neurospora crassa | Cell fusion in genetically identical Neurospora crassa germlings and in hyphae is a highly regulated process involving the activation of a conserved MAP kinase cascade that includes NRC-1, MEK-2 and MAK-2. During chemotrophic growth in germlings, the MAP kinase cascade members localize to conidial anastomosis tube (CAT... | Cell fusion between genetically identical cells of the fungus Neurospora crassa occurs when germinating asexual cells (conidia) sense each other's proximity and redirect their growth. Chemotropic growth is dependent upon the assembly of a MAPK cascade (NRC-1/MEK-2/MAK-2) at the cell cortex (conidial anastomosis tubes; ... | Fusion between genetically identical cells occurs in many different organisms and plays pivotal roles in different developmental processes, such as myoblast fusion during muscle formation, macrophage fusion involved in tissue remodeling and fusion of trophoblasts during placental development [1], [2]. Cell fusion is al... |
10.1371/journal.ppat.1002644 | The Baculovirus Uses a Captured Host Phosphatase to Induce Enhanced Locomotory Activity in Host Caterpillars | The baculovirus is a classic example of a parasite that alters the behavior or physiology of its host so that progeny transmission is maximized. Baculoviruses do this by inducing enhanced locomotory activity (ELA) that causes the host caterpillars to climb to the upper foliage of plants. We previously reported that thi... | Pathogens are known to usurp or alter the behavior of their hosts for their own benefit. Such behavior modification by animal and even plant viruses is widely observed in insect hosts. One of the earliest documented examples of such behavior modification is Wipfelkrankheit, a baculovirus-induced disease that causes cat... | Viruses and other parasites are known to usurp or alter the behavior of their hosts for their own benefit. This type of behavior modification by animal and even plant viruses is widely observed in arthropod hosts [1], [2]. One of the earliest documented examples of such behavior modification is Wipfelkrankheit or tree-... |
10.1371/journal.pntd.0005857 | Enhancing case definitions for surveillance of human monkeypox in the Democratic Republic of Congo | Human monkeypox (MPX) occurs at appreciable rates in the Democratic Republic of Congo (DRC). Infection with varicella zoster virus (VZV) has a similar presentation to that of MPX, and in areas where MPX is endemic these two illnesses are commonly mistaken. This study evaluated the diagnostic utility of two surveillance... | Human monkeypox is the most significant Orthopoxvirus infection since the eradication of smallpox. The disease is endemic in Africa and the majority of cases occur in the Congo Basin. Correct identification of patients is critical to deployment of efficient control measures to prevent further transmission and appropria... | Since the global eradication of smallpox, the most important Orthopoxvirus infection in humans in terms of ongoing numbers of cases, morbidity, and mortality has been human monkeypox (MPX) [1, 2]. Monkeypox virus (MPXV) is maintained by an enzootic cycle, with zoonotic introductions to humans often being followed by mo... |
10.1371/journal.pntd.0004661 | Projected Impact of Dengue Vaccination in Yucatán, Mexico | Dengue vaccines will soon provide a new tool for reducing dengue disease, but the effectiveness of widespread vaccination campaigns has not yet been determined. We developed an agent-based dengue model representing movement of and transmission dynamics among people and mosquitoes in Yucatán, Mexico, and simulated vario... | Dengue is a mosquito-transmitted viral disease that is common throughout the tropics. Despite a long history in humans and extensive efforts to control dengue transmission in many countries, the number, severity, and geographic range of reported cases is increasing. Most control efforts have focused on controlling mosq... | Dengue is currently the most important arboviral disease of humans and has an increasing global public health burden [1]. Worldwide, the combined annual number of infections by the four dengue serotypes has been estimated to be close to 400 million, of which 96 million develop symptomatic disease [2]. Globally, dengue ... |
10.1371/journal.pntd.0005384 | Human cystic echinococcosis in Morocco: Ultrasound screening in the Mid Atlas through an Italian-Moroccan partnership | Cystic echinococcosis (CE) is a neglected parasitic zoonosis with considerable socioeconomic impact on affected pastoral communities. CE is endemic throughout the Mediterranean, including Morocco, where the Mid Atlas is the most prevalent area for both human and animal infection. The highest hospital annual incidence o... | Cystic Echinococcosis (CE) is a parasitic infection whose natural domestic cycle develops between dogs and sheep (and other livestock). Human infection is endemic in pastoral communities, where close contact with the dog-sheep cycle occurs. In humans, as well as in livestock, the parasite develops as fluid-filled cyst ... | Cystic Echinococcosis (CE) is a globally distributed parasitic zoonosis, caused by the larval stage of the dog tapeworm Echinococcus granulosus sensu lato. Its life cycle develops between the dog (and other canids), which is the definitive host harbouring the adult parasites in the intestine, and the sheep (and other u... |
10.1371/journal.pmed.1002170 | Exposure Patterns Driving Ebola Transmission in West Africa: A Retrospective Observational Study | The ongoing West African Ebola epidemic began in December 2013 in Guinea, probably from a single zoonotic introduction. As a result of ineffective initial control efforts, an Ebola outbreak of unprecedented scale emerged. As of 4 May 2015, it had resulted in more than 19,000 probable and confirmed Ebola cases, mainly i... | Knowing how and from whom individuals acquire infection can help inform the response to limit the impact of an epidemic; this study presents updated versions of analyses initially performed to assist the international response during the 2013–2016 Ebola epidemic in West Africa.
Over 19,000 individuals with confirmed or... | The ongoing West African Ebola epidemic began in December 2013 in Guinea, probably from a single zoonotic introduction [1,2]. As a result of ineffective initial control efforts, an Ebola outbreak of unprecedented scale emerged. As of 4 May 2015, it had resulted in more than 19,000 probable and confirmed Ebola cases, ma... |
10.1371/journal.pcbi.1006397 | Methods for computing the maximum performance of computational models of fMRI responses | Computational neuroimaging methods aim to predict brain responses (measured e.g. with functional magnetic resonance imaging [fMRI]) on the basis of stimulus features obtained through computational models. The accuracy of such prediction is used as an indicator of how well the model describes the computations underlying... | Encoding computational models in brain responses measured with fMRI allows testing the algorithmic representations carried out by the neural population within voxels. The accuracy of a model in predicting new responses is used as a measure of the brain validity of the computational model being tested, but the result of... | Computational modelling approaches applied to functional magnetic resonance imaging (fMRI) measurements aim to explain and predict the brain responses by expressing them as a function of model features that describe the sensory (or cognitive) stimuli [1–5]. By doing so, computational neuroimaging methods have been prop... |
10.1371/journal.ppat.1004817 | Hepatitis C Virus RNA Replication Depends on Specific Cis- and Trans-Acting Activities of Viral Nonstructural Proteins | Many positive-strand RNA viruses encode genes that can function in trans, whereas other genes are required in cis for genome replication. The mechanisms underlying trans- and cis-preferences are not fully understood. Here, we evaluate this concept for hepatitis C virus (HCV), an important cause of chronic liver disease... | RNA viruses encode one or more proteins that form an RNA replicase, which serves to propagate the viral RNA genome. Some replication genes can function in trans, meaning that proteins expressed by one viral genome can complement and assist in the replication of a defective mutant virus within the same cell. Other viral... | The low-fidelity of RNA virus replication gives rise to swarms of mutant variants [1], which can genetically interact with one another. Mutant viruses may complement or inhibit one another in trans, with important consequences on virus evolution, pathogenesis, and the emergence of drug-resistance [2–5]. For instance, s... |
10.1371/journal.pcbi.1000721 | The Impact of Contact Tracing in Clustered Populations | The tracing of potentially infectious contacts has become an important part of the control strategy for many infectious diseases, from early cases of novel infections to endemic sexually transmitted infections. Here, we make use of mathematical models to consider the case of partner notification for sexually transmitte... | There are multiple ways to control infectious diseases—vaccination and drugs such as antibiotics or anti-virals form part of the pharmaceutical approach, however another route is to stop people infecting each other. This can be done either through general efforts to reduce epidemiologically relevant contacts, or throug... | Modelling has become a central tool in understanding the epidemiology of infectious disease, and designing control strategies. One control method, contact tracing, has been considered in a large number of disease contexts. These include the 2003 SARS pandemic [1],[2], the 2001 UK FMD epidemic [3]–[6], contingency plann... |
10.1371/journal.pcbi.1002048 | Quantitative Epistasis Analysis and Pathway Inference from Genetic Interaction Data | Inferring regulatory and metabolic network models from quantitative genetic interaction data remains a major challenge in systems biology. Here, we present a novel quantitative model for interpreting epistasis within pathways responding to an external signal. The model provides the basis of an experimental method to de... | Cells have evolved elaborate pathways that allow them to optimally use available nutrients, for example, and alter gene expression in response to external challenges. The mapping of these pathways provides an understanding of cell function critical for advancements in a number of fields, from biofuel production to drug... | Inferring biological pathways and gene networks from measurements of genotype-phenotype relationships has been a central problem in genetics research for decades [1], [2]. These relationships represent the basic building blocks of biological network models, and underpin much of our knowledge about genes and their funct... |
10.1371/journal.pntd.0002026 | Increasing Incidence of Plasmodium knowlesi Malaria following Control of P. falciparum and P. vivax Malaria in Sabah, Malaysia | The simian parasite Plasmodium knowlesi is a common cause of human malaria in Malaysian Borneo and threatens the prospect of malaria elimination. However, little is known about the emergence of P. knowlesi, particularly in Sabah. We reviewed Sabah Department of Health records to investigate the trend of each malaria sp... | The simian parasite Plasmodium knowlesi is a common cause of malaria in Malaysian Borneo; however, little is known about its emergence over time, particularly in Sabah. We reviewed all available Sabah Department of health malaria notification records from 1992–2011, and considered notifications of P. malariae and P. kn... | Malaria elimination is now a goal of many countries in Southeast Asia and the Western Pacific, and large reductions in malaria prevalence have been achieved [1]. However, significant challenges remain, and while the threat of artemisinin resistance has been the focus of much international concern, zoonotic malaria spec... |
10.1371/journal.pgen.1000258 | Bidirectional Transcription Directs Both Transcriptional Gene Activation and Suppression in Human Cells | Small RNAs targeted to gene promoters in human cells have been shown to modulate both transcriptional gene suppression and activation. However, the mechanism involved in transcriptional activation has remained poorly defined, and an endogenous RNA trigger for transcriptional gene silencing has yet to be identified. Des... | Non-coding RNAs have been shown to modulate transcriptional expression of genes in human cells. This form of gene regulation has been shown to be the result of RNA directing silent state epigenetic changes to the targeted gene promoter. Shortly after this seminal observation, small RNAs targeted to AT-rich regions of g... | Over the past few years it has become increasingly apparent that many RNA-mediated modes of gene regulation are operative in biological systems [1]. It is only now becoming appreciated just how pervasive this network is and to what extent it may be possible to apply this phenomenon for therapeutic benefit. Adding to th... |
10.1371/journal.pntd.0005902 | Use of rhodamine B to mark the body and seminal fluid of male Aedes aegypti for mark-release-recapture experiments and estimating efficacy of sterile male releases | Recent interest in male-based sterile insect technique (SIT) and incompatible insect technique (IIT) to control Aedes aegypti and Aedes albopictus populations has revealed the need for an economical, rapid diagnostic tool for determining dispersion and mating success of sterilized males in the wild. Previous reports fr... | The recent resurgence in male-based “rear and release” strategies (release of radiation sterilised males or those harbouring Wolbachia) to control diseases transmitted by urban Aedes mosquitoes, including dengue, chikungunya, and Zika, has revealed the need for an economical and rapid diagnostic tool to assess the mati... | Knowledge of key entomological parameters that contribute to the transmission of mosquito-borne diseases such as dispersal range, blood-feeding rates, population size, survival, and length of gonotrophic cycles is invaluable for understanding disease transmission dynamics and for determining the extent of control measu... |
10.1371/journal.pntd.0001179 | Economic Impact of Cystic Echinococcosis in Peru | Cystic echinococcosis (CE) constitutes an important public health problem in Peru. However, no studies have attempted to estimate the monetary and non-monetary impact of CE in Peruvian society.
We used official and published sources of epidemiological and economic information to estimate direct and indirect costs assoc... | Cystic echinococcosis (CE), caused by infection with the larval stage of the cestode Echinococcus granulosus, constitutes an important public health problem in Peru. Despite its high prevalence in endemic communities no studies have attempted to estimate the economic impact of CE in Peruvian society. We used official a... | Cystic echinococcosis (CE) is caused by infection with the larval stage of the cestode Echinococcus granulosus. CE has a cosmopolitan distribution and is an important public health problem in sheep-raising areas of South America [1]. CE has a serious impact on human health and livestock production in Peru as demonstrat... |
10.1371/journal.pcbi.1007242 | Uncertainty reduction in biochemical kinetic models: Enforcing desired model properties | A persistent obstacle for constructing kinetic models of metabolism is uncertainty in the kinetic properties of enzymes. Currently, available methods for building kinetic models can cope indirectly with uncertainties by integrating data from different biological levels and origins into models. In this study, we use the... | Kinetic models are the most promising tool for understanding the complex dynamic behavior of living cells. The primary goal of kinetic models is to capture the properties of the metabolic networks as a whole, and thus we need large-scale models for dependable in silico analyses of metabolism. However, uncertainty in ki... | Kinetic models are one of the cornerstones of rational metabolic engineering as they allow us to capture the dynamic behavior of metabolism and to predict dynamic responses of living organisms to genetic and environmental changes. With reliable kinetic models, metabolic engineering and synthetic biology strategies for ... |
10.1371/journal.pcbi.1006778 | Computational design of improved standardized chemotherapy protocols for grade II oligodendrogliomas | Here we put forward a mathematical model describing the response of low-grade (WHO grade II) oligodendrogliomas (LGO) to temozolomide (TMZ). The model describes the longitudinal volumetric dynamics of tumor response to TMZ of a cohort of 11 LGO patients treated with TMZ. After finding patient-specific parameters, diffe... | We developed a mathematical model describing the longitudinal volumetric growth data of grade II oligodendroglioma patients and their response to temozolomide. The model was used to explore alternative therapeutic protocols for the in-silico twins of the patients and in virtual clinical trials. The simulations show tha... | Oligodendrogliomas are low-incidence glial tumors, affecting mostly young adults. They are slowly growing, infiltrative tumors with isocitrate dehydrogenase 1 or 2 mutations and codeletion of chromosomal arms 1p and 19q. Grade II oligodendrogliomas (LGOs) are well differentiated tumors with a low mitotic index [1]. In ... |
10.1371/journal.pbio.1001247 | Structural and Functional Loss in Restored Wetland Ecosystems | Wetlands are among the most productive and economically valuable ecosystems in the world. However, because of human activities, over half of the wetland ecosystems existing in North America, Europe, Australia, and China in the early 20th century have been lost. Ecological restoration to recover critical ecosystem servi... | Wetlands, which include tropical mangroves and boreal peatlands, are among the most valuable ecosystems in the world because they provide critical ecosystem goods and services, such as carbon storage, biodiversity conservation, fish production, water purification, and erosion control. As global change accelerates the l... | From tropical mangroves to boreal peatlands, wetlands are amongst the most productive and economically valuable ecosystems in the world [1]. They provide critical ecosystem goods and services, including carbon storage, biodiversity conservation, fish production, fuel production, water purification, flood and shoreline ... |
10.1371/journal.ppat.1002911 | The Cyclase-Associated Protein Cap1 Is Important for Proper Regulation of Infection-Related Morphogenesis in Magnaporthe oryzae | Surface recognition and penetration are critical steps in the infection cycle of many plant pathogenic fungi. In Magnaporthe oryzae, cAMP signaling is involved in surface recognition and pathogenesis. Deletion of the MAC1 adenylate cyclase gene affected appressorium formation and plant infection. In this study, we used... | In Magnaporthe oryzae, cAMP signaling is known to play an important role in surface recognition and plant penetration. The Mac1 adenylate cyclase is essential for plant infection. To better understand Mac1 activation mechanisms, in this study we used the affinity purification approach to identify proteins that are asso... | Magnaporthe oryzae, a heterothallic ascomycete, is the causal agent of rice blast, which is one of the most destructive diseases of rice in the world. It infects the rice plant in a manner typical of many foliar pathogens. Germ tubes differentiate into specialized infection structures called appressoria. The fungus gen... |
10.1371/journal.ppat.1000848 | Cryptococcus neoformans Overcomes Stress of Azole Drugs by Formation of Disomy in Specific Multiple Chromosomes | Cryptococcus neoformans is a haploid environmental organism and the major cause of fungal meningoencephalitis in AIDS patients. Fluconazole (FLC), a triazole, is widely used for the maintenance therapy of cryptococcosis. Heteroresistance to FLC, an adaptive mode of azole resistance, was associated with FLC therapy fail... | Cryptococcus neoformans is an environmental fungus that causes life threatening brain disease, primarily in AIDS patients. The disease is estimated to claim 700,000 lives annually world-wide but most heavily in Africa. Fluconazole (FLC), a fungistatic antifungal drug, is commonly used to treat patients for long term ma... | Cryptococcus neoformans is the most common cause of fungal meningoencephalitis world-wide. A major predisposing factor is the profound cellular immune defect caused by HIV infection or other underlying conditions. Cryptococcal meningoencephalitis is fatal unless treated and even with the most advanced treatment it is k... |
10.1371/journal.ppat.1000871 | Keratinocytes Determine Th1 Immunity during Early Experimental Leishmaniasis | Experimental leishmaniasis is an excellent model system for analyzing Th1/Th2 differentiation. Resistance to Leishmania (L.) major depends on the development of a L. major specific Th1 response, while Th2 differentiation results in susceptibility. There is growing evidence that the microenvironment of the early affecte... | To clear skin infections with the parasite Leishmania major, a specific T-helper (Th)-cell immune response has to be generated. The type of Th-cell response is determined early after infection by yet unknown mechanisms. In resistant mice a Th1-pattern is generated. A Th2-pattern in BALB/c mice, however, results in susc... | Experimental leishmaniasis has been the first model to directly demonstrate the relevance of the T helper 1/T helper 2 (Th1/Th2) dichotomy for the outcome of an infection or disease in vivo. Upon cutaneous infection with L. major, C57BL/6 mice generate a Th1 response and subsequently control infection, mainly due to ac... |
10.1371/journal.ppat.1003999 | Interferon Regulatory Factor-1 Protects from Fatal Neurotropic Infection with Vesicular Stomatitis Virus by Specific Inhibition of Viral Replication in Neurons | The innate immune system protects cells against invading viral pathogens by the auto- and paracrine action of type I interferon (IFN). In addition, the interferon regulatory factor (IRF)-1 can induce alternative intrinsic antiviral responses. Although both, type I IFN and IRF-1 mediate their antiviral action by inducin... | IRFs are a family of transcription factors that play a key role in viral defense. Apart from their function in the adaptive immune system, recent work revealed that several IRFs contribute to antiviral response independent of secreted IFN. IRFs have been developed earlier in evolution than IFN and are regarded as precu... | The rapid production of type I Interferon (IFN) in response to a viral attack serves as a crucial antiviral defense mechanism in mammals [1]–[3]. The type I IFN response to invading pathogens is a biphasic phenomenon. First, the detection of RNA viruses occurs through the recognition of pathogen associated molecular pa... |
10.1371/journal.ppat.1000514 | NFATc1 Mediates Toll-Like Receptor-Independent Innate Immune Responses during Trypanosoma cruzi Infection | Host defense against the intracellular protozoan parasite Trypanosoma cruzi depends on Toll-like receptor (TLR)-dependent innate immune responses. Recent studies also suggest the presence of TLR-independent responses to several microorganisms, such as viruses, bacteria, and fungi. However, the TLR-independent responses... | Trypanosoma cruzi is an intracellular protozoan parasite that causes Chagas diseases in humans. Invasion of T. cruzi into the host is sensed by Toll-like receptors (TLRs), which recognize microbial components that are present in microbes but not in the host. TLRs are essential for the initiation of immune responses aga... | The host defense against invasion of intracellular pathogens relies on Th1 cell-derived IFN-γ that activates macrophages to kill the engulfed pathogens [1]. Toll-like receptor (TLR)-mediated recognition of pathogens has been established to induce activation of innate immune cells such as dendritic cells (DCs) and subse... |
10.1371/journal.pbio.1001101 | Ligand Activation of the Prokaryotic Pentameric Ligand-Gated Ion Channel ELIC | While the pentameric ligand-gated ion channel ELIC has recently provided first insight into the architecture of the family at high resolution, its detailed investigation was so far prevented by the fact that activating ligands were unknown. Here we describe a study on the functional characterization of ELIC by electrop... | Electrical signal transduction at chemical synapses of nerve and muscle cells is initiated by the binding of neurotransmitters to their receptors, which function as gated ion channels that open a selective ion conduction path in the ligand-bound state. The pentameric ligand-gated ion channels constitute a very importan... | The pentameric ligand-gated ion channels (pLGICs) constitute a large family of ionotropic neurotransmitter receptors that are ubiquitously expressed in the animal kingdom. In vertebrates the family encompasses cation selective serotonin and nicotinic acetylcholine receptors (nAChRs) and anion selective GABA and glycine... |
10.1371/journal.pgen.1007086 | AtHKT1 drives adaptation of Arabidopsis thaliana to salinity by reducing floral sodium content | Arabidopsis thaliana high-affinity potassium transporter 1 (AtHKT1) limits the root-to-shoot sodium transportation and is believed to be essential for salt tolerance in A. thaliana. Nevertheless, natural accessions with ‘weak allele’ of AtHKT1, e.g. Tsu-1, are mainly distributed in saline areas and are more tolerant to... | Identifying the genetic variation driving plant adaptation to salinity is critical for understanding natural selection and evolutionary mechanisms. In this study, we have revealed that the gene AtHKT1 drives natural variation in the adaptation of A. thaliana to salinity. Our evidences directly show that the AtHKT1 alle... | Although plants are sessile and are passively exposed to varying environments, they can successfully complete their life cycle and disperse across a range of environmental conditions. These capabilities are attributable to their physiological plastic and complex gene regulation networks, as well as to their affluent ge... |
10.1371/journal.pcbi.1006156 | Firing-rate based network modeling of the dLGN circuit: Effects of cortical feedback on spatiotemporal response properties of relay cells | Visually evoked signals in the retina pass through the dorsal geniculate nucleus (dLGN) on the way to the visual cortex. This is however not a simple feedforward flow of information: there is a significant feedback from cortical cells back to both relay cells and interneurons in the dLGN. Despite four decades of experi... | On route from the retina to primary visual cortex, visually evoked signals have to pass through the dorsal lateral geniculate nucleus (dLGN). However, this is not an exclusive feedforward flow of information as feedback exists from neurons in the cortex back to both relay cells and interneurons in the dLGN. The functio... | Visually evoked signals pass the dorsal geniculate nucleus (dLGN) on the route from retina to primary visual cortex in the early visual pathway. This is however not a simple feedforward flow of information, as there is a significant feedback from primary visual cortex back to dLGN. Cortical cells feed back to both rela... |
10.1371/journal.pntd.0007302 | The role of perceptions and knowledge of leprosy in the elimination of leprosy: A baseline study in Fatehpur district, northern India | With the introduction of new interventions to prevent leprosy, such as post-exposure prophylaxis (PEP) given to contacts of leprosy patients, it is necessary to update our understanding of knowledge and perception of leprosy among the populations where these interventions will be introduced, in order to tailor communic... | With the introduction of new interventions to prevent leprosy, such as post-exposure prophylaxis (PEP) given to contacts of leprosy patients, it is necessary to update our understanding of knowledge and perception of leprosy among the populations where these interventions will be introduced, in order to tailor communic... | Leprosy is an infectious disease caused by Mycobacterium leprae. Leprosy primarily affects the peripheral nerves and skin. The damage of the nerves may affect the sensory, motor and autonomic functions of the nerves, resulting ultimately in disability [1,2]. In addition to the physical consequences of leprosy, social s... |
10.1371/journal.pntd.0005752 | Different but overlapping populations of Strongyloides stercoralis in dogs and humans—Dogs as a possible source for zoonotic strongyloidiasis | Strongyloidiasis is a much-neglected soil born helminthiasis caused by the nematode Strongyloides stercoralis. Human derived S. stercoralis can be maintained in dogs in the laboratory and this parasite has been reported to also occur in dogs in the wild. Some authors have considered strongyloidiasis a zoonotic disease ... | Infections of humans with the nematode Strongyloides stercoralis can persist for a very long time, due to the capacity of this pathogen to undergo an autoinfective life cycle and re-infect the same host over and over again. Clinical manifestation, known as human stongyloidiasis, may be fatal and can arise many years an... | Soil-transmitted helminthiasis (STH) affects up to one in four individuals in the world, disproportionately impacting impoverished populations with less access to clean water, sanitation, and opportunities for socioeconomic development [1]. Strongyloidiasis is one of the most neglected tropical diseases [2,3]. Estimate... |
10.1371/journal.pmed.1002360 | Community burden of undiagnosed HIV infection among adolescents in Zimbabwe following primary healthcare-based provider-initiated HIV testing and counselling: A cross-sectional survey | Children living with HIV who are not diagnosed in infancy often remain undiagnosed until they present with advanced disease. Provider-initiated testing and counselling (PITC) in health facilities is recommended for high-HIV-prevalence settings, but it is unclear whether this approach is sufficient to achieve universal ... | In Zimbabwe, older children are rarely tested for HIV, and thus, they do not access the care they need.
For 2 years in 7 clinics in Harare, every child aged 6–15 years who came into the clinic was offered an HIV test.
The aim of this study was to find out how effective the clinic testing had been in finding undiagnosed... | Worldwide, an estimated 1.8 million children under the age of 15 years are living with HIV, 90% of them in sub-Saharan Africa [1]. The incidence of HIV infection in infants has fallen substantially over the past decade because of the scale-up of interventions for prevention of mother-to-child HIV transmission (PMTCT), ... |
10.1371/journal.pcbi.1004218 | Measuring Fisher Information Accurately in Correlated Neural Populations | Neural responses are known to be variable. In order to understand how this neural variability constrains behavioral performance, we need to be able to measure the reliability with which a sensory stimulus is encoded in a given population. However, such measures are challenging for two reasons: First, they must take int... | A central problem in systems neuroscience is to understand how the activity of neural populations is mapped onto behavior. Neural responses in sensory areas vary substantially upon repeated presentations of the same stimulus, and this limits the reliability with which two similar stimuli can be discriminated by any rea... | The advent of technical advances like multi-electrode recordings and calcium imaging allows the simultaneous recording of an ever increasing number of neurons. The availability of this data allows us to explore not only the qualitative properties of the neural code but also the reliability of coding.
One challenge of ... |
10.1371/journal.pntd.0002605 | Scrub Typhus Is an Under-recognized Cause of Acute Febrile Illness with Acute Kidney Injury in India | Infection-related acute kidney injury (AKI) is an important preventable cause of morbidity and mortality in the tropical region. The prevalence and outcome of kidney involvement, especially AKI, in scrub typhus is not known. We investigated all patients with undiagnosed fever and multisystem involvement for scrub typhu... | A large number of patients present to Indian hospitals with acute febrile illness and multisystem involvement. Acute kidney injury is an important component. Clinical manifestations do not allow distinction between infectious etiologies with overlapping presentations. Many of the cases remain undiagnosed and therefore ... | Infections are responsible for a substantial portion of community acquired acute kidney injury (AKI) in India. The commonly implicated conditions include malaria, leptospirosis, dengue, enteric fever, viral and bacterial infections. Despite being endemic in Asia with an estimated one million cases occurring annually, s... |
10.1371/journal.pntd.0001525 | Actigraphy in Human African Trypanosomiasis as a Tool for Objective Clinical Evaluation and Monitoring: A Pilot Study | Human African trypanosomiasis (HAT) or sleeping sickness leads to a complex neuropsychiatric syndrome with characteristic sleep alterations. Current division into a first, hemolymphatic stage and second, meningoencephalitic stage is primarily based on the detection of white blood cells and/or trypanosomes in the cerebr... | The clinical picture of the parasitic disease human African trypanosomiasis (HAT, also called sleeping sickness) is dominated by sleep alterations. We here used actigraphy to evaluate patients affected by the Gambiense form of HAT. Actigraphy is based on the use of battery-run, wrist-worn devices similar to watches, wi... | Human African trypanosomiasis (HAT), commonly known as sleeping sickness, is caused by subspecies of the protozoan parasite Trypanosoma brucei (T.b.) and transmitted by tsetse fly bites in sub-Saharan Africa. This disease, which mainly affects rural populations, is one of the most neglected tropical diseases, and is fa... |
10.1371/journal.pcbi.1000861 | G-Quadruplex DNA Sequences Are Evolutionarily Conserved and Associated with Distinct Genomic Features in Saccharomyces cerevisiae | G-quadruplex DNA is a four-stranded DNA structure formed by non-Watson-Crick base pairing between stacked sets of four guanines. Many possible functions have been proposed for this structure, but its in vivo role in the cell is still largely unresolved. We carried out a genome-wide survey of the evolutionary conservati... | DNA can form structures other than the traditional double helix. The G-quadruplex, a stable four-stranded structure formed by guanine-rich DNA, is one such alternative structure. Sequence motifs with the potential to form G-quadruplex structures (G4 DNA motifs) are found in the genomes of many species. However, since s... | DNA primarily exists as a double helix. However, DNA can also adopt other structural conformations that have the potential to play critical roles in a range of biological processes. One such structure is G-quadruplex DNA (G4 DNA structure), which was discovered in the late 1980s when biochemical experiments demonstrate... |
10.1371/journal.ppat.1005531 | Reversal of the Progression of Fatal Coronavirus Infection in Cats by a Broad-Spectrum Coronavirus Protease Inhibitor | Coronaviruses infect animals and humans causing a wide range of diseases. The diversity of coronaviruses in many mammalian species is contributed by relatively high mutation and recombination rates during replication. This dynamic nature of coronaviruses may facilitate cross-species transmission and shifts in tissue or... | Coronaviruses are important pathogens in humans and animals. Although some coronaviruses can cause severe illness in humans and animals with considerable fatality, there is no antiviral drugs available for coronavirus infections. Feline infectious peritonitis (FIP), caused by virulent feline coronavirus, is the leading... | Coronaviruses comprise a large family of RNA viruses that infect a wide variety of mammalian and avian hosts causing a broad spectrum of diseases. Coronaviruses have a single-stranded, positive-sense RNA genome and are classified into four genera of alpha-, beta-, gamma-, and deltacoronaviruses [1]. Coronaviruses are p... |
10.1371/journal.pgen.1005905 | SPARC Promotes Cell Invasion In Vivo by Decreasing Type IV Collagen Levels in the Basement Membrane | Overexpression of SPARC, a collagen-binding glycoprotein, is strongly associated with tumor invasion through extracellular matrix in many aggressive cancers. SPARC regulates numerous cellular processes including integrin-mediated cell adhesion, cell signaling pathways, and extracellular matrix assembly; however, the me... | SPARC is an extracellular matrix protein that is present at high levels in many metastatic cancers where it promotes tumor invasion into neighboring tissues. The mechanism linking a surplus of SPARC to cell invasion, however, is not clear due to the challenge of examining SPARCs function in complex tumor environments. ... | Cell invasion through extracellular matrix (ECM) is a critical step in the progression of many diseases including cancer metastasis [1,2]. Basement membrane (BM), a dense, sheet-like form of ECM that surrounds most tissues, poses a significant barrier for invasive cells [3]. Although traditionally thought of as a stati... |
10.1371/journal.ppat.1007906 | Controlled human malaria infection with Plasmodium falciparum demonstrates impact of naturally acquired immunity on virulence gene expression | The pathogenesis of Plasmodium falciparum malaria is linked to the variant surface antigen PfEMP1, which mediates tethering of infected erythrocytes to the host endothelium and is encoded by approximately 60 var genes per parasite genome. Repeated episodes of malaria infection result in the gradual acquisition of prote... | Parasites of the species Plasmodium falciparum are responsible for the most severe form of malaria, particularly affecting children under the age of five years, and escape from the human immune response by antigenic variation. This is achieved by alteration of the host cell surface exposed protein PfEMP1, which tethers... | The virulence of the malaria parasite Plasmodium falciparum has been linked to the ability of infected erythrocytes to adhere to a range of cell surface molecules expressed on the vascular endothelium. This phenomenon, known as sequestration, prevents the passage of infected erythrocytes through the spleen, which would... |
10.1371/journal.pntd.0005317 | Spatial Analysis of Dengue Seroprevalence and Modeling of Transmission Risk Factors in a Dengue Hyperendemic City of Venezuela | Dengue virus (DENV) transmission is spatially heterogeneous. Hence, to stratify dengue prevalence in space may be an efficacious strategy to target surveillance and control efforts in a cost-effective manner particularly in Venezuela where dengue is hyperendemic and public health resources are scarce. Here, we determin... | Dengue is a mosquito-borne viral disease of global impact. In Venezuela, dengue is endemic with the co-circulation of the 4 viral serotypes and has become one of the most important public health problems of urban areas. During 2010 and 2011, a baseline cross-sectional study was carried out as part of a dengue prospecti... | The incidence of dengue, a vector-borne viral disease, has risen markedly in the last decades affecting more than half of the world’s population [1]. According to a recent study, 390 million dengue infections are estimated to occur annually [2]. Dengue and its vectors have spread into previously unaffected areas and pr... |
10.1371/journal.pcbi.1006400 | Interactive reservoir computing for chunking information streams | Chunking is the process by which frequently repeated segments of temporal inputs are concatenated into single units that are easy to process. Such a process is fundamental to time-series analysis in biological and artificial information processing systems. The brain efficiently acquires chunks from various information ... | Varieties of information processing require chunking, but chunking arbitrary complex sequences as flexibly as the brain does remains a challenge. In this study, we solved this important but difficult problem of chunking by "reservoir computing" inferred from brain computation. In the method, chunking occurs automatical... | When a sequence of stimuli is repeated, they may be segmented into “chunks,” which are then processed and stored as discrete units. This process, called “chunking” or "bracketing" [1], takes place during various cognitive behaviors that require hierarchical sequence processing [2–5]. For instance, in motor learning, a ... |
10.1371/journal.pntd.0000659 | A Target-Based High Throughput Screen Yields Trypanosoma brucei Hexokinase Small Molecule Inhibitors with Antiparasitic Activity | The parasitic protozoan Trypanosoma brucei utilizes glycolysis exclusively for ATP production during infection of the mammalian host. The first step in this metabolic pathway is mediated by hexokinase (TbHK), an enzyme essential to the parasite that transfers the γ-phospho of ATP to a hexose. Here we describe the ident... | African sleeping sickness is a disease found in sub-Saharan Africa that is caused by the single-celled parasite Trypanosoma brucei. The drugs used widely now to treat infections are 50 years old and notable for their toxicity, emphasizing the need for development of new therapeutics. In the search for potential drug ta... | African sleeping sickness conjures historical images of disease-induced fatal slumbering striking down men, women, and children, consequently decimating villages of colonial Africa. Unfortunately, people living in many countries of sub-Saharan Africa today know that African sleeping sickness is not a disease of history... |
10.1371/journal.pcbi.1000336 | Natural Image Coding in V1: How Much Use Is Orientation Selectivity? | Orientation selectivity is the most striking feature of simple cell coding in V1 that has been shown to emerge from the reduction of higher-order correlations in natural images in a large variety of statistical image models. The most parsimonious one among these models is linear Independent Component Analysis (ICA), wh... | Since the Nobel Prize winning work of Hubel and Wiesel it has been known that orientation selectivity is an important feature of simple cells in the primary visual cortex. The standard description of this stage of visual processing is that of a linear filter bank where each neuron responds to an oriented edge at a cert... | It is a long standing hypothesis that neural representations in sensory systems are adapted to the statistical regularities of the environment [1],[2]. Despite widespread agreement that neural processing in the early visual system must be influenced by the statistics of natural images, there are many different viewpoin... |
10.1371/journal.pcbi.1007329 | Predicting gene expression in the human malaria parasite Plasmodium falciparum using histone modification, nucleosome positioning, and 3D localization features | Empirical evidence suggests that the malaria parasite Plasmodium falciparum employs a broad range of mechanisms to regulate gene transcription throughout the organism’s complex life cycle. To better understand this regulatory machinery, we assembled a rich collection of genomic and epigenomic data sets, including infor... | The parasite responsible for the most lethal form of malaria, Plasmodium falciparum, employs a variety of mechanisms to modify the expression of its genes throughout its complex life cycle. In this work, we gather a rich collection of data describing various aspects of the gene regulatory apparatus in P. falciparum, an... | Plasmodium falciparum is the deadliest species of malaria parasite, responsible for 445,000 deaths in 2016 [1]. As resistance to antimalarial drugs spreads, demand for novel antimalarials increases. Designing such novel drugs would require an improved understanding of the biology of this parasite. Currently, one of the... |
10.1371/journal.pgen.1006693 | Joint genetic analysis using variant sets reveals polygenic gene-context interactions | Joint genetic models for multiple traits have helped to enhance association analyses. Most existing multi-trait models have been designed to increase power for detecting associations, whereas the analysis of interactions has received considerably less attention. Here, we propose iSet, a method based on linear mixed mod... | Genetic effects on phenotypes can depend on external contexts, including environment. Statistical tests for identifying such interactions are important to understand how individual genetic variants may act in different contexts. Interaction effects can either be studied using measurements of a given phenotype in differ... | Understanding genetic interactions with external context (GxC), including environment, is a major challenge in quantitative genetics. Linear mixed models (LMMs) have emerged as the framework of choice for many genetic analyses, mainly because the random effect component in this class of models provides robust control f... |
10.1371/journal.pntd.0001711 | Impact of PGL-I Seropositivity on the Protective Effect of BCG Vaccination among Leprosy Contacts: A Cohort Study | Contacts of leprosy patients are at increased risk of developing leprosy and need to be targeted for early diagnosis. Seropositivity to the phenolic glycolipid I (PGL-I) antigen of Mycobacterium leprae has been used to identify contacts who have an increased risk of developing leprosy. In the present study, we studied ... | Although leprosy has become a neglected disease, it is an important cause of disability, and 250,000 new cases are still diagnosed worldwide every year. The current study was carried out in Brazil, where almost 40,000 new cases of leprosy are diagnosed every year. The study targeted contacts of leprosy patients, who ar... | It was widely expected that the treatment of all newly diagnosed leprosy cases with multidrug therapy (MDT) would not only cure the disease but also prevent the further spread of Mycobacterium leprae (M. leprae). In fact, from 2004 to 2010, the number of newly diagnosed cases worldwide fell by 44%. Nonetheless, inciden... |
10.1371/journal.ppat.1004792 | Lipidomic Analysis Links Mycobactin Synthase K to Iron Uptake and Virulence in M. tuberculosis | The prolonged survival of Mycobacterium tuberculosis (M. tb) in the host fundamentally depends on scavenging essential nutrients from host sources. M. tb scavenges non-heme iron using mycobactin and carboxymycobactin siderophores, synthesized by mycobactin synthases (Mbt). Although a general mechanism for mycobactin bi... | M. tuberculosis (M. tb) survives only if it can acquire iron from its human host, so new therapies for tuberculosis might be discovered if the pathways necessary for iron acquisition are identified. M. tb scavenges iron in two ways: from free iron, or from the blood in the form of heme. To bind free iron, M. tb uses my... | Mycobacterium tuberculosis (M. tb), an obligate human pathogen, causes tuberculosis, typically through a decades-long infection. Long-term survival in the host necessitated the evolution of mechanisms for scavenging essential nutrients. Iron plays crucial roles in bacterial respiration and DNA synthesis, and its availa... |
10.1371/journal.ppat.1003981 | Human Genome-Wide RNAi Screen Identifies an Essential Role for Inositol Pyrophosphates in Type-I Interferon Response | The pattern recognition receptor RIG-I is critical for Type-I interferon production. However, the global regulation of RIG-I signaling is only partially understood. Using a human genome-wide RNAi-screen, we identified 226 novel regulatory proteins of RIG-I mediated interferon-β production. Furthermore, the screen ident... | The innate immune system is critical for viral infection control by host organisms. The type I interferons are a family of major antiviral cytokines produced upon the activation of innate immune pattern recognition receptors (PRRs) by viruses. The RIG-I is a major PRR that uniquely detects RNA viruses within the cytopl... | The innate immune system, a primordial yet highly organized defense mechanism, plays critical roles in the host response against RNA viruses. The first step in the innate immune response involves recognition of pathogen-associated molecular patterns by several host encoded pattern recognition receptors (PRR). A key med... |
10.1371/journal.pcbi.1003008 | An Integrated Computational/Experimental Model of Lymphoma Growth | Non-Hodgkin's lymphoma is a disseminated, highly malignant cancer, with resistance to drug treatment based on molecular- and tissue-scale characteristics that are intricately linked. A critical element of molecular resistance has been traced to the loss of functionality in proteins such as the tumor suppressor p53. We ... | Non-Hodgkin's lymphoma is a cancer that develops from white blood cells called lymphocytes in the immune system, whose role is to fight disease throughout the body. This cancer can spread throughout the whole body and be very lethal – in the US, one third of patients will die from this disease within five years of diag... | Monoclonal antibodies and small molecule inhibitors of intracellular targets are being developed alongside a host of anti-non-Hodgkin's lymphoma therapeutic options [1]. Yet the tumor tissue-scale effects from these molecular-scale manipulations are not well-understood. With the ultimate goal to more rationally optimiz... |
10.1371/journal.pcbi.1006743 | Sparse discriminative latent characteristics for predicting cancer drug sensitivity from genomic features | Drug screening studies typically involve assaying the sensitivity of a range of cancer cell lines across an array of anti-cancer therapeutics. Alongside these sensitivity measurements high dimensional molecular characterizations of the cell lines are typically available, including gene expression, copy number variation... | A core tenant of precision medicine is that treatment should be tailored to the patient. In the context of cancer, large-scale screens, assaying the sensitivity of many cell-lines to panels of drugs, have the potential to enable discovery of biomarkers of sensitivity to specific therapeutics. However, existing computat... | Several drug screening studies have assayed the sensitivity of a library of cancer cell lines to an array of anti-cancer compounds. Notable examples are the Cancer Cell Line Encyclopedia [1, CCLE], Genomics of Drug Sensitivity in Cancer [2, 3] the 2012 DREAM challenge [4, 5] and the Cancer Therapeutics Response Portal ... |
10.1371/journal.pntd.0004258 | Functional Analysis of the Unique Cytochrome P450 of the Liver Fluke Opisthorchis felineus | The basic metabolic cytochrome P450 (CYP) system is essential for biotransformation of sterols and xenobiotics including drugs, for synthesis and degradation of signaling molecules in all living organisms. Most eukaryotes including free-living flatworms have numerous paralogues of the CYP gene encoding heme monooxygena... | The basic metabolic system CYP (cytochrome P450) is essential for biotransformation of sterols and xenobiotics, for synthesis and degradation of signaling molecules in all living organisms. Most eukaryotes including free-living flatworms evolved numerous paralogues of the CYP gene. Notably, by contrast, flukes and tape... | The heme-containing enzymes cytochromes P450 (CYPs) are widely distributed in living organisms from bacteria to mammals [reviewed in Refs. 1, 2–3]. CYP enzymes act as components of a monooxygenase system; they display biological functions ranging from detoxification of environmental pollutants to synthesis and degradat... |
10.1371/journal.pgen.1002107 | Trade-Off between Bile Resistance and Nutritional Competence Drives Escherichia coli Diversification in the Mouse Gut | Bacterial diversification is often observed, but underlying mechanisms are difficult to disentangle and remain generally unknown. Moreover, controlled diversification experiments in ecologically relevant environments are lacking. We studied bacterial diversification in the mammalian gut, one of the most complex bacteri... | The mechanisms generating the huge biodiversity on earth are not entirely understood. Bacterial populations are powerful models to explore the mechanisms of evolution, owing to their big population size, rapid growth, and high mutation rate. One of the more complex bacterial community is the mammalian gut microbiota, a... | Understanding why there are so many species is a fundamental problem in evolutionary biology that is far from being understood. Numerous experimental evolution studies have shown that the amount of diversity that evolves from initially genetically uniform population increases as a function of environmental complexity, ... |
10.1371/journal.pgen.1006363 | Combined Use of Genome-Wide Association Data and Correlation Networks Unravels Key Regulators of Primary Metabolism in Arabidopsis thaliana | Plant primary metabolism is a highly coordinated, central, and complex network of biochemical processes regulated at both the genetic and post-translational levels. The genetic basis of this network can be explored by analyzing the metabolic composition of genetically diverse genotypes in a given plant species. Here, w... | Primary metabolites are key elements in plant growth and development. Our partial understanding of their biosynthesis and regulation derives mostly from biochemical and genetic modification experiments. The recent generation of large-scale genome-wide data, along with the advances in mass-spectrometry techniques, allow... | Plants produce a large array of structurally and biologically diverse metabolites. Largely due to the missing underlying biochemistry, the genes encoding metabolite-related enzymes or regulatory proteins are known for only a fraction of the metabolites. With the development of metabolomic and genomic tools, alternative... |
10.1371/journal.pgen.1007457 | A component of the TOR (Target Of Rapamycin) nutrient-sensing pathway plays a role in circadian rhythmicity in Neurospora crassa | The TOR (Target of Rapamycin) pathway is a highly-conserved signaling pathway in eukaryotes that regulates cellular growth and stress responses. The cellular response to amino acids or carbon sources such as glucose requires anchoring of the TOR kinase complex to the lysosomal/vacuolar membrane by the Ragulator (mammal... | Circadian clocks drive 24-hour rhythms in living things at all levels of organization, from single cells to whole organisms. In spite of the importance of daily clocks for organizing the activities and internal functions of organisms, there are still many unsolved problems concerning the molecular mechanisms. In eukary... | The TOR (Target of Rapamycin) pathway is a highly conserved cellular pathway in eukaryotes that monitors nutritional and stress signals from both extracellular and intracellular sources to regulate cellular growth, division, autophagy and stress responses. It has been extensively studied in mammals [1] and yeast [2]. I... |
10.1371/journal.ppat.1000326 | A Chromosomally Encoded Virulence Factor Protects the Lyme Disease Pathogen against Host-Adaptive Immunity | Borrelia burgdorferi, the bacterial pathogen of Lyme borreliosis, differentially expresses select genes in vivo, likely contributing to microbial persistence and disease. Expression analysis of spirochete genes encoding potential membrane proteins showed that surface-located membrane protein 1 (lmp1) transcripts were e... | The pathogen of Lyme borreliosis, Borrelia burgdorferi, causes disease in many parts of the world, resulting in multi-system complications in infected humans and animals. The microbe produces certain antigens in response to host environments that potentially allow it to persist and cause disease. Here, we analyzed the ... | Lyme borreliosis, caused by Borrelia burgdorferi sensu lato, is the most prevalent tick-borne human disease in the United States, Europe and many parts of Asia [1]. Once the pathogen is deposited in the mammalian dermis by feeding Ixodes ticks, it establishes a localized infection at the bite site, then disseminates to... |
10.1371/journal.ppat.1003232 | TIM-family Proteins Promote Infection of Multiple Enveloped Viruses through Virion-associated Phosphatidylserine | Human T-cell Immunoglobulin and Mucin-domain containing proteins (TIM1, 3, and 4) specifically bind phosphatidylserine (PS). TIM1 has been proposed to serve as a cellular receptor for hepatitis A virus and Ebola virus and as an entry factor for dengue virus. Here we show that TIM1 promotes infection of retroviruses and... | To infect cells, enveloped viruses typically utilize cellular receptors, which mediate specific, high-affinity interactions with the viral entry protein and prime the entry protein for subsequent steps in the viral entry process. Viral entry is also enhanced by attachment factors. Although less specific than receptors,... | The entry of enveloped viruses is a multi-stage process. Following attachment, some viruses fuse to cells at the plasma membrane, whereas others are internalized through various endocytic routes and, primed by low pH or compartment-resident factors, fuse at the endo/lysosomal membranes. Viruses attach to the cell surfa... |
10.1371/journal.ppat.1004417 | A Novel Function of Human Pumilio Proteins in Cytoplasmic Sensing of Viral Infection | RIG-I-like receptor (RLR) plays a pivotal role in the detection of invading pathogens to initiate type I interferon (IFN) gene transcription. Since aberrant IFN production is harmful, RLR signaling is strictly regulated. However, the regulatory mechanisms are not fully understood. By expression cloning, we identified P... | Mammals utilize innate immune system to counteract viral infections. The host pattern-recognition receptors, such as RIG-I-like receptors (RLRs), sense invading pathogens and initiate innate immune responses. RLRs are composed of three RNA helicases, RIG-I, MDA5 and LGP2, and detect a series of RNA viruses, such as inf... | The host innate immune system is the first line of defense against invading pathogens. Pattern-recognition receptors (PRRs) detect pathogen molecules, termed pathogen-associated molecular patterns (PAMPs), to initiate innate immune responses [1], [2], [3], [4], [5]. Viruses invade host cells to replicate their genome a... |
10.1371/journal.pntd.0007236 | The prevalence of Leptospira among invasive small mammals on Puerto Rican cattle farms | Leptospirosis, an emerging infectious disease caused by bacteria of the genus Leptospira, is thought to be the most widespread zoonotic disease in the world. A first step in preventing the spread of Leptospira is delineating the animal reservoirs that maintain and disperse the bacteria. Quantitative PCR (qPCR) methods ... | Leptospirosis is a global zoonotic disease that recently has shown an increase of human cases in many regions, Puerto Rico being one of them. To decrease human Leptospira infections it is necessary to ascertain the role of animal reservoirs to maintain the pathogen in the environment. However, no studies of wild mammal... | Along with increasing globalization, climate change, and urban expansion, the rising number of emerging infectious diseases is a major concern. Among emerging infectious diseases, over 60% are multi-host zoonoses many of which are classified as “neglected” owing to a general lack of knowledge about their epidemiology, ... |
10.1371/journal.ppat.1004339 | TLR2 Signaling Decreases Transmission of Streptococcus pneumoniae by Limiting Bacterial Shedding in an Infant Mouse Influenza A Co-infection Model | While the importance of transmission of pathogens is widely accepted, there is currently little mechanistic understanding of this process. Nasal carriage of Streptococcus pneumoniae (the pneumococcus) is common in humans, especially in early childhood, and is a prerequisite for the development of disease and transmissi... | In this study, we sought to identify factors contributing to the transmission of the bacterial pathogen Streptococcus pneumoniae (the pneumococcus), a major cause of otitis media, pneumonia, and septicemia. Often found as a co-infection with other bacterial and viral pathogens, the pneumococcus is commonly carried by y... | The bacterial pathogen Streptococcus pneumoniae (the pneumococcus) robustly colonizes the upper respiratory tract of humans and is commonly carried asymptomatically. Colonization rates are highest in early childhood, where they can exceed 80% [1]; in crowded environments such as daycare centers [2]; and when viral resp... |
10.1371/journal.ppat.1006231 | Structure of a pentameric virion-associated fiber with a potential role in Orsay virus entry to host cells | Despite the wide use of Caenorhabditis elegans as a model organism, the first virus naturally infecting this organism was not discovered until six years ago. The Orsay virus and its related nematode viruses have a positive-sense RNA genome, encoding three proteins: CP, RdRP, and a novel δ protein that shares no homolog... | Orsay, the only virus known to naturally infect the nematode Caenorhabditis elegans, expresses a capsid-δ fusion protein. We have demonstrated that the Orsay fusion protein is incorporated into Orsay capsid and forms a ~420-Å long fiber protruding from the capsid surface. Crystal structure of an N-terminal fragment of ... | For the past four decades, the nematode Caenorhabditis elegans (C. elegans) has been used as an important model organism for studying biological processes such as development, metabolism, aging, cell cycle and gene regulation [1]. However, it was not until the year 2011 that Orsay, the first virus that naturally infect... |
10.1371/journal.pcbi.1004322 | Changes in Postural Syntax Characterize Sensory Modulation and Natural Variation of C. elegans Locomotion | Locomotion is driven by shape changes coordinated by the nervous system through time; thus, enumerating an animal's complete repertoire of shape transitions would provide a basis for a comprehensive understanding of locomotor behaviour. Here we introduce a discrete representation of behaviour in the nematode C. elegans... | Technology for recording neural activity is advancing rapidly and whole-brain imaging with single neuron resolution has already been demonstrated for smaller animals. To interpret such complex neural recordings, we need comprehensive characterizations of behaviour, which is the principal output of the brain. Animal tra... | Animal behaviour can be difficult to study because it involves complex movements that vary continuously in time. This is especially true for limbed animals such as insects and mammals, because they have many degrees of freedom and can adopt an even larger number of different postures. Detailed characterization without ... |
10.1371/journal.pgen.1006408 | Dual Role of a SAS10/C1D Family Protein in Ribosomal RNA Gene Expression and Processing Is Essential for Reproduction in Arabidopsis thaliana | In eukaryotic cells, ribosomal RNAs (rRNAs) are transcribed, processed, and assembled with ribosomal proteins in the nucleolus. Regulatory mechanisms of rRNA gene (rDNA) transcription and processing remain elusive in plants, especially their connection to nucleolar organization. We performed an in silico screen for ess... | The rRNA regulatory network underlying the structure and function of the plant nucleolus is largely unknown. We identified a previously uncharacterized SAS10/C1D family protein THAL as a novel component important for both rRNA gene expression and processing, which further impacts nucleolar structure. thal-2 mutant had ... | The biogenesis of mature 5.8S, 18S, and 25S ribosomal RNAs (rRNAs) requires transcription of 45S rRNA genes (rDNA) and processing of 45S precursor rRNAs (pre-rRNAs) in the nucleolus [1]. The nucleolus is not enclosed by a membrane; its formation is driven by the active transcription of rDNA and structured by pre-rRNA p... |
10.1371/journal.pntd.0003448 | Tsetse GmmSRPN10 Has Anti-complement Activity and Is Important for Successful Establishment of Trypanosome Infections in the Fly Midgut | The complement cascade in mammalian blood can damage the alimentary tract of haematophagous arthropods. As such, these animals have evolved their own repertoire of complement-inactivating factors, which are inadvertently exploited by blood-borne pathogens to escape complement lysis. Unlike the bloodstream stages, the p... | Blood feeding arthropods are exploited by blood borne parasites as vectors of transmission. Trypanosoma brucei, a salivarian trypanosome species, must survive, migrate and differentiate in the tsetse until they become mature, mammalian-infective forms within the fly salivary glands. This constitutes a significant chall... | Mammalian blood constitutes a challenging source of nutrition, yet a multitude of arthropods have evolved to exploit this survival niche [1]. Besides developing physical and behavioural adaptations to evade their hosts, haematophagous arthropods have also adapted physiologically to ingest a food source that is relative... |
10.1371/journal.pgen.1001073 | Microtubule Actin Crosslinking Factor 1 Regulates the Balbiani Body and Animal-Vegetal Polarity of the Zebrafish Oocyte | Although of fundamental importance in developmental biology, the genetic basis for the symmetry breaking events that polarize the vertebrate oocyte and egg are largely unknown. In vertebrates, the first morphological asymmetry in the oocyte is the Balbiani body, a highly conserved, transient structure found in vertebra... | How the axes of the embryo are established is an important question in developmental biology. In many organisms, the axes of the embryo are established during oogenesis through the generation of a polarized egg. Very little is known regarding the mechanisms of polarity establishment and maintenance in vertebrate oocyte... | The animal-vegetal axis is the first axis to form in the vertebrate embryo; however, the cellular and genetic pathways by which it is specified are the least well understood. In lower vertebrates, such as frogs and fish, this axis forms during early oogenesis, while in mouse, it becomes apparent during oocyte maturatio... |
10.1371/journal.pcbi.1004028 | Inference of Quantitative Models of Bacterial Promoters from Time-Series Reporter Gene Data | The inference of regulatory interactions and quantitative models of gene regulation from time-series transcriptomics data has been extensively studied and applied to a range of problems in drug discovery, cancer research, and biotechnology. The application of existing methods is commonly based on implicit assumptions o... | A wide variety of methods for the reverse engineering of regulatory networks and the identification of quantitative regulation functions are available. We investigate some common assumptions that are made in the application of these methods to time-series transcriptomics data, in the context of a central module in the ... | DNA microarrays, RNA sequencing, and other high-throughput technologies yield huge amounts of data on the state of the transcriptional program in bacterial cells in different growth conditions and genetic backgrounds, at different time-points in an experiment. The information on the (relative) RNA abundances thus obtai... |
10.1371/journal.pntd.0006890 | Monitoring the elimination of human African trypanosomiasis: Update to 2016 | Human African trypanosomiasis (HAT) is a neglected tropical disease targeted for elimination ‘as a public health problem’ by 2020. The indicators to monitor progress towards the target are based on the number of reported cases, the related areas and populations exposed at various levels of risk, and the coverage of sur... | Human African trypanosomiasis (HAT), also known as sleeping sickness, is a rare disease today, but throughout the 20th century it has demonstrated its potential for devastating epidemics. Over the last twenty years, substantial efforts against HAT enabled to dramatically reduce its prevalence, and the disease is now ta... | Since the beginning of the 21st century, and following the reinforcement of control and surveillance activities against human African trypanosomiasis (HAT), the number of reported cases has been decreasing steadily [1, 2]. Control activities have been coordinated and implemented by National Sleeping Sickness Control Pr... |
10.1371/journal.pgen.1004265 | Parent-of-Origin Effects Implicate Epigenetic Regulation of Experimental Autoimmune Encephalomyelitis and Identify Imprinted Dlk1 as a Novel Risk Gene | Parent-of-origin effects comprise a range of genetic and epigenetic mechanisms of inheritance. Recently, detection of such effects implicated epigenetic mechanisms in the etiology of multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system. We here sought to dissect the magnitude and the ty... | Even with recent progress in determining the genetic basis of complex diseases, the issue of ‘missing heritability’ remains and its potential sources are frequently speculated about but rarely explained. Parent-of-origin effects might contribute to the ‘missing heritability’ and involve genetic and epigenetic mechanism... | Complex diseases, like common chronic inflammatory conditions, arise from an interplay between multiple risk genes and environmental factors. Etiology is often largely unknown with variable penetrance and expressivity making it difficult to identify contributing factors.
Epigenetic mechanisms might act at the interfac... |
10.1371/journal.pgen.1006120 | Expansion of GA Dinucleotide Repeats Increases the Density of CLAMP Binding Sites on the X-Chromosome to Promote Drosophila Dosage Compensation | Dosage compensation is an essential process that equalizes transcript levels of X-linked genes between sexes by forming a domain of coordinated gene expression. Throughout the evolution of Diptera, many different X-chromosomes acquired the ability to be dosage compensated. Once each newly evolved X-chromosome is target... | From stem cells to neurons, regulation of gene dosage is essential in all tissues and species in which it has been studied. Gene dosage must be balanced largely because it is critical to maintain the stoichiometry of components of multi-protein complexes that are encoded at diverse locations throughout the genome. The ... | Changes in primary DNA sequence that occur over evolutionary time alter transcription factor occupancy on DNA [1,2]. Differential occupancy of transcription factors throughout the genome controls the essential gene regulatory programs that define growth and development [3]. Sex chromosome dosage compensation is a key m... |
10.1371/journal.ppat.1000721 | Marburg Virus Evades Interferon Responses by a Mechanism Distinct from Ebola Virus | Previous studies have demonstrated that Marburg viruses (MARV) and Ebola viruses (EBOV) inhibit interferon (IFN)-α/β signaling but utilize different mechanisms. EBOV inhibits IFN signaling via its VP24 protein which blocks the nuclear accumulation of tyrosine phosphorylated STAT1. In contrast, MARV infection inhibits I... | The closely related members of the filovirus family, Ebola virus (EBOV) and Marburg virus (MARV), cause severe hemorrhagic disease in humans with high fatality rates. Infected individuals exhibit dysregulated immune responses which appear to result from several factors, including virus-mediated impairment of innate imm... | Filoviruses, which include the genera ebolavirus (EBOV) and marburgvirus (MARV), are enveloped negative-strand RNA viruses that cause highly lethal hemorrhagic fever in humans and in non-human primates. The ability of filoviruses to counteract innate antiviral responses of the host, particularly the IFNα/β response is ... |
10.1371/journal.pgen.1007019 | Incomplete dominance of deleterious alleles contributes substantially to trait variation and heterosis in maize | Deleterious alleles have long been proposed to play an important role in patterning phenotypic variation and are central to commonly held ideas explaining the hybrid vigor observed in the offspring of a cross between two inbred parents. We test these ideas using evolutionary measures of sequence conservation to ask whe... | A key long-term goal of biology is understanding the genetic basis of phenotypic variation. Although most new mutations are likely disadvantageous, their prevalence and importance in explaining patterns of phenotypic variation is controversial and not well understood. In this study we combine whole genome-sequencing an... | Understanding the genetic basis of phenotypic variation is critical to many biological endeavors from human health to conservation and agriculture. Although most new mutations are likely deleterious [1], their importance in patterning phenotypic variation is controversial and not well understood [2]. Empirical work sug... |
10.1371/journal.pgen.1001155 | Comprehensive Analysis Reveals Dynamic and Evolutionary Plasticity of Rab GTPases and Membrane Traffic in Tetrahymena thermophila | Cellular sophistication is not exclusive to multicellular organisms, and unicellular eukaryotes can resemble differentiated animal cells in their complex network of membrane-bound structures. These comparisons can be illuminated by genome-wide surveys of key gene families. We report a systematic analysis of Rabs in a c... | Single-celled organisms appear simple compared to multicellular organisms, but this may not be true at the level of the individual cell. In fact, microscopic observations suggest that protists can possess networks of organelles just as elaborate as those in animal cells. Consistent with this idea, recent analysis has i... | Cells can respond to and shape their environments by taking up and releasing macromolecules. Both in- and outbound transport is facilitated by a network of membrane-bound compartments that represent one of the hallmarks of eukaryotic cells [1]. Traffic through the network is highly regulated, and a convergence of data ... |
10.1371/journal.ppat.1006667 | In vitro characterization of the antivirulence target of Gram-positive pathogens, peptidoglycan O-acetyltransferase A (OatA) | The O-acetylation of the essential cell wall polymer peptidoglycan occurs in most Gram-positive bacterial pathogens, including species of Staphylococcus, Streptococcus and Enterococcus. This modification to peptidoglycan protects these pathogens from the lytic action of the lysozymes of innate immunity systems and, as ... | Multi-drug resistance amongst important human pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE) and drug-resistant Streptococcus pneumoniae (DRSP), continues to challenge clinicians and threaten the lives of infected patients. Of the several approaches being ... | Multi-drug resistance amongst important human pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE) and drug-resistant Streptococcus pneumoniae, continues to challenge clinicians and threaten the lives of infected patients to the extent that the United Nations re... |
10.1371/journal.pcbi.1007230 | FAMoS: A Flexible and dynamic Algorithm for Model Selection to analyse complex systems dynamics | Most biological systems are difficult to analyse due to a multitude of interacting components and the concomitant lack of information about the essential dynamics. Finding appropriate models that provide a systematic description of such biological systems and that help to identify their relevant factors and processes c... | Identifying the systematic interactions of multiple components within a complex biological system can be challenging due to the number of potential processes and the concomitant lack of information about the essential dynamics. Selection algorithms that allow an automated evaluation of a large number of different model... | Experiments often allow time-resolved measurements of individual components of a biological system. Revealing the most appropriate systematic representation to describe the connectivity and dynamical interactions of these individual components based on such measurements represents a major challenge in order to identify... |
10.1371/journal.pbio.2004285 | Beyond fitness tracking: The use of consumer-grade wearable data from normal volunteers in cardiovascular and lipidomics research | The use of consumer-grade wearables for purposes beyond fitness tracking has not been comprehensively explored. We generated and analyzed multidimensional data from 233 normal volunteers, integrating wearable data, lifestyle questionnaires, cardiac imaging, sphingolipid profiling, and multiple clinical-grade cardiovasc... | Little is known about how data from wearable sensors can be used apart from fitness tracking. We comprehensively studied 233 normal volunteers, integrating data from wearable sensors with lifestyle questionnaires, cardiac imaging, sphingolipid profiling, and clinical measurements of various heart and metabolic disease ... | Public adoption of consumer-grade wearable activity trackers (“wearables”) has been steadily increasing in recent years [1,2], and it is estimated that the global market for wearables will exceed $34 billion US$ by 2020 [3]. Basic activity trackers provide accelerometer-based activity data, whereas more sophisticated m... |
10.1371/journal.pcbi.1000822 | Constraint-Based Model of Shewanella oneidensis MR-1 Metabolism: A Tool for Data Analysis and Hypothesis Generation | Shewanellae are gram-negative facultatively anaerobic metal-reducing bacteria commonly found in chemically (i.e., redox) stratified environments. Occupying such niches requires the ability to rapidly acclimate to changes in electron donor/acceptor type and availability; hence, the ability to compete and thrive in such ... | The role of members of the genus Shewanella in global carbon and nutrient cycles is implicated based on their wide distribution and their ability to link organic matter oxidation to reduction of many organic and inorganic electron acceptors both natural and artificial. These bacteria are also important in bioremediatio... | Shewanella are common organoheterotrophic organisms in both marine and fresh water environments, particularly in those receiving high inputs of organic matter and where redox conditions fluctuate in space and time. Shewanella oneidensis MR-1 is a dissimilatory manganese-reducing bacterium isolated from Lake Oneida in u... |
10.1371/journal.ppat.1004217 | Influenza A Virus Host Shutoff Disables Antiviral Stress-Induced Translation Arrest | Influenza A virus (IAV) polymerase complexes function in the nucleus of infected cells, generating mRNAs that bear 5′ caps and poly(A) tails, and which are exported to the cytoplasm and translated by host machinery. Host antiviral defences include mechanisms that detect the stress of virus infection and arrest cap-depe... | Like all viruses, Influenza A virus (IAV) is absolutely dependent on host-cell protein synthesis machinery. This dependence makes the virus vulnerable to the innate ability of cells to inhibit protein synthesis in response to various types of stress. This inhibition, termed translation arrest, helps cells survive adver... | Transcription of Influenza A virus (IAV) genes is performed by a viral polymerase that generates 5′-capped and polyadenylated (poly[A]) messenger RNAs (mRNAs) structurally similar to host mRNAs [1]. Despite this similarity, IAV transcripts gain preferential access to cellular translation machinery through a host shutof... |
10.1371/journal.pbio.0050198 | Open Syntaxin Docks Synaptic Vesicles | Synaptic vesicles dock to the plasma membrane at synapses to facilitate rapid exocytosis. Docking was originally proposed to require the soluble N-ethylmaleimide–sensitive fusion attachment protein receptor (SNARE) proteins; however, perturbation studies suggested that docking was independent of the SNARE proteins. We ... | Like Olympic swimmers crouched on their starting blocks, synaptic vesicles prepare for fusion with the neuronal plasma membrane long before the starting gun fires. This preparation enables vesicles to fuse rapidly, synchronously, and in the correct place when the signal finally arrives. A well-known but poorly understo... | Fusion of synaptic vesicles with the plasma membrane is thought to occur in three ordered steps: docking, priming, and fusion [1]. The biological state of a synaptic vesicle can be defined by three distinct parameters: morphology (its location in the synapse); physiology (its release competence); and molecular interact... |
10.1371/journal.pntd.0007660 | Amblyomma americanum serpin 27 (AAS27) is a tick salivary anti-inflammatory protein secreted into the host during feeding | Ticks successfully feed and transmit pathogens by injecting pharmacological compounds in saliva to thwart host defenses. We have previously used LC-MS/MS to identify proteins that are present in saliva of unfed Amblyomma americanum ticks that were exposed to different hosts. Here we show that A. americanum serine prote... | Ticks are blood-feeding arthropods that salivate while they puncture host skin in their search of blood. Tick saliva contains hundreds of compounds that have anti-coagulant, vasodilatory, anti-inflammatory, and immunomodulatory functions. While helping the vector to feed, tick saliva also modifies the site where pathog... | The lone star tick Amblyomma americanum is a hard tick species of medical and veterinary importance in the United States and Mexico [1–3]. This tick species is a known vector of a number of tick-borne diseases (TBD) agents including Borrelia lonestari, the causative agent of southern tick-associated rash illness (STARI... |
10.1371/journal.pntd.0001741 | Leishmania major Infection in Humanized Mice Induces Systemic Infection and Provokes a Nonprotective Human Immune Response | Leishmania (L.) species are the causative agent of leishmaniasis. Due to the lack of efficient vaccine candidates, drug therapies are the only option to deal with cutaneous leishmaniasis. Unfortunately, chemotherapeutic interventions show high toxicity in addition to an increased risk of dissemination of drug-resistant... | As many as 12 million people suffer from Leishmania (L.) infection worldwide with about one to two million newly infected people every year. Due to the lack of vaccine strategies, the only option is chemotherapeutic intervention which can cause serious side effects. Therefore, new prevention or treatment strategies are... | Over the last decades inbred mice were used to investigate the mechanisms of adaptive and innate immune responses against the obligatory intracellular parasite Leishmania (L.) major. From these studies fundamental paradigms regarding the elimination of the parasites were generated [1]. It could be demonstrated that in ... |
10.1371/journal.pgen.1000257 | CTCF cis-Regulates Trinucleotide Repeat Instability in an Epigenetic Manner: A Novel Basis for Mutational Hot Spot Determination | At least 25 inherited disorders in humans result from microsatellite repeat expansion. Dramatic variation in repeat instability occurs at different disease loci and between different tissues; however, cis-elements and trans-factors regulating the instability process remain undefined. Genomic fragments from the human sp... | The human genome contains many repetitive sequences. In 1991, we discovered that excessive lengthening of a three-nucleotide (trinucleotide) repeat sequence could cause a human genetic disease. We now know that this unique type of genetic mutation, known as a “repeat expansion,” occurs in at least 25 different diseases... | Trinucleotide repeat expansion is the cause of at least 25 inherited neurological disorders, including Huntington's disease (HD), fragile X mental retardation, and myotonic dystrophy (DM1) [1]. One intriguing aspect of trinucleotide repeat disorders is ‘anticipation’ – a phenomenon whereby increased disease severity an... |
10.1371/journal.pcbi.1006125 | Switchable slow cellular conductances determine robustness and tunability of network states | Neuronal information processing is regulated by fast and localized fluctuations of brain states. Brain states reliably switch between distinct spatiotemporal signatures at a network scale even though they are composed of heterogeneous and variable rhythms at a cellular scale. We investigated the mechanisms of this netw... | Brain information processing involves electrophysiological signals at multiple temporal and spatial timescales, from the single neuron level to whole brain areas. A fast and local control of these signals by neurochemicals called neuromodulators is essential in complex tasks such as movement initiation and attentional ... | Neuronal processing is constantly shaped by fluctuations in population rhythmic activities, each defining distinctive brain states [1–4]. Neuromodulators organize the switch between different brain states [5,6], changing the way networks process neural signals [7,8]. Precise temporal and spatial control of brain states... |
10.1371/journal.pgen.1002965 | Phosphatase-Dead Myotubularin Ameliorates X-Linked Centronuclear Myopathy Phenotypes in Mice | Myotubularin MTM1 is a phosphoinositide (PPIn) 3-phosphatase mutated in X-linked centronuclear myopathy (XLCNM; myotubular myopathy). We investigated the involvement of MTM1 enzymatic activity on XLCNM phenotypes. Exogenous expression of human MTM1 in yeast resulted in vacuolar enlargement, as a consequence of its phos... | X-linked centronuclear myopathy is a muscle disorder characterized by neonatal hypotonia and abnormal organelle positioning in skeletal muscle. This myopathy is due to different mutations in the MTM1 gene encoding the phosphoinositide phosphatase myotubularin. Disease-causing mutations are found all along the protein s... | X-linked centronuclear myopathy (XLCNM, also called myotubular myopathy; OMIM 310400) is a recessive congenital muscle disorder affecting mainly males and due to mutations in the MTM1 gene coding for the phosphoinositides (PPIn) phosphatase myotubularin [1]. The most severe form of XLCNM is characterised by hypotonia a... |
10.1371/journal.pgen.1003757 | Functional Dissection of Regulatory Models Using Gene Expression Data of Deletion Mutants | Genome-wide gene expression profiles accumulate at an alarming rate, how to integrate these expression profiles generated by different laboratories to reverse engineer the cellular regulatory network has been a major challenge. To automatically infer gene regulatory pathways from genome-wide mRNA expression profiles be... | The complex functions of a living cell are carried out through hierarchically organized regulatory pathways composed of complex interactions between regulators themselves and between regulators and their targets. Here we developed a Bayesian network inference algorithm, Deletion Mutant Bayesian Network (DM_BN) to rever... | The complex functions in eukaryotic cells are implemented through a highly organized regulatory network composed of concerted activities of many genes and gene products. Gene expression can be directly regulated by transcription factors (TFs) [1], the states of chromatin structures [2], [3] and small RNAs, and interact... |
10.1371/journal.pgen.1006069 | The Pilin N-terminal Domain Maintains Neisseria gonorrhoeae Transformation Competence during Pilus Phase Variation | The obligate human pathogen Neisseria gonorrhoeae is the sole aetiologic agent of the sexually transmitted infection, gonorrhea. Required for gonococcal infection, Type IV pili (Tfp) mediate many functions including adherence, twitching motility, defense against neutrophil killing, and natural transformation. Critical ... | Neisseria gonorrhoeae, the bacterium responsible for the disease gonorrhea, is capable of undergoing natural DNA transformation, a critical mechanism by which bacteria can take up DNA from the environment. Uptake of foreign DNA can lead to adaptation to a changing environment and allow the spread of antibiotic resistan... | Neisseria gonorrhoeae is a Gram-negative, obligate human pathogen and the etiological agent of gonorrhea [1]. Each year, the bacterium causes an estimated 106 million new cases worldwide[2].The rise of resistance to all available antibiotics coupled with the lack of any viable vaccine candidates have led the Centers fo... |
10.1371/journal.pgen.1003495 | High-Resolution Transcriptome Maps Reveal Strain-Specific Regulatory Features of Multiple Campylobacter jejuni Isolates | Campylobacter jejuni is currently the leading cause of bacterial gastroenteritis in humans. Comparison of multiple Campylobacter strains revealed a high genetic and phenotypic diversity. However, little is known about differences in transcriptome organization, gene expression, and small RNA (sRNA) repertoires. Here we ... | Many species have evolved into diverse strains with phenotypic and genotypic variations that facilitate adaptation to different ecological niches and, in the case of pathogens, to different hosts. Whereas comparison of genome sequences reveals differences and similarities among strains, the consequences of genomic vari... | Deep RNA–sequencing (RNA–seq) has been revolutionizing transcriptome analyses of both pro- and eukaryotes [1], [2]. Several recent RNA–seq studies have revealed an unexpectedly complex transcriptional output from bacterial genomes and have been successfully used for the global identification of small RNA (sRNA) genes a... |
10.1371/journal.ppat.1003112 | Messenger RNA Sequence Rather than Protein Sequence Determines the Level of Self-synthesis and Antigen Presentation of the EBV-encoded Antigen, EBNA1 | Unique purine-rich mRNA sequences embedded in the coding sequences of a distinct group of gammaherpesvirus maintenance proteins underlie the ability of the latently infected cell to minimize immune recognition. The Epstein-Barr virus nuclear antigen, EBNA1, a well characterized lymphocryptovirus maintenance protein has... | Viruses establishing persistent latent infections have evolved various mechanisms to avoid immune surveillance. The Epstein-Barr virus-encoded nuclear antigen, EBNA1, expressed in all EBV-associated malignancies, modulates its own protein levels at quantities sufficient to maintain viral infection but low enough so as ... | Members of the viral family Herpesviridae, which are widely distributed throughout the animal kingdom, are characterized by their large double-stranded, linear DNA genomes. The gammaherpesviruses, one of three sub-families of Herpesviridae, predominantly replicate and persist in lymphoid cells with the distinguishing c... |
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