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10.1371/journal.pcbi.1002867 | Passive Dendrites Enable Single Neurons to Compute Linearly Non-separable Functions | Local supra-linear summation of excitatory inputs occurring in pyramidal cell dendrites, the so-called dendritic spikes, results in independent spiking dendritic sub-units, which turn pyramidal neurons into two-layer neural networks capable of computing linearly non-separable functions, such as the exclusive OR. Other ... | Classical views on single neuron computation treat dendrites as mere collectors of inputs, that is forwarded to the soma for linear summation and causes a spike output if it is sufficiently large. Such a single neuron model can only compute linearly separable input-output functions, representing a small fraction of all... | Seminal neuron models, like the McCulloch & Pitts unit [1] or point neurons (see [2] for an overview), assume that synaptic integration is linear. Despite being pervasive mental models of single neuron computation, and frequently used in network models, the linearity assumption has long been known to be false. Measurem... |
10.1371/journal.pgen.1001041 | Requirement of Male-Specific Dosage Compensation in Drosophila Females—Implications of Early X Chromosome Gene Expression | Dosage compensation equates between the sexes the gene dose of sex chromosomes that carry substantially different gene content. In Drosophila, the single male X chromosome is hypertranscribed by approximately two-fold to effect this correction. The key genes are male lethal and appear not to be required in females, or ... | When substantially different, sex chromosomes present the challenge of not only gene dose inequity between the sexes, in the heterogametic sex where one chromosome (frequently the Y) carries few genes, but also an inequity relative to the autosomes which are diploid. Dosage compensation refers to the process which equa... | When the sex chromosomes carry substantially different gene numbers, dosage compensation is necessary to equalize gene expression between the two sexes. In the three best studied model systems Drosophila, C. elegans and mammals where males are XY and females XX, this involves targeting X-specific components which modif... |
10.1371/journal.ppat.1000887 | Identification of a Mutant PfCRT-Mediated Chloroquine Tolerance Phenotype in Plasmodium falciparum | Mutant forms of the Plasmodium falciparum transporter PfCRT constitute the key determinant of parasite resistance to chloroquine (CQ), the former first-line antimalarial, and are ubiquitous to infections that fail CQ treatment. However, treatment can often be successful in individuals harboring mutant pfcrt alleles, ra... | Plasmodium falciparum resistance to the antimalarial drug chloroquine has been found to result primarily from point mutations in PfCRT, which provide a highly sensitive marker of in vivo treatment failure and in vitro resistance. Debate has nonetheless continued about the singular role of mutant PfCRT and the contribut... | The massive use of chloroquine (CQ) in the 20th century heralded substantial gains in the global fight against malaria. These advances were later lost as CQ resistance (CQR) arose and spread throughout malaria-endemic areas [1], [2]. Today, CQ and the alternative first-line antimalarial sulfadoxine-pyrimethamine have o... |
10.1371/journal.ppat.1004396 | MHC Class II Restricted Innate-Like Double Negative T Cells Contribute to Optimal Primary and Secondary Immunity to Leishmania major | Although it is generally believed that CD4+ T cells play important roles in anti-Leishmania immunity, some studies suggest that they may be dispensable, and that MHC II-restricted CD3+CD4−CD8− (double negative, DN) T cells may be more important in regulating primary anti-Leishmania immunity. In addition, while there ar... | Although it is generally believed that CD4+ T cells mediate anti-Leishmania immunity, some studies suggest that CD3+CD4−CD8− (double negative, DN) T cells may play a more important role in regulating primary anti-Leishmania immunity. Here, we report that DN T cells extensively proliferate and produce effector cytokines... | The spectrum of disease collectively called Leishmaniasis is caused by several species of protozoan parasites belonging to the genus Leishmania. The disease is currently endemic in 88 countries, affecting an estimated 12 million people with over 1.5–2 million new cases and 70,000 deaths each year [1]. Because Leishmani... |
10.1371/journal.pntd.0001162 | Latent Microsporidial Infection in Immunocompetent Individuals – A Longitudinal Study | Microsporidia (Fungi) have been repeatedly identified as the cause of opportunistic infections predominantly in immunodeficient individuals such as AIDS patients. However, the global epidemiology of human microsporidiosis is poorly understood and the ability of microsporidia to survive and multiply in immunocompetent h... | Microsporidia are a group of obligate intracellular parasitic fungi that have risen over the past two decades from obscure organisms to well recognized human pathogens. Out of 14 species reported to infect humans and causing more severe symptoms in immunocompromised individuals, microsporidia of the species Encephalito... | Microsporidia have emerged as causative agents of opportunistic infections in AIDS patients and other immunodeficient individuals. Several species of microsporidia can cause disease in humans. Intestinal microsporidiosis due to Encephalitozoon (Septata) intestinalis and Enterocytozoon bieneusi are most frequently repor... |
10.1371/journal.pcbi.1000355 | An Analytically Solvable Model for Rapid Evolution of Modular
Structure | Biological systems often display modularity, in the sense that they can be
decomposed into nearly independent subsystems. Recent studies have suggested
that modular structure can spontaneously emerge if goals (environments) change
over time, such that each new... | Biological systems often display modularity, in the sense that they can be
decomposed into nearly independent subsystems. The evolutionary origin of
modularity has recently been the focus of renewed attention. A series of studies
suggested that modularity can ... | Biological systems often display modularity, defined as the seperability of the
design into units that perform independently, at least to a first approximation
[1]–[5]. Modularity can be seen
in the design of organisms (organs, limbs, sensory systems), in the design o... |
10.1371/journal.pcbi.1004100 | Resting-State Temporal Synchronization Networks Emerge from Connectivity Topology and Heterogeneity | Spatial patterns of coherent activity across different brain areas have been identified during the resting-state fluctuations of the brain. However, recent studies indicate that resting-state activity is not stationary, but shows complex temporal dynamics. We were interested in the spatiotemporal dynamics of the phase ... | The spontaneous or resting-state activity of the brain is organized into multiple spatial patterns of correlated activity. These patterns have been associated with functional interacting brain networks. Recent studies show that the correlations among brain regions are not stationary, but evolve over time, and have refo... | The spontaneous activity of the brain is organized into multiple spatial patterns of correlated activity across different brain regions, known as ‘resting-state networks’ (RSNs) [1–12]. The topography of the resting-state networks overlaps with functional networks observed during cognitive load, including the default m... |
10.1371/journal.pntd.0005890 | Control of Phlebotomus argentipes (Diptera: Psychodidae) sand fly in Bangladesh: A cluster randomized controlled trial | A number of studies on visceral leishmaniasis (VL) vector control have been conducted during the past decade, sometimes came to very different conclusion. The present study on a large sample investigated different options which are partially unexplored including: (1) indoor residual spraying (IRS) with alpha cypermethr... | Integrated vector management (IVM) is of the important elements in the Regional Visceral Leishmaniasis (VL) elimination strategy. VL supposed to be eliminated from the Region (Bangladesh, India and Nepal) by 2015 which is extended up to 2017. There are several factors are responsible for not achieving the elimination g... | Visceral leishmaniasis (VL) [known as kala-azar in the Indian sub-continent] is a parasitic disease present in South-East Asia since before the early 1800’s [1]. VL appears to have spread along the Ganges and the Brahmaputra rivers, the major transport routs of Bengal and Bangladesh. In this area, VL was first describe... |
10.1371/journal.ppat.1002233 | Impairment of Immunoproteasome Function by β5i/LMP7 Subunit Deficiency Results in Severe Enterovirus Myocarditis | Proteasomes recognize and degrade poly-ubiquitinylated proteins. In infectious disease, cells activated by interferons (IFNs) express three unique catalytic subunits β1i/LMP2, β2i/MECL-1 and β5i/LMP7 forming an alternative proteasome isoform, the immunoproteasome (IP). The in vivo function of IPs in pathogen-induced in... | The proteasome recognizes and degrades protein substrates tagged with poly-ubiquitin chains. Immune cells and cells activated by inflammatory cytokines/interferons express immunoproteasomes (IPs) that are characterized by unique catalytic subunits with increased substrate turnover. In infectious disease, the function o... | Unfolded or misfolded proteins are potentially harmful to cells and have to be efficiently eliminated before they intoxicate the intracellular environment. This is of particular importance during proteotoxic stress as a consequence of intrinsic or extrinsic factors when the levels of misfolded proteins are transiently ... |
10.1371/journal.pbio.1000305 | Shape Invariant Coding of Motion Direction in Somatosensory Cortex | Invariant representations of stimulus features are thought to play an important role in producing stable percepts of objects. In the present study, we assess the invariance of neural representations of tactile motion direction with respect to other stimulus properties. To this end, we record the responses evoked in ind... | When we physically interact with an object, our hands convey information about the shape of the object, its texture, its compliance, and its thermal properties. This information allows us to manipulate tools and to recognize objects based on tactile exploration alone. One of the hallmarks of tactile object recognition ... | In both vision and touch, information about form and motion is inferred from a spatio-temporal pattern of activation across a two-dimensional sensory sheet (the retina and the skin). The early stages of form processing have been shown to be similar in these two modalities in that both involve decomposing the stimulus i... |
10.1371/journal.pgen.1002106 | CorE from Myxococcus xanthus Is a Copper-Dependent RNA Polymerase Sigma Factor | The dual toxicity/essentiality of copper forces cells to maintain a tightly regulated homeostasis for this metal in all living organisms, from bacteria to humans. Consequently, many genes have previously been reported to participate in copper detoxification in bacteria. Myxococcus xanthus, a prokaryote, encodes many pr... | Copper exerts a dual effect on living organisms. It is essential for life, but an excess provokes cell damage, forcing cells to maintain a regulated homeostasis for this metal. These two antagonistic biological effects of copper are clearly illustrated by two human genetic disorders, Menkes syndrome and Wilson disease,... | Myxococcus xanthus is a soil-dwelling δ-proteobacterium of the group of myxobacteria used as a model to study multicellular behavior and differentiation, because it exhibits a complex developmental cycle triggered by starvation [1]. However, M. xanthus cells not only have to adapt their metabolism and behavior to chang... |
10.1371/journal.ppat.1002502 | HCMV Targets the Metabolic Stress Response through Activation of AMPK Whose Activity Is Important for Viral Replication | Human Cytomegalovirus (HCMV) infection induces several metabolic activities that have been found to be important for viral replication. The cellular AMP-activated protein kinase (AMPK) is a metabolic stress response kinase that regulates both energy-producing catabolic processes and energy-consuming anabolic processes.... | Human Cytomegalovirus (HCMV) is a ubiquitous human pathogen that is a major cause of birth defects. HCMV can also cause severe disease in immunocompromised individuals including transplant recipients, leukemia patients and those infected with HIV. It is clear that upon infection, HCMV takes control of numerous cellular... | Upon infection, viruses must create a cellular environment conducive to viral replication. While there are many different aspects of this virally-induced environment, a critical component of this cellular reprogramming is the diversion of cellular resources such as energy and molecular building blocks to the production... |
10.1371/journal.pcbi.1003201 | Model-Based Analysis of HER Activation in Cells Co-Expressing EGFR, HER2 and HER3 | The HER/ErbB family of receptor tyrosine kinases drives critical responses in normal physiology and cancer, and the expression levels of the various HER receptors are critical determinants of clinical outcomes. HER activation is driven by the formation of various dimer complexes between members of this receptor family.... | A family of cell surface molecules called the HER receptor family plays important roles in normal physiology and cancer. This family has four members, HER1-4. These receptors convert signals received from the extracellular environment into cell decisions such as growth and survival – a process termed signal transductio... | The HER family (Human Epidermal growth factor Receptor, also known as the ErbB family) of cell surface receptors plays critical roles in normal cell physiology, development, and cancer pathophysiology [1], [2], [3], [4]. The family consists of the four closely related transmembrane receptor tyrosine kinases HER1 (EGFR)... |
10.1371/journal.ppat.1003274 | Experimental Human Pneumococcal Carriage Augments IL-17A-dependent T-cell Defence of the Lung | Pneumococcal carriage is both immunising and a pre-requisite for mucosal and systemic disease. Murine models of pneumococcal colonisation show that IL-17A-secreting CD4+ T-cells (Th-17 cells) are essential for clearance of pneumococci from the nasopharynx. Pneumococcal-responding IL-17A-secreting CD4+ T-cells have not ... | Pneumococcal carriage is an important step in the development of cellular and humoral pneumococcal immunity but paradoxically may lead to mucosal diseases such as pneumonia. The frequency of carriage and pneumonia in young healthy adults is very low despite frequent exposures suggesting the presence of appropriate muco... | Nasopharyngeal colonisation with Streptococcus pneumoniae (the pneumococcus) peaks in prevalence at 2–3 years of age [1] and declines thereafter becoming 10% or less in adult-hood and undetectable in the elderly [2]. Perturbations in host defence and/or increased pneumococcal pathogenicity facilitate colonisation and i... |
10.1371/journal.pmed.1002142 | Tradeoffs in Introduction Policies for the Anti-Tuberculosis Drug Bedaquiline: A Model-Based Analysis | New drugs for the treatment of tuberculosis (TB) are becoming available for the first time in over 40 y. Optimal strategies for introducing these drugs have not yet been established. The objective of this study was to compare different strategies for introducing the new TB drug bedaquiline based on patients’ resistance... | Bedaquiline is a new tuberculosis (TB) drug approved by the United States Food and Drug Administration in 2012 for patients with multidrug resistant (MDR) TB without other treatment options.
Although the initial clinical trials of bedaquiline in combination with an optimized background regimen for MDR TB showed promisi... | Only approximately 50% of the 111,000 people started on treatment for multidrug-resistant tuberculosis (MDR TB) in 2014 are likely to be successfully treated [1]. The remainder will experience high mortality, risk acquisition of extensively drug-resistant (XDR) TB, and may continue to infect others. New antibiotics hav... |
10.1371/journal.pntd.0004088 | Snakebite is Under Appreciated: Appraisal of Burden from West Africa | Snakebite envenoming (SBE) is a major problem in rural areas of West Africa (WA). Compared to other Neglected Tropical Diseases (NTD), the public health burden of SBE has not been well characterized. We estimated the impact of snakebite mortality and morbidity using the Disability Adjusted Life Years (DALYs) metrics fo... | Snakebite envenoming (SBE) is a major problem in rural West Africa (WA). However, despite the high incidence of SBE in this region, government funding for the prevention or treatment of SBE is generally limited. In this analysis, we attempted to estimate how the public health burden of SBE compares to other more widely... | Snakebite envenoming (SBE) is a major public health problem among communities of the savanna region of West Africa, notably in Benin, Burkina-Faso, Cameroon, Chad, Ghana, Nigeria, Senegal and Togo [1,2,3,4]. The precise incidence of snakebite is difficult to determine and is often grossly underestimated. An early estim... |
10.1371/journal.pcbi.1005909 | Molecular recognition and packing frustration in a helical protein | Biomolecular recognition entails attractive forces for the functional native states and discrimination against potential nonnative interactions that favor alternate stable configurations. The challenge posed by the competition of nonnative stabilization against native-centric forces is conceptualized as frustration. Ex... | Biomolecules need to recognize one another with high specificity: promoting “native” functional intermolecular binding events while avoiding detrimental “nonnative” bound configurations; i.e., “frustration”—the tendency for nonnative interactions—has to be minimized. Folding of globular proteins entails a similar discr... | Molecular recognition is the basis of biological function. For different parts of the same molecule or different molecules to recognize one another, a target set of interactions need to be favored while other potential interactions are disfavored. Biomolecules accomplish these simultaneous tasks via the heterogeneous i... |
10.1371/journal.pcbi.1005710 | Funneled potential and flux landscapes dictate the stabilities of both the states and the flow: Fission yeast cell cycle | Using fission yeast cell cycle as an example, we uncovered that the non-equilibrium network dynamics and global properties are determined by two essential features: the potential landscape and the flux landscape. These two landscapes can be quantified through the decomposition of the dynamics into the detailed balance ... | We have uncovered that the non-equilibrium network dynamics and global properties are determined by two essential features: the potential landscape and the flux landscape. We have found that the funneled potential landscape is crucial for the stability of the states on the cell cycle, however, the stabilities of the os... | The global stability and robustness are crucial for maintaining the function. They are also important for uncovering underlying mechanisms of the networks. [1–7] However, it is difficult to quantify them for dynamic systems and networks. This presents a challenge for the dynamical systems and the field of systems biolo... |
10.1371/journal.pgen.1003351 | Spreading of a Prion Domain from Cell-to-Cell by Vesicular Transport in Caenorhabditis elegans | Prion proteins can adopt self-propagating alternative conformations that account for the infectious nature of transmissible spongiform encephalopathies (TSEs) and the epigenetic inheritance of certain traits in yeast. Recent evidence suggests a similar propagation of misfolded proteins in the spreading of pathology of ... | Alzheimer's, Parkinson's, Huntington's, frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and prion diseases are all age-related, fatal neurodegenerative disorders. Hallmarks of these diseases include the expression of toxic protein species. The ability to spread and infect naive cells was ... | Transmissible spongiform encephalopathies (TSEs) or prion diseases are fatal, age-related, and infectious neurodegenerative disorders that affect humans (e.g., Creutzfeldt-Jakob disease) and animals (e.g., scrapie in sheep and bovine spongiform encephalopathy in cattle) [1]. At the molecular level, prions propagate by ... |
10.1371/journal.pgen.1003419 | Genome-Wide Testing of Putative Functional Exonic Variants in Relationship with Breast and Prostate Cancer Risk in a Multiethnic Population | Rare variation in protein coding sequence is poorly captured by GWAS arrays and has been hypothesized to contribute to disease heritability. Using the Illumina HumanExome SNP array, we successfully genotyped 191,032 common and rare non-synonymous, splice site, or nonsense variants in a multiethnic sample of 2,984 breas... | For breast and prostate cancer, GWAS have revealed many risk variants (>70 for each cancer as of this report). All together the common variants in these regions explain only a minority of familial risk of these cancers. Using the Illumina HumanExome SNP array, we explored the hypothesis of rare coding variation contrib... | For most common diseases and traits the genetic basis underlying susceptibility has yet to be completely revealed. While genome-wide association studies (GWAS) have been remarkably successful in identifying common genetic variants associated with risk, the effect sizes of the risk alleles have been modest (relative ris... |
10.1371/journal.ppat.1007238 | Diverse pathways of escape from all well-characterized VRC01-class broadly neutralizing HIV-1 antibodies | Many broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus type 1 (HIV-1) were shown effective in animal models, and are currently evaluated in clinical trials. However, use of these antibodies in humans is hampered by the rapid emergence of resistant viruses. Here we show that soft-randomization... | Several potent antibodies against human immunodeficiency virus type 1 (HIV-1) have been evaluated in clinical trials. Use of these antibodies in humans, however, is problematic, because easy viral escape remains a major concern. To gain greater insights, we sought to develop an approach to rapidly assess the likelihood... | A large number of potent broadly neutralizing antibodies (bNAbs) have been generated from HIV-1-infected individuals (reviewed in [1–5]). Many of these bNAbs, including 2F5, 4E10, PGT121, VRC01, 3BNC117 and 10–1074, have been or will be evaluated in clinical trials [6–12]. A number of animal studies have shown that adm... |
10.1371/journal.pntd.0006514 | The human-snail transmission environment shapes long term schistosomiasis control outcomes: Implications for improving the accuracy of predictive modeling | Schistosomiasis is a chronic parasitic trematode disease that affects over 240 million people worldwide. The Schistosoma lifecycle is complex, involving transmission via specific intermediate-host freshwater snails. Predictive mathematical models of Schistosoma transmission have often chosen to simplify or ignore the d... | Infection with blood fluke Schistosoma parasites is a major cause of disease burden around the world. Control of schistosomiasis, which is transmitted through intermediate host freshwater snails, is a priority for national and global health programs working in at-risk regions of Africa, the Mideast, Asia, the Philippin... | Schistosomiasis is a neglected tropical disease (NTD) having an estimated global prevalence of 240 million infected persons, many of whom experience significant morbidity within the infected communities of Africa, the Mideast, South America, Asia, and the Philippines [1]. For global control of the disease schistosomias... |
10.1371/journal.ppat.1002032 | Investigating the Host Binding Signature on the Plasmodium
falciparum PfEMP1 Protein Family | The Plasmodium falciparum erythrocyte membrane protein 1
(PfEMP1) family plays a central role in antigenic variation and cytoadhesion of
P. falciparum infected erythrocytes. PfEMP1
proteins/var genes are classified into three main
s... | The malaria parasite Plasmodium falciparum persists in the human
host partly by avoiding elimination in the spleen during blood stage infection.
This strategy depends principally upon members of the large and diverse PfEMP1
family of proteins that are exported... | Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a
clonally variant adhesion protein that mediates binding of infected erythrocytes
(IE) to blood microvasculature and other host cells [1]. Adherence of IEs to
microvascular endothelium is a major virulence ... |
10.1371/journal.pbio.2000106 | Decoding Spontaneous Emotional States in the Human Brain | Pattern classification of human brain activity provides unique insight into the neural underpinnings of diverse mental states. These multivariate tools have recently been used within the field of affective neuroscience to classify distributed patterns of brain activation evoked during emotion induction procedures. Here... | Functional brain imaging techniques provide a window into neural activity underpinning diverse cognitive processes, including visual perception, decision-making, and memory, among many others. By treating functional imaging data as a pattern-recognition problem, similar to face- or character-recognition, researchers ha... | Functional neuroimaging offers unique insight into how mental representations are encoded in brain activity [1,2]. Seminal cognitive neuroscience studies demonstrated that distributed patterns of cortical activity measured with functional magnetic resonance imaging (fMRI) contain information capable of differentiating ... |
10.1371/journal.ppat.1005009 | Sequence-Specific Fidelity Alterations Associated with West Nile Virus Attenuation in Mosquitoes | High rates of error-prone replication result in the rapid accumulation of genetic diversity of RNA viruses. Recent studies suggest that mutation rates are selected for optimal viral fitness and that modest variations in replicase fidelity may be associated with viral attenuation. Arthropod-borne viruses (arboviruses) a... | West Nile virus (WNV) is the most geographically widespread arthropod-borne virus (arbovirus) in the world. Like most arboviruses, WNV is a RNA virus which is highly mutable and exists in nature as genetically diverse mutant swarms. Although many recent studies have investigated the relationship between virus mutation ... | Lack of proofreading mechanisms and high replication rates among most RNA viruses make them inherently error-prone, yet there is also variation in mutation rates among both species and strains of RNA viruses, making fidelity itself a trait with a genetic basis subject to some fine-tuning by selection [1–3]. The general... |
10.1371/journal.pgen.1003339 | A Role for the Malignant Brain Tumour (MBT) Domain Protein LIN-61 in DNA Double-Strand Break Repair by Homologous Recombination | Malignant brain tumour (MBT) domain proteins are transcriptional repressors that function within Polycomb complexes. Some MBT genes are tumour suppressors, but how they prevent tumourigenesis is unknown. The Caenorhabditis elegans MBT protein LIN-61 is a member of the synMuvB chromatin-remodelling proteins that control... | The genome is continually under threat from exogenous sources of DNA damage, as well as from sources that originate within the cell. DNA double-strand breaks (DSBs) are arguably the most problematic type of damage as they can cause dangerous chromosome rearrangements, which can lead to cancer, as well as mutation at th... | DNA is maintained in the cell as chromatin: double-stranded DNA wrapped around core histone octomers to form nucleosome subunits. Chromatin folds into higher order structures depending on how tightly DNA is wrapped around the histones and how closely the nucleosomes interact [1]. Condensed chromatin acts as a physical ... |
10.1371/journal.pgen.1001033 | Inter- and Intra-Individual Variation in Allele-Specific DNA Methylation and Gene Expression in Children Conceived using Assisted Reproductive Technology | Epidemiological studies have reported a higher incidence of rare disorders involving imprinted genes among children conceived using assisted reproductive technology (ART), suggesting that ART procedures may be disruptive to imprinted gene methylation patterns. We examined intra- and inter-individual variation in DNA me... | We have screened a population of children conceived in vitro for epigenetic alterations at two loci that carry parent-of-origin specific methylation marks. We made the observation that epigenetic variability was greater in extraembryonic tissues than embryonic tissues in both groups, as has also been demonstrated in th... | Several epidemiological studies have reported a higher incidence of rare disorders involving imprinted genes (Angelman syndrome [1]–[3] and Beckwith-Wiedemann syndrome [4]–[8]) among children conceived using assisted reproductive technologies (ART). Studies on imprinted gene expression and parental allele-specific DNA ... |
10.1371/journal.pcbi.1003074 | “Gate-keeper” Residues and Active-Site Rearrangements in DNA Polymerase μ Help Discriminate Non-cognate Nucleotides | Incorporating the cognate instead of non-cognate substrates is crucial for DNA polymerase function. Here we analyze molecular dynamics simulations of DNA polymerase μ (pol μ) bound to different non-cognate incoming nucleotides including A:dCTP, A:dGTP, A(syn):dGTP, A:dATP, A(syn):dATP, T:dCTP, and T:dGTP to study the s... | DNA polymerase μ (pol μ) is an enzyme that participates in DNA repair and thus has a central role in maintaining the integrity of genetic information. To efficiently repair the DNA, discriminating the cognate instead of non-cognate nucleotides (“fidelity-checking”) is required. Here we analyze molecular dynamics simula... | The integrity of genetic information depends largely on DNA polymerases that are central to DNA replication, damage repair, and recombination. DNA polymerase errors are associated with numerous diseases, including various cancers and neurological conditions [1]–[13]. One of the most basic types of errors that DNA polym... |
10.1371/journal.pcbi.1002762 | Phenomenological Model for Predicting the Catabolic Potential of an Arbitrary Nutrient | The ability of microbial species to consume compounds found in the environment to generate commercially-valuable products has long been exploited by humanity. The untapped, staggering diversity of microbial organisms offers a wealth of potential resources for tackling medical, environmental, and energy challenges. Unde... | The ability of microbial species to consume compounds found in the environment to generate commercially-valuable products has long been exploited by humanity. The vast untapped diversity of microbial species offers a wealth of potential resources. However, little is known about most microbial species. While the metabol... | Predicting microbial metabolism under a broad range of conditions would enable us to leverage microbes for applications in critical areas such as energy production [1], pollution amelioration [2], [3], bioengineering [4], physiology or medicine [5], [6] to name a few. While systematic in vivo growth experiments could i... |
10.1371/journal.pntd.0000183 | T Helper 1–Inducing Adjuvant Protects against Experimental Paracoccidioidomycosis | Immunostimulatory therapy is a promising approach to improving the treatment of systemic fungal infections such as paracoccidioidomycosis (PCM), whose drug therapy is usually prolonged and associated with toxic side effects and relapses. The current study was undertaken to determine if the injection of a T helper (Th) ... | P. brasiliensis is a thermally dimorphic human pathogenic fungus that causes paracoccidioidomycosis (PCM), the most prevalent human systemic mycosis in Latin America, whose drug therapy is usually prolonged and associated with toxic side effects and relapses. Although immunostimulatory therapy is a promising approach t... | Paracoccidioides brasiliensis is a thermally dimorphic human pathogenic fungus that causes paracoccidioidomycosis (PCM), the most prevalent human systemic mycosis in Latin America, being endemic in Brazil, Argentina, Venezuela and Colombia. This infection is acquired by inhalation of airborne propagules found in nature... |
10.1371/journal.pcbi.1001095 | Identifying Causal Genes and Dysregulated Pathways in Complex Diseases | In complex diseases, various combinations of genomic perturbations often lead to the same phenotype. On a molecular level, combinations of genomic perturbations are assumed to dys-regulate the same cellular pathways. Such a pathway-centric perspective is fundamental to understanding the mechanisms of complex diseases a... | It is now being recognized that complex diseases should be studied from the perspective of dys-regulated pathways and processes rather than individual genes. Indeed, various combinations of molecular perturbations might lead to the same disease. In such cases, responses to these perturbations are expected to converge t... | Complex diseases are typically caused by combinations of molecular perturbations that might vary strongly in different patients, yet dys-regulate the same component of a cellular system [1]. In recent years, whole-genome gene expression sets have increasingly been used to search for markers, allowing an improved diagno... |
10.1371/journal.pcbi.1006842 | Analyzing the symmetrical arrangement of structural repeats in proteins with CE-Symm | Many proteins fold into highly regular and repetitive three dimensional structures. The analysis of structural patterns and repeated elements is fundamental to understand protein function and evolution. We present recent improvements to the CE-Symm tool for systematically detecting and analyzing the internal symmetry a... | Many protein structures show a great deal of regularity. Even within single polypeptide chains, about 25% of proteins contain self-similar repeating structures, which can be organized in ring-like symmetric arrangements or linear open repeats. The repeats are often related, and thus comparing the sequence and structure... | François Jacob described molecular evolution as a “tinkering” process, where pre-existing elements are combined and repurposed to solve new biological problems [1]. Traces of this “tinkerer evolution” can be seen in the widespread reuse of structural elements in proteins at different scales: small motifs [2], functiona... |
10.1371/journal.pntd.0006694 | Isolation of pathogenic Leptospira strains from naturally infected cattle in Uruguay reveals high serovar diversity, and uncovers a relevant risk for human leptospirosis | Leptospirosis is a neglected zoonosis with worldwide distribution. The causative agents are spirochete bacteria of the Leptospira genus, displaying huge diversity of serovars, the identity of which is critical for effective diagnosis and vaccination purposes. Among many other mammalian species, Leptospira infects cattl... | Several species of the genus Leptospira cause leptospirosis, a disease that is transmitted from animals to humans (zoonosis). Leptospirosis is the most extended zoonosis worldwide, with over a million human cases each year. Leptospira spp. infect a broad range of wildlife and domestic animals, including cattle. In seve... | Leptospirosis is a zoonotic disease of worldwide importance caused by pathogenic spirochetes belonging to the genus Leptospira [1]. It affects humans and a broad range of domestic animals and wildlife. In cattle, leptospirosis is an important cause of reproductive failure, including abortions and stillbirths [2]. Infec... |
10.1371/journal.pgen.1003142 | Dynamic and Differential Regulation of Stem Cell Factor FoxD3 in the Neural Crest Is Encrypted in the Genome | The critical stem cell transcription factor FoxD3 is expressed by the premigratory and migrating neural crest, an embryonic stem cell population that forms diverse derivatives. Despite its important role in development and stem cell biology, little is known about what mediates FoxD3 activity in these cells. We have unc... | FoxD3 is an important stem cell factor expressed in many types of embryonic cells including neural crest cells. In the embryo, neural crest cells are a type of stem cell that forms diverse derivatives, including nerve cells, pigment cells, and facial structures. To better understand neural crest development and differe... | The neural crest (NC) is a transient population of cells that migrates throughout the embryo and forms many different cell types, including neurons and glia of the peripheral and enteric nervous systems, bone and cartilage of the craniofacial skeleton and melanocytes [1], [2]. Induction of the neural crest is thought t... |
10.1371/journal.pgen.1005672 | The QTL within the H2 Complex Involved in the Control of Tuberculosis Infection in Mice Is the Classical Class II H2-Ab1 Gene | The level of susceptibility to tuberculosis (TB) infection depends upon allelic variations in numerous interacting genes. In our mouse model system, the whole-genome quantitative trait loci (QTLs) scan revealed three QTLs involved in TB control on chromosomes 3, 9, and in the vicinity of the H2 complex on chromosome 17... | Many genes of the host regulate interactions with Mycobacterium tuberculosis and determine the level of susceptibility to, and severity of, tuberculosis (TB). Identification of these genes and their alleles is continuing and contributes new knowledge about the host-pathogen interactions. So far, forward genetic approac... | Tuberculosis (TB) remains a significant public health problem: one-third of the human population is infected with Mycobacterium tuberculosis (MTB) and 10% of those are at a risk of developing overt TB during their lifetime [1, 2]. Although there is growing body of evidence that the outcome of infection is modulated bot... |
10.1371/journal.pntd.0002281 | Phylogenetic Analysis Reveals a High Prevalence of Sporothrix brasiliensis in Feline Sporotrichosis Outbreaks | Sporothrix schenckii, previously assumed to be the sole agent of human and animal sporotrichosis, is in fact a species complex. Recently recognized taxa include S. brasiliensis, S. globosa, S. mexicana, and S. luriei, in addition to S. schenckii sensu stricto. Over the last decades, large epidemics of sporotrichosis oc... | Sporotrichosis is a subcutaneous mycosis acquired by traumatic inoculation of soil and plant material contaminated with infectious propagules of the pathogen. The transmission of the disease by cats to other animals and humans occurs by biting or scratching, promoting direct inoculation of yeast cells into host tissue.... | Mycotic diseases, particularly those caused by dimorphic fungi such as Sporothrix, can be considered as an emerging threat to various species of animals. Upon introduction of propagules into the mammalian host, the fungus undergoes a thermodimorphic transition to a yeast-like phase, leading to infections varying betwee... |
10.1371/journal.pntd.0006594 | Evidence of vertical transmission of Zika virus in field-collected eggs of Aedes aegypti in the Brazilian Amazon | Arboviruses are viruses transmitted to humans and other animals by the bite of hematophagous arthropods. Infections caused by chikungunya virus (CHIKV), dengue virus (DENV), Zika virus (ZIKV), and the deadlier yellow fever virus (YFV) are current public health problems in several countries, mainly those located in trop... | The control of the vast majority of arbovirus infections relies on entomological measures to reduce mosquito infestation. Therefore, this study analyzed the use of ovitraps for arboviral surveillance in a mid-size city of the Amazonas state, Brazil. We found one larva pool infected with chikungunya virus, before the fi... | The arboviruses transmitted by mosquitoes of the genus Aedes, like chikungunya virus (CHIKV), dengue virus (DENV), Zika virus (ZIKV), and yellow fever virus (YFV) have reached threatening numbers in the last years, with a huge impact on public health systems in several countries throughout the world [1–7]. Nevertheless... |
10.1371/journal.pcbi.1006285 | Learning the payoffs and costs of actions | A set of sub-cortical nuclei called basal ganglia is critical for learning the values of actions. The basal ganglia include two pathways, which have been associated with approach and avoid behavior respectively and are differentially modulated by dopamine projections from the midbrain. Inspired by the influential oppon... | The basal ganglia are structures underneath the surface of the vertebrate brain, associated with error-driven learning. Much is known about the anatomical and biological features of the basal ganglia; scientists now try to understand the algorithms implemented by these structures. Numerous models aspire to capture the ... | What guides rational behavior in a complex environment? Certainly, knowledge of the typical payoffs and costs of acting a certain way is critical for successful action selection. Those payoffs and costs do not only depend on the action that is carried out, but also on the environmental state, henceforth referred to a ‘... |
10.1371/journal.pntd.0000933 | Activities of Rifampin, Rifapentine and Clarithromycin Alone and in Combination against Mycobacterium ulcerans Disease in Mice | Treatment of Mycobacterium ulcerans disease, or Buruli ulcer (BU), has shifted from surgery to treatment with streptomycin(STR)+rifampin(RIF) since 2004 based on studies in a mouse model and clinical trials. We tested two entirely oral regimens for BU treatment, rifampin(RIF)+clarithromycin(CLR) and rifapentine(RPT)+cl... | Buruli ulcer (BU) is found throughout the world but is particularly prevalent in West Africa. Until 2004, treatment for this disfiguring disease was surgical excision followed by skin grafting, procedures often requiring months of hospitalization. More recently, an 8-week regimen of oral rifampin and streptomycin admin... | Mycobacterium ulcerans disease, also known as Buruli ulcer (BU), is the third most prevalent disease caused by mycobacteria [1]. It is characterized by deep and necrotizing skin ulcers with undermined edges resulting from the secretion by M. ulcerans of an immunosuppressive macrolide toxin, termed mycolactone [2]. It i... |
10.1371/journal.ppat.1006908 | A protein coevolution method uncovers critical features of the Hepatitis C Virus fusion mechanism | Amino-acid coevolution can be referred to mutational compensatory patterns preserving the function of a protein. Viral envelope glycoproteins, which mediate entry of enveloped viruses into their host cells, are shaped by coevolution signals that confer to viruses the plasticity to evade neutralizing antibodies without ... | Several virus-mediated molecular processes remain poorly described, which dampen the development of potent anti-viral therapies. Hence, new experimental strategies need to be undertaken to improve and accelerate our understanding of these processes. Here, as a proof of concept, we employ amino-acid coevolution as a too... | Flaviviridae such as Hepatitis C Virus (HCV), Dengue Virus (DENV), Zika Virus (ZIKV) or West Nile Virus (WNV) are cause of several acute and chronic diseases worldwide. The continuous investigation of the molecular processes by which these RNA viruses infect and replicate into their host is critical to develop innovati... |
10.1371/journal.ppat.1004131 | Human Cytomegalovirus Fcγ Binding Proteins gp34 and gp68 Antagonize Fcγ Receptors I, II and III | Human cytomegalovirus (HCMV) establishes lifelong infection with recurrent episodes of virus production and shedding despite the presence of adaptive immunological memory responses including HCMV immune immunoglobulin G (IgG). Very little is known how HCMV evades from humoral and cellular IgG-dependent immune responses... | Herpes viruses persist lifelong continuously alternating between latency and virus production and transmission. The latter events occur despite the presence of immune IgG antibodies. IgG acts by neutralization of virions and activation of immune cells bearing one or more surface receptors, called FcγRs, recognizing the... | Human cytomegalovirus (HCMV) constitutes the prototypical human pathogenic β-herpesvirus found worldwide with high immunoglobulin G (IgG) seroprevalence rates of 50–98% [1]. Despite the expression of a very large antigenic proteome of approximately 750 translational products [2], HCMV avoids sterile immunity and invari... |
10.1371/journal.ppat.1004134 | Suppressor of Cytokine Signaling 4 (SOCS4) Protects against Severe Cytokine Storm and Enhances Viral Clearance during Influenza Infection | Suppressor of cytokine signaling (SOCS) proteins are key regulators of innate and adaptive immunity. There is no described biological role for SOCS4, despite broad expression in the hematopoietic system. We demonstrate that mice lacking functional SOCS4 protein rapidly succumb to infection with a pathogenic H1N1 influe... | The suppressor of cytokine signaling proteins are key regulators of immunity. As yet there is no described biological role for SOCS4, despite its broad expression in cells of the immune system. Given the important role of other SOCS proteins in controlling the immune response, we have generated SOCS4-mutant mice and us... | Influenza is a highly infectious, acute respiratory disease that causes profound morbidity and mortality. Annual seasonal influenza epidemics result in ∼500,000 deaths worldwide and substantial losses to global economies [1]. The development of a “cytokine storm” coupled with damage to pulmonary epithelium has been con... |
10.1371/journal.pntd.0007078 | Synthetic peptides as a novel approach for detecting antibodies against sand fly saliva | Hosts repeatedly bitten by sand flies develop antibodies against sand fly saliva and screening of these immunoglobulins can be employed to estimate the risk of Leishmania transmission, to indicate the feeding preferences of sand flies, or to evaluate the effectiveness of vector control campaigns. Previously, antibodies... | Previously, two types of antigens were used for detection of antibodies to sand flies: 1) salivary gland homogenate (SGH), which requires maintaining a sand fly colony and laborious work to obtain a sufficient amount of antigen or 2) recombinant proteins with the need to use cell expression and a complicated purificati... | The specific IgG antibody response against salivary proteins is induced in repeatedly exposed hosts after being bitten by the female sand fly (reviewed by Ribeiro and Francischetti [1] and Lestinova et al. [2]). In sand flies this antibody response is species-specific [3,4] and correlates with the biting intensity [5–8... |
10.1371/journal.pntd.0003821 | Toward Measuring Schistosoma Response to Praziquantel Treatment with Appropriate Descriptors of Egg Excretion | The control of schistosomiasis emphasizes preventive chemotherapy with praziquantel, which aims at decreasing infection intensity and thus morbidity in individuals, as well as transmission in communities. Standardizing methods to assess treatment efficacy is important to compare trial outcomes across settings, and to m... | To identify whether a person is infected with parasitic worms, stool or urine samples are examined for worm eggs. The drug praziquantel is used against the parasitic disease schistosomiasis. However, there is no definitive agreement as to how the efficacy of praziquantel is best expressed. We put together a database fr... | Schistosomiasis is a parasitic disease caused by blood flukes of the genus Schistosoma. The three main species infecting humans are S. haematobium (causing urogenital schistosomiasis), S. japonicum, and S. mansoni (the latter two responsible for intestinal schistosomiasis) [1]. The backbone of the global strategy for c... |
10.1371/journal.pgen.1002681 | MicroRNA-277 Modulates the Neurodegeneration Caused by Fragile X Premutation rCGG Repeats | Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder, has been recognized in older male fragile X premutation carriers and is uncoupled from fragile X syndrome. Using a Drosophila model of FXTAS, we previously showed that transcribed premutation repeats alone are sufficient to ca... | Fragile X–associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder, usually affecting males over 50 years of age. FXTAS patients are the carriers of fragile X premutation alleles. Using a FXTAS Drosophila model, we previously demonstrated that fragile X premutation rCGG repeats alone could... | Fragile X syndrome (FXS), the most common form of inherited mental retardation, is caused by expansion of the rCGG trinucleotide repeat in the 5′ untranslated region (5′ UTR) of the fragile X mental retardation 1 (FMR1) gene, which leads to silencing of its transcript and the loss of the encoded fragile X mental retard... |
10.1371/journal.pgen.1007316 | ZMYND10 stabilizes intermediate chain proteins in the cytoplasmic pre-assembly of dynein arms | Zinc finger MYND-type-containing 10 (ZMYND10), a cytoplasmic protein expressed in ciliated cells, causes primary ciliary dyskinesia (PCD) when mutated; however, its function is poorly understood. Therefore, in this study, we examined the roles of ZMYND10 using Zmynd10–/–mice exhibiting typical PCD phenotypes, including... | Dynein arm defects are linked to primary ciliary dyskinesia (PCD). ZMYND10 increased the stability of its interacting proteins and specifically regulated intermediate chain protein assembly, revealing tightly regulated mechanisms underlying dynein arm assembly and PCD-related pathogenesis. Increasing protein stability ... | Primary ciliary dyskinesia (PCD) is an autosomal-recessive disorder caused by defective motile cilia or flagella that is characterized by respiratory distress, impaired mucociliary clearance, chronic cough, sinusitis, bronchiectasis, male infertility, laterality defects, and cardiac anomalies in term neonates [1, 2]. T... |
10.1371/journal.pgen.1002653 | Mutations in MITF and PAX3 Cause “Splashed White” and Other White Spotting Phenotypes in Horses | During fetal development neural-crest-derived melanoblasts migrate across the entire body surface and differentiate into melanocytes, the pigment-producing cells. Alterations in this precisely regulated process can lead to white spotting patterns. White spotting patterns in horses are a complex trait with a large pheno... | White spotting coat color phenotypes are the result of aberrations in the development of melanocytes. The analysis of domestic animals with heritable white spotting phenotypes thus helps to better understand the complicated genetic network controlling the proliferation, migration, differentiation, and survival of pigme... | Coat color is a well-studied model trait for geneticists. Coat color phenotypes are relatively easy to record, which facilitates their analysis. In mammals melanocytes cover the entire body surface and are responsible for the pigmentation of skin, hairs, and eyes. Melanocytes are formed during fetal development from me... |
10.1371/journal.ppat.1005099 | Microbial Regulation of p53 Tumor Suppressor | p53 tumor suppressor has been identified as a protein interacting with the large T antigen produced by simian vacuolating virus 40 (SV40). Subsequent research on p53 inhibition by SV40 and other tumor viruses has not only helped to gain a better understanding of viral biology, but also shaped our knowledge of human tum... | This review focuses on a novel aspect of host–bacteria interactions: the direct interplay between bacterial pathogens and tumor suppression mechanisms that protect the host from cancer development. Recent studies revealed that various pathogenic bacteria actively inhibit the major tumor suppression pathway mediated by ... | p53 protein has been receiving significant attention for more than 30 years. This interest originates from the protein’s prominent role in tumor suppression that was eloquently paraphrased in the scientific literature as “the guardian of the genome” [1]. p53 is a key component of the cellular mechanisms controlling cel... |
10.1371/journal.pntd.0007231 | A computational method for the identification of Dengue, Zika and Chikungunya virus species and genotypes | In recent years, an increasing number of outbreaks of Dengue, Chikungunya and Zika viruses have been reported in Asia and the Americas. Monitoring virus genotype diversity is crucial to understand the emergence and spread of outbreaks, both aspects that are vital to develop effective prevention and treatment strategies... | Dengue (DENV), Chikungunya (CHIKV) and Zika (ZIKV) are considered major public health challenges. In addition to the epidemic caused by DENV, which has been described in many tropical countries, the introduction of CHIKV and ZIKV in these countries is a major public health concern. These arboviruses are primarily trans... | In the recent years, an increasing number of outbreaks of Dengue (DENV), Chikungunya (CHIKV) and Zika (ZIKV) viruses have been reported in Asia and the Americas [1–3]. The predominant mosquito species transmitting DENV, CHIKV and ZIKV, are Aedes aegypti and Aedes Albopictus, which are widely distributed in tropical and... |
10.1371/journal.pntd.0001264 | A Multi-Center Randomized Trial to Assess the Efficacy of Gatifloxacin versus Ciprofloxacin for the Treatment of Shigellosis in Vietnamese Children | The bacterial genus Shigella is the leading cause of dysentery. There have been significant increases in the proportion of Shigella isolated that demonstrate resistance to nalidixic acid. While nalidixic acid is no longer considered as a therapeutic agent for shigellosis, the fluoroquinolone ciprofloxacin is the curren... | The bacterial genus Shigella is the most common cause of dysentery (diarrhea containing blood and/or mucus) and the disease is common in developing countries with limitations in sanitation. Children are most at risk of infection and frequently require hospitalization and antimicrobial therapy. The WHO currently recomme... | Dysentery is an infection of the gastrointestinal tract characterized by diarrhea containing blood and/or mucous, abdominal cramping and tenesmus. The major cause of dysentery is the bacterial genus Shigella. Humans are the only known reservoir of Shigella, which are transmitted from person to person by the fecal-oral ... |
10.1371/journal.pgen.1000565 | Origin of an Alternative Genetic Code in the Extremely Small and GC–Rich Genome of a Bacterial Symbiont | The genetic code relates nucleotide sequence to amino acid sequence and is shared across all organisms, with the rare exceptions of lineages in which one or a few codons have acquired novel assignments. Recoding of UGA from stop to tryptophan has evolved independently in certain reduced bacterial genomes, including tho... | The genetic code, which relates DNA sequence to protein sequence, is nearly universal across all life. Examples of recodings do exist, but new instances are rare. Genomes that exhibit recodings typically have other extreme properties, including reduced size, reduced gene sets, and low guanine plus cytosine (GC) content... | The GC content of bacterial genomes has been known to vary widely since at least the 1950s [1]. Currently sequenced genomes range from 17–75% GC and show a strong correlation between genome size and GC content [2]–[4] (Figure 1). The tiny genomes of symbionts of sap-feeding insects are extreme exemplars of this relatio... |
10.1371/journal.pcbi.1005443 | Geometry can provide long-range mechanical guidance for embryogenesis | Downstream of gene expression, effectors such as the actomyosin contractile machinery drive embryo morphogenesis. During Drosophila embryonic axis extension, actomyosin has a specific planar-polarised organisation, which is responsible for oriented cell intercalation. In addition to these cell rearrangements, cell shap... | The morphogenesis of living organisms is a facinating process during which a genetic programme controls a sequence of molecular changes which will cause the original embryo to acquire a new shape. While we have a growing knowledge of the timing and spatial distribution of key molecules downstream of genetic programmes,... | The morphogenesis of living organisms involves precise shape changes and displacements of the tissues that constitute the embryo under the control of gene expression [1]. These movements result from changes in the mechanical balance, which can be caused by local growth [2] or by local activation of the contractile mach... |
10.1371/journal.pntd.0000838 | Mass Treatment with Azithromycin for Trachoma Control: Participation Clusters in Households | Mass treatment to trachoma endemic communities is a critical part of the World Health Organization SAFE strategy. However, non-participation may not be at random, affecting coverage surveys and effectiveness if infection is differential.
As part of the Partnership for Rapid Elimination of Trachoma (PRET), 32 communitie... | Trachoma, an infectious disease, continues to cause blindness. A great deal of the trachoma burden is concentrated in developing countries. The World Health Organization recommends mass treatment for entire communities in trachoma-endemic regions. In 32 Tanzanian and 48 Gambian communities with trachoma, mass treatment... | Trachoma is the leading infectious cause of blindness [1]. As the most common ocular neglected tropical disease, active trachoma is estimated to affect 40.6 million people worldwide, and another 8.2 million experience visual impairment or blindness [2]. Trachoma is largely confined to regions of extreme poverty [3].The... |
10.1371/journal.pbio.1000172 | Persistent cAMP-Signals Triggered by Internalized G-Protein–Coupled Receptors | G-protein–coupled receptors (GPCRs) are generally thought to signal to second messengers like cyclic AMP (cAMP) from the cell surface and to become internalized upon repeated or prolonged stimulation. Once internalized, they are supposed to stop signaling to second messengers but may trigger nonclassical signals such a... | Cells respond to many environmental cues through the activity of cell surface receptor proteins, which sense these cues and convey that information to signaling molecules inside the cell. G-protein–coupled receptors (GPCRs) form the largest eukaryotic family of plasma membrane receptors. They convert the information pr... | G-protein–coupled receptor (GPCR) signaling is thought to involve a series of steps occurring at the cell surface: coupling of receptors to G-proteins, activation of G-proteins, and ultimately, triggering of G-protein-regulated effectors (i.e., adenylyl cyclase, phospholipase C, calcium channels, GIRK channels, etc.) [... |
10.1371/journal.pcbi.1002731 | How Recent History Affects Perception: The Normative Approach and Its Heuristic Approximation | There is accumulating evidence that prior knowledge about expectations plays an important role in perception. The Bayesian framework is the standard computational approach to explain how prior knowledge about the distribution of expected stimuli is incorporated with noisy observations in order to improve performance. H... | In this paper we study how history affects perception using an auditory delayed comparison task, in which human participants repeatedly compare the frequencies of two, temporally-separated pure tones. We demonstrate that the history of the experiment has a substantial effect on participants' performance: when both tone... | Perception is a complex cognitive process, in which noisy signals are extracted from the environment and interpreted. It is generally believed that perceptual resolution is limited by internal noise that constrains our ability to differentiate physically similar stimuli. The magnitude of this internal noise is typicall... |
10.1371/journal.pbio.2001461 | Neuronal synchrony and the relation between the blood-oxygen-level dependent response and the local field potential | The most widespread measures of human brain activity are the blood-oxygen-level dependent (BOLD) signal and surface field potential. Prior studies report a variety of relationships between these signals. To develop an understanding of how to interpret these signals and the relationship between them, we developed a mode... | There are several methods for measuring activity in the living human brain. Here, we studied functional magnetic resonance imaging (fMRI), which depends on the vascular response to neuronal activity, and surface field potentials, which measure electrical activity from many neurons. These two widely used measurements of... | Most measurements of activity in the living human brain arise from the responses of large populations of neurons, spanning the millimeter scale of functional magnetic resonance imaging (fMRI) and electrocorticography (ECoG) to the centimeter scale of electro- and magneto-encephalography (EEG and MEG). Integrating resul... |
10.1371/journal.pmed.1002585 | The association of lifetime alcohol use with mortality and cancer risk in older adults: A cohort study | While current research is largely consistent as to the harms of heavy drinking in terms of both cancer incidence and mortality, there are disparate messages regarding the safety of light-moderate alcohol consumption, which may confuse public health messages. We aimed to evaluate the association between average lifetime... | The detrimental health impacts of heavy alcohol intakes are well known, and even light-moderate alcohol intakes have been linked to increased risks of cancer.
However, light-moderate drinking has also been suggested to be protective for cardiovascular disease, which has led to contradictory public health messages. We c... | Alcohol consumption appears to have a complex and somewhat controversial relationship to health [1–4]. The “J-shaped” relationship between alcohol intake and mortality, particularly from cardiovascular disease, observed in various cohort studies has been well cited within both scientific and mainstream publications [5–... |
10.1371/journal.ppat.1004507 | The Toll-Dorsal Pathway Is Required for Resistance to Viral Oral Infection in Drosophila | Pathogen entry route can have a strong impact on the result of microbial infections in different hosts, including insects. Drosophila melanogaster has been a successful model system to study the immune response to systemic viral infection. Here we investigate the role of the Toll pathway in resistance to oral viral inf... | Pathogenic microbes can enter their hosts through different routes. This can have a strong impact on which host defensive mechanisms are elicited and in disease outcome. We used the model organism Drosophila melanogaster to understand how resistance to viruses differs between infection by direct virus entry into the bo... | Pathogens can infect their hosts through many different routes. In humans, for instance, microbes can directly enter the host through skin lesions or mediated by insect vectors. However, most of human infections start at mucosal surfaces of the respiratory, digestive or genital tracts. Pathogens specialize in different... |
10.1371/journal.ppat.1004514 | PUL21a-Cyclin A2 Interaction is Required to Protect Human Cytomegalovirus-Infected Cells from the Deleterious Consequences of Mitotic Entry | Entry into mitosis is accompanied by dramatic changes in cellular architecture, metabolism and gene expression. Many viruses have evolved cell cycle arrest strategies to prevent mitotic entry, presumably to ensure sustained, uninterrupted viral replication. Here we show for human cytomegalovirus (HCMV) what happens if ... | Cyclin A2 is a key regulator of the cell division cycle. Interactors of Cyclin A2 typically contain short sequence elements (RXL/Cy motifs) that bind with high affinity to a hydrophobic patch in the Cyclin A2 protein. Two types of RXL/Cy-containing factors are known: i) cyclin-dependent kinase (CDK) substrates, which a... | HCMV (also referred to as human herpesvirus-5, HHV5) is widely distributed in the human population. Acute HCMV infection can cause severe complications in immunocompromised individuals, like neonates, transplant recipients and AIDS patients. Persistent HCMV infection has been implicated as a contributing factor in the ... |
10.1371/journal.pgen.1005292 | DNA Damage Regulates Translation through β-TRCP Targeting of CReP | The Skp1-Cul1-F box complex (SCF) associates with any one of a number of F box proteins, which serve as substrate binding adaptors. The human F box protein βTRCP directs the conjugation of ubiquitin to a variety of substrate proteins, leading to the destruction of the substrate by the proteasome. To identify βTRCP subs... | Approximately 600 human genes encode enzymes that act as ubiquitin ligases, which facilitate the transfer of the small protein ubiquitin to thousands of substrate proteins; “tagging” with ubiquitin often promotes the degradation of the substrate by the proteasome. In this paper, we adapt a technique called Ligase Trapp... | E3 ubiquitin ligases, which facilitate the attachment of anywhere from one to a long chain of the small protein ubiquitin to substrate proteins, are important regulators of the cell cycle and the response to stress. The best-studied outcome of ubiquitination is destruction of the substrate by the proteasome. There has ... |
10.1371/journal.ppat.1002750 | Molecular and Electrophysiological Characterization of a Novel Cation Channel of Trypanosoma cruzi | We report the identification, functional expression, purification, reconstitution and electrophysiological characterization of a novel cation channel (TcCat) from Trypanosoma cruzi, the etiologic agent of Chagas disease. This channel is potassium permeable and shows inward rectification in the presence of magnesium. We... | The use of high-resolution electrophysiological techniques to study ion channels has provided a large amount of information on functional aspects of these important membrane proteins. However, the study of ion channels in unicellular eukaryotes has been limited to detection of ion conductances in large cells, gene iden... | Trypanosoma cruzi is a unicellular parasitic eukaryote and the etiologic agent of Chagas disease, which currently affects millions of people in North, Central and South America, and is becoming frequently diagnosed in non-endemic countries [1], [2].
T. cruzi has a complex life cycle involving insect and mammalia... |
10.1371/journal.pcbi.1000781 | Impact of Dendritic Size and Dendritic Topology on Burst Firing in Pyramidal Cells | Neurons display a wide range of intrinsic firing patterns. A particularly relevant pattern for neuronal signaling and synaptic plasticity is burst firing, the generation of clusters of action potentials with short interspike intervals. Besides ion-channel composition, dendritic morphology appears to be an important fac... | Neurons possess highly branched extensions, called dendrites, which form characteristic tree-like structures. The morphology of these dendritic arborizations can undergo significant changes in many pathological conditions. It is still poorly known, however, how alterations in dendritic morphology affect neuronal activi... | Neurons exhibit a wide range of intrinsic firing patterns with respect to both spike frequency and spike pattern [1]–[3]. A distinct type of firing pattern that is critically involved in neuronal signaling and synaptic plasticity is burst firing, the generation of clusters of spikes with short interspike intervals [4].... |
10.1371/journal.ppat.1003600 | Kinetics of Myeloid Dendritic Cell Trafficking and Activation: Impact on Progressive, Nonprogressive and Controlled SIV Infections | We assessed the role of myeloid dendritic cells (mDCs) in the outcome of SIV infection by comparing and contrasting their frequency, mobilization, phenotype, cytokine production and apoptosis in pathogenic (pigtailed macaques, PTMs), nonpathogenic (African green monkeys, AGMs) and controlled (rhesus macaques, RMs) SIVa... | Myeloid dendritic cells (mDCs) are potent antigen-presenting cells that regulate both innate and adaptive immune responses and act as “watch-dogs”, sensing and controlling aberrant immune activation; as such, they may significantly impact the outcome of HIV/SIV infection. By comparing and contrasting the frequency, fun... | Myeloid dendritic cells (mDCs) are potent antigen-presenting cells which are responsible for initiating both innate and adaptive immune responses. mDCs stimulate NK, B and T cells [1], [2], but can also act as “watch-dogs” to sense and regulate aberrant immune activation, induce tolerance and thus prevent autoimmune di... |
10.1371/journal.pcbi.1003168 | Finding Associations among Histone Modifications Using Sparse Partial Correlation Networks | Histone modifications are known to play an important role in the regulation of transcription. While individual modifications have received much attention in genome-wide analyses, little is known about their relationships. Some authors have built Bayesian networks of modifications, however most often they have used disc... | Nucleosomes are protein complexes around which the DNA is wrapped for compactness. They are made of histone proteins that can be post-translationally modified and these histone modifications can affect the expression of surrounding genes. In the past decade, scientists have developed a strong interest in the part of ge... | The study of gene regulation is traditionally based on DNA sequence analysis, gene interactions and transcription factor binding events. It has however over the past decade been revolutionized by genome-wide maps of epigenetic marks, specifically DNA methylation and histone modifications. Histone modifications are post... |
10.1371/journal.ppat.0040029 | A Mouse Model for Chikungunya: Young Age and Inefficient Type-I Interferon Signaling Are Risk Factors for Severe Disease | Chikungunya virus (CHIKV) is a re-emerging arbovirus responsible for a massive outbreak currently afflicting the Indian Ocean region and India. Infection from CHIKV typically induces a mild disease in humans, characterized by fever, myalgia, arthralgia, and rash. Cases of severe CHIKV infection involving the central ne... | Chikungunya virus (CHIKV) is transmitted by mosquito bites. CHIKV has recently re-emerged and is responsible for a massive outbreak in the Indian Ocean region and India. It has also reached Italy, indicating that CHIKV has a great potential to spread globally. Infection from CHIKV typically induces a mild disease in hu... | Chikungunya virus (CHIKV) was first isolated in Tanzania in 1953 [1], and has recently emerged in islands of the Indian Ocean in 2005, and engendered the largest Chikungunya fever epidemic on record [2]. The most affected region was the island of La Réunion, where CHIKV infected approximately a third of the island's in... |
10.1371/journal.pgen.1004243 | The Membrane-Associated Transcription Factor NAC089 Controls ER-Stress-Induced Programmed Cell Death in Plants | The unfolded protein response (UPR) is activated to sustain cell survival by reducing misfolded protein accumulation in the endoplasmic reticulum (ER). The UPR also promotes programmed cell death (PCD) when the ER stress is severe; however, the underlying molecular mechanisms are less understood, especially in plants. ... | Protein folding is fundamentally important for development and responses to environmental stresses in eukaryotes. When excess misfolded proteins are accumulated in the endoplasmic reticulum (ER), the unfolded protein response (UPR) is triggered to promote cell survival through optimizing protein folding, and also promo... | In eukaryotic cells, ER is a major site for the production of secreted, plasma membrane and organelle proteins. Cells have evolved a sophisticated quality control system to ensure the accuracy of protein folding through optimizing the protein-folding machinery and ER-associated degradation (ERAD) [1], [2], [3]. To coor... |
10.1371/journal.pgen.1000749 | Stoichiometry of Base Excision Repair Proteins Correlates with Increased Somatic CAG Instability in Striatum over Cerebellum in Huntington's Disease Transgenic Mice | Huntington's disease (HD) is a progressive neurodegenerative disorder caused by expansion of an unstable CAG repeat in the coding sequence of the Huntingtin (HTT) gene. Instability affects both germline and somatic cells. Somatic instability increases with age and is tissue-specific. In particular, the CAG repeat seque... | Huntington's disease (HD) is a neurodegenerative disorder that belongs to a family of genetic diseases caused by abnormal expansion of CAG/CTG repetitive sequences. The instability of trinucleotide repeat expansions in germline and somatic cells has deleterious clinical consequences in HD. For instance, transmission of... | Huntington's disease (HD) is a neurodegenerative disorder caused by aberrant expansion of a CAG repeat tract within the coding sequence of the Huntingtin (HTT) gene, resulting in the production of a mutant protein with a toxic elongated polyglutamine (polyQ) stretch. This dominantly inherited disease, which shares the ... |
10.1371/journal.pntd.0004162 | Complete Protection against Pneumonic and Bubonic Plague after a Single Oral Vaccination | No efficient vaccine against plague is currently available. We previously showed that a genetically attenuated Yersinia pseudotuberculosis producing the Yersinia pestis F1 antigen was an efficient live oral vaccine against pneumonic plague. This candidate vaccine however failed to confer full protection against bubonic... | Yersinia pestis, the agent of plague, is among the deadliest infectious agents affecting humans. Injected in the skin by infected fleas, Y. pestis causes bubonic plague, which occasionally evolves into the very lethal and contagious pneumonic plague. Y. pestis is also a dangerous potential bioweapon but no plague vacci... | Plague has been one of the deadliest bacterial infections in human history, causing millions of deaths during three major historical pandemics and leaving an indelible mark engraved in human's collective memory. In addition to ancient foci of the disease in Asia and Africa, the last pandemic (plague of modern times), w... |
10.1371/journal.pgen.1000658 | Broad-Scale Recombination Patterns Underlying Proper Disjunction in Humans | Although recombination is essential to the successful completion of human meiosis, it remains unclear how tightly the process is regulated and over what scale. To assess the nature and stringency of constraints on human recombination, we examined crossover patterns in transmissions to viable, non-trisomic offspring, us... | In humans, as in most sexually reproducing organisms, recombination plays a fundamental role in meiosis, helping to align chromosomes and to ensure their proper segregation. Recombination events are tightly regulated both in terms of their minimum number (the rule of “crossover assurance”) and placement (due to “crosso... | Like most sexually reproducing organisms, humans undergo meiotic recombination. This process plays an important role in evolutionary dynamics, generating new combination of alleles on which natural selection can act ([1] and references therein), and in DNA repair. In humans, recombination is also fundamental to the suc... |
10.1371/journal.pntd.0002456 | Non-Invasive Sampling of Schistosomes from Humans Requires Correcting for Family Structure | For ethical and logistical reasons, population-genetic studies of parasites often rely on the non-invasive sampling of offspring shed from their definitive hosts. However, if the sampled offspring are naturally derived from a small number of parents, then the strong family structure can result in biased population-leve... | Genetic epidemiology uses genetic data to uncover patterns of disease processes. To acquire data for these analyses, individual pathogens are collected and scored at genetic markers, and the resultant data are analyzed to infer biological patterns about the pathogen populations. In lieu of invasive sampling of adult pa... | Infectious disease research is rapidly adopting the tools of evolutionary biology and molecular ecology [1]–[5]. Molecular genetic data, evolutionary theory, and population genetic tools can provide methodology to uncover epidemiological processes that cannot be easily determined otherwise. Such processes include patho... |
10.1371/journal.ppat.1005648 | An Oncogenic Virus Promotes Cell Survival and Cellular Transformation by Suppressing Glycolysis | Aerobic glycolysis is essential for supporting the fast growth of a variety of cancers. However, its role in the survival of cancer cells under stress conditions is unclear. We have previously reported an efficient model of gammaherpesvirus Kaposi’s sarcoma-associated herpesvirus (KSHV)-induced cellular transformation ... | KSHV is causally associated with the development of Kaposi’s sarcoma and primary effusion lymphoma; however, the mechanism underlying KSHV-induced malignant transformation remains unclear. The recent development of an efficient KSHV-induced cellular transformation model of primary rat mesenchymal stem cells should faci... | It has been recognized that metabolic reprogramming is a core hallmark of cancer[1]. The Warburg effect describes the dependence of cancer cells on aerobic glycolysis for their growth and proliferation[2]. Increased glucose uptake and aerobic glycolysis are widely observed in cancer and clinically exploited for diagnos... |
10.1371/journal.pntd.0005966 | Programmatic factors associated with the limited impact of Community-Directed Treatment with Ivermectin to control Onchocerciasis in three drainage basins of South West Cameroon | The CDTI model is known to have enhanced community participation in planning and resource mobilization toward the control of onchocerciasis. These effects were expected to translate into better individual acceptance of the intervention and hence high Treatment Coverage, leading to a sustainable community-led strategy a... | River blindness is caused by a very tiny, thread-like worm. The disease is better controlled when affected communities are included in the planning and carrying out of distribution of Ivermectin used to treat the disease. For a community to be able to prevent people from getting this disease, members must take Ivermect... | The Community-Directed Treatment with Ivermectin (CTDI) approach adopted by the African Programme for Onchocerciasis Control [1] accelerated progress towards control of Onchocerciasis through increased community participation and higher treatment coverage of affected populations [2,3]. The CDTI model is known to be cos... |
10.1371/journal.ppat.1001319 | Sheep and Goat BSE Propagate More Efficiently than Cattle BSE in Human PrP Transgenic Mice | A new variant of Creutzfeldt Jacob Disease (vCJD) was identified in humans and linked to the consumption of Bovine Spongiform Encephalopathy (BSE)-infected meat products. Recycling of ruminant tissue in meat and bone meal (MBM) has been proposed as origin of the BSE epidemic. During this epidemic, sheep and goats have ... | Prion diseases, also referred as transmissible spongiform encephalopathies, are fatal neurodegenerative diseases caused by proteinaceous infectious particles denominated “prions.” Prion diseases acquired their first real public relevance with the outbreak of bovine spongiform encephalopathy (BSE) (“mad cow disease”) in... | Transmissible Spongiform Encephalopathies (TSEs) are fatal neurodegenerative diseases which include Scrapie in sheep and goats, Bovine Spongiform Encephalopathy (BSE) and Creutzfeldt-Jakob disease (CJD) in humans. Prions, the causal agents of these diseases are thought to be infectious protein particles essentially com... |
10.1371/journal.pbio.1002452 | Functional Sites Induce Long-Range Evolutionary Constraints in Enzymes | Functional residues in proteins tend to be highly conserved over evolutionary time. However, to what extent functional sites impose evolutionary constraints on nearby or even more distant residues is not known. Here, we report pervasive conservation gradients toward catalytic residues in a dataset of 524 distinct enzym... | The basic biochemical functions of life are carried out by large molecules called enzymes. Enzymes consist of long chains of amino acids folded into a three-dimensional structure. Within that structure, a specific cluster of amino acids, known as the active site, performs the biochemical function. Substituting one amin... | Enzymes facilitate the chemical reactions necessary for life. To function properly, enzymes must reconcile two competing demands: they must fold stably into the correct three-dimensional conformation, and they must display the correct catalytic residues in their active sites. As enzymes evolve, mutations that are funct... |
10.1371/journal.ppat.1004406 | Persistence of Virus Reservoirs in ART-Treated SHIV-Infected Rhesus Macaques after Autologous Hematopoietic Stem Cell Transplant | Despite many advances in AIDS research, a cure for HIV infection remains elusive. Here, we performed autologous hematopoietic stem cell transplantation (HSCT) in three Simian/Human Immunodeficiency Virus (SHIV)-infected, antiretroviral therapy (ART)-treated rhesus macaques (RMs) using HSCs collected prior to infection ... | While antiretroviral therapy (ART) can reduce HIV replication, it does not eradicate the virus from an infected individual. Replication-competent viruses persist on ART and our incomplete understanding of these viral reservoirs greatly complicates the generation of a cure for HIV. In this study we performed, for the fi... | The introduction of antiretroviral therapy (ART) has dramatically reduced the morbidity and mortality associated with HIV infection and AIDS. However, currently available ART requires life long treatment with significant potential side effects and a cost that places an inordinate burden on public health systems. While ... |
10.1371/journal.pntd.0001895 | Chrysomya putoria, a Putative Vector of Diarrheal Diseases | Chrysomya spp are common blowflies in Africa, Asia and parts of South America and some species can reproduce in prodigious numbers in pit latrines. Because of their strong association with human feces and their synanthropic nature, we examined whether these flies are likely to be vectors of diarrheal pathogens.
Flies w... | While it is well recognized that the house fly can transmit enteric pathogens, here we show the common African latrine fly, Chrysomya putoria, is likely to be an important vector of these pathogens, since an average latrine can produce 100,000 latrine flies each year. Our behavioral studies of flies in The Gambia show ... | Controlling diarrheal deaths is crucial to achieve Millennium Development Goal 4; reducing mortality in children under five years by two thirds between 1990 and 2015 [1]. Diarrhea is the second leading cause of death in this age group and is responsible for killing about 1.5 million children each year [2]. In sub-Sahar... |
10.1371/journal.pcbi.1005914 | Model-driven discovery of long-chain fatty acid metabolic reprogramming in heterogeneous prostate cancer cells | Epithelial-mesenchymal-transition promotes intra-tumoral heterogeneity, by enhancing tumor cell invasiveness and promoting drug resistance. We integrated transcriptomic data for two clonal subpopulations from a prostate cancer cell line (PC-3) into a genome-scale metabolic network model to explore their metabolic diffe... | The coexistence within the same tumor of a variety of subpopulations, featuring different phenotypes (intra-tumoral heterogeneity) represents a challenge for diagnosis, prognosis and targeted therapies. In this work, we have explored the metabolic differences underlying tumor heterogeneity by building cell-type-specifi... | Prostate cancer (PC) is the most commonly diagnosed non-cutaneous malignancy among Western men and accounts for the second leading cause of cancer-related death [1]. In the majority of cases, PC eventually becomes independent of androgens, resuming growth after androgen-deprivation therapies in a more aggressive and th... |
10.1371/journal.pbio.1002288 | Phosphatidylthreonine and Lipid-Mediated Control of Parasite Virulence | The major membrane phospholipid classes, described thus far, include phosphatidylcholine (PtdCho), phosphatidylethanolamine (PtdEtn), phosphatidylserine (PtdSer), and phosphatidylinositol (PtdIns). Here, we demonstrate the natural occurrence and genetic origin of an exclusive and rather abundant lipid, phosphatidylthre... | Lipids are essential constituents of biological membranes, and most organisms across the tree of life use a relatively limited repertoire of lipids in their membranes. This work reveals the natural and abundant presence of an exclusive lipid phosphatidylthreonine (PtdThr) in Toxoplasma gondii, a ubiquitous protozoan pa... | Intracellular protozoan parasites impose a substantial threat to human and animal health. Toxoplasma gondii is one of the most prevalent protozoan parasites, infecting nearly all warm-blooded vertebrates, including humans [1]. Over the last two decades, T. gondii has also become a popular model organism to understand t... |
10.1371/journal.pgen.1000175 | Segmental Duplications Arise from Pol32-Dependent Repair of Broken Forks through Two Alternative Replication-Based Mechanisms | The propensity of segmental duplications (SDs) to promote genomic instability is of increasing interest since their involvement in numerous human genomic diseases and cancers was revealed. However, the mechanism(s) responsible for their appearance remain mostly speculative. Here, we show that in budding yeast, replicat... | Duplications of long segments of chromosomes are frequently observed in multicellular organisms (∼5% of our genome, for instance). They appear as a fundamental trait of the recent genome evolution in great apes and are often associated with chromosomal instability, capable of increasing genetic polymorphism among indiv... | In humans, segmental duplications (SD) cover up to 5.2% of the genome [1] and are responsible for numerous gene-dosage imbalances [2], gene fusions and disruption events 3,4,5. Together with large insertions/deletions, SDs lead to gene copy number variations (CNVs) which represent a major source of polymorphism between... |
10.1371/journal.pgen.1006956 | Recruitment of Armitage and Yb to a transcript triggers its phased processing into primary piRNAs in Drosophila ovaries | Small RNAs called PIWI -interacting RNAs (piRNAs) are essential for transposon control and fertility in animals. Primary processing is the small RNA biogenesis pathway that uses long single-stranded RNA precursors to generate millions of individual piRNAs, but the molecular mechanisms that identify a transcript as a pr... | PIWI-interacting RNAs (piRNAs) are 24–30 nucleotide (nt) small RNAs that are exclusively expressed in animal germlines and are essential for suppression of transposable elements or ‘jumping genes’. Millions of piRNAs are produced from single-stranded transcripts that arise from large RNA polymerase II transcription uni... | Bulk of the eukaryotic genomes are composed of genetic material derived from mobile genetic elements called transposons. Their mobility within the genome can cause mutations or deletions, impacting genome integrity [1]. Given the diversity of transposable elements within any genome, small RNAs are used to sequence-spec... |
10.1371/journal.ppat.0030131 | Phylogenetic Analysis Reveals the Global Migration of Seasonal Influenza A Viruses | The winter seasonality of influenza A virus in temperate climates is one of the most widely recognized, yet least understood, epidemiological patterns in infectious disease. Central to understanding what drives the seasonal emergence of this important human pathogen is determining what becomes of the virus during the n... | The winter seasonality of influenza A virus in temperate climates is one of the most puzzling epidemiological patterns in infectious disease. To help resolve the issue of influenza seasonality, we studied, using viral genome sequence data, the patterns of global migration of influenza A virus, particularly between the ... | Influenza A virus is able to persistently re-infect human populations by continually evading host immunity through the rapid evolution of surface antigens (“antigenic drift”) [1]. Influenza virus epidemics strike temperate latitudes of the world each winter, from November to March in the northern hemisphere and from Ma... |
10.1371/journal.pntd.0006358 | Report of a series of 82 cases of Buruli ulcer from Nigeria treated in Benin, from 2006 to 2016 | Nigeria is one of the countries endemic for Buruli ulcer (BU) in West Africa but did not have a control programme until recently. As a result, BU patients often access treatment services in neighbouring Benin where dedicated health facilities have been established to provide treatment free of charge for BU patients. Th... | Buruli ulcer (BU) is a neglected tropical disease that mainly affects the skin. The disease results from infection with Mycobacterium ulcerans, an environmental bacterium. In Benin, the BU treatment centres usually receive patients from Nigeria. In 2014, a study from one of the treatment centres (CDTUB, Pobe) which bor... | Buruli ulcer (BU) is a neglected tropical disease that mainly affects the skin. The disease results from infection with Mycobacterium ulcerans, an environmental bacterium. BU is found in often swampy and humid areas. The mode of transmission remains obscure to this day, although several hypotheses have been proposed. M... |
10.1371/journal.pgen.1003667 | ATM Release at Resected Double-Strand Breaks Provides Heterochromatin Reconstitution to Facilitate Homologous Recombination | Non-homologous end-joining (NHEJ) and homologous recombination (HR) represent the two main pathways for repairing DNA double-strand breaks (DSBs). During the G2 phase of the mammalian cell cycle, both processes can operate and chromatin structure is one important factor which determines DSB repair pathway choice. ATM f... | Double-strand breaks (DSBs) are critical DNA lesions because they can lead to cell death or, which is even more devastating, the formation of genomic rearrangements. Cells are equipped with two main pathways to repair such lesions, homologous recombination (HR) and non-homologous end-joining (NHEJ). HR is an error-free... | DNA double-strand breaks (DSBs) are among the most deleterious cellular lesions since they threaten genomic integrity and cell viability. To counteract cell degeneration and to preserve genomic integrity, a complex network of DSB repair and signaling processes has evolved [1]–[4].
Two main DSB repair pathways exist, c... |
10.1371/journal.pntd.0003683 | Down Regulation of NO Signaling in Trypanosoma cruzi upon Parasite-Extracellular Matrix Interaction: Changes in Protein Modification by Nitrosylation and Nitration | Adhesion of the Trypanosoma cruzi trypomastigotes, the causative agent of Chagas' disease in humans, to components of the extracellular matrix (ECM) is an important step in host cell invasion. The signaling events triggered in the parasite upon binding to ECM are less explored and, to our knowledge, there is no data av... | Interaction of Trypanosoma cruzi with the extracellular matrix (ECM) is an essential step in the invasion of mammalian cells. However, the nature of the signaling triggered in the parasite is poorly understood. Herein the key role of nitric oxide in T. cruzi signaling is described, using an ECM preparation, in the abse... | Trypanosoma cruzi is the etiological agent of Chagas disease, an infectious disease affecting areas of poor socioeconomic development. The parasite infects a wide range of mammalian hosts, including humans, from which 7–8 million are infected and other 25 million are at risk of contamination [1]. T. cruzi trypomastigot... |
10.1371/journal.pmed.1002095 | Cardiometabolic Risk Factor Changes Observed in Diabetes Prevention Programs in US Settings: A Systematic Review and Meta-analysis | The Diabetes Prevention Program (DPP) study showed that weight loss in high-risk adults lowered diabetes incidence and cardiovascular disease risk. No prior analyses have aggregated weight and cardiometabolic risk factor changes observed in studies implementing DPP interventions in nonresearch settings in the United St... | In the United States and in many other countries, rates of both obesity and diabetes continue to increase every year.
The US Diabetes Prevention Program (DPP) trial studied people with a high risk of diabetes and placed them in a program encouraging adoption of both a healthy diet and exercise, consisting of 16 core se... | Diabetes currently affects approximately 9.3% of the United States population [1], and by 2050, its prevalence is expected to reach 25% [2]. Adults with diabetes have two to four times higher rates of death from heart disease or stroke, and they have medical expenses that are more than two times higher than those for p... |
10.1371/journal.pntd.0003552 | Lipid-Free Antigen B Subunits from Echinococcus granulosus: Oligomerization, Ligand Binding, and Membrane Interaction Properties | The hydatid disease parasite Echinococcus granulosus has a restricted lipid metabolism, and needs to harvest essential lipids from the host. Antigen B (EgAgB), an abundant lipoprotein of the larval stage (hydatid cyst), is thought to be important in lipid storage and transport. It contains a wide variety of lipid class... | Echinococcus granulosus is a causative agent of hydatidosis, a parasitic disease that affects humans and livestock with significant economic and public health impact worldwide. Antigen B (EgAgB), an abundant product of E. granulosus larvae, is a lipoprotein that carries a wide variety of lipids, including fatty acids a... | Cystic echinococcosis (CE), one of two major types of hydatid disease, is a worldwide zoonosis caused by the larval stage (metacestode) of Echinococcus granulosus sensu lato (E. granulosus s.l.), which includes a series of species traditionally considered to comprise different strains or genotypes of E. granulosus [1,2... |
10.1371/journal.pgen.1004938 | Asymmetry of the Budding Yeast Tem1 GTPase at Spindle Poles Is Required for Spindle Positioning But Not for Mitotic Exit | The asymmetrically dividing yeast S. cerevisiae assembles a bipolar spindle well after establishing the future site of cell division (i.e., the bud neck) and the division axis (i.e., the mother-bud axis). A surveillance mechanism called spindle position checkpoint (SPOC) delays mitotic exit and cytokinesis until the sp... | In asymmetrically dividing cells, proper positioning of the mitotic spindle relative to polarity determinants is crucial to ensure the unequal fate of daughter cells. In stem cells, derangement of the mechanisms controlling asymmetric cell division, including spindle positioning, affects the developmental fate of daugh... | Asymmetric cell division generates two daughter cells genetically identical but that differ in fate and/or in size and cytoplasmic material. During asymmetric cell division, polarity factors are first concentrated to specific locations to define the poles of cell division. Afterwards the spindle orients according to th... |
10.1371/journal.pntd.0004622 | Effects of Mother’s Illness and Breastfeeding on Risk of Ebola Virus Disease in a Cohort of Very Young Children | Young children who contract Ebola Virus Disease (EVD) have a high case fatality rate, but their sources of infection and the role of breastfeeding are unclear.
Household members of EVD survivors from the Kerry Town Ebola Treatment Centre in Sierra Leone were interviewed four to 10 months after discharge to establish ex... | Our study is the first to quantify sources of infection and describe risk of transmission of Ebola to young children. We found that the risk of a child under three developing Ebola disease was low unless their mother had EVD, and that the risk was particularly high if their mother died of EVD. But we found no additiona... | Young children experience a high case fatality rate from Ebola, but the incidence of Ebola Virus Disease (EVD) in children appears to be lower than in adults.[1–4] Young children may have limited exposure outside the home, but within the household maintaining hygiene in young children is difficult, although efforts may... |
10.1371/journal.ppat.1006827 | The fungal myosin I is essential for Fusarium toxisome formation | Myosin-I molecular motors are proposed to function as linkers between membranes and the actin cytoskeleton in several cellular processes, but their role in the biosynthesis of fungal secondary metabolites remain elusive. Here, we found that the myosin I of Fusarium graminearum (FgMyo1), the causal agent of Fusarium hea... | The mycotoxin deoxynivalenol (DON) is the most frequently detected secondary metabolite produced by Fusarium graminearum and other Fusarium spp. To date, relatively few studies have addressed how mycotoxin biosynthesis occurs in fungal cells. Here we found that myosin I governs translation of DON biosynthetic enzyme Tr... | Fusarium head blight (FHB) caused predominately by Fusarium graminearum is an economically devastating disease of small grain cereal crops [1]. This disease not only reduces yield and seed quality but also poses a great risk to human and animal health owing to its ability to contaminate grains with mycotoxins. The comm... |
10.1371/journal.pntd.0006344 | Experimental Chagas disease-induced perturbations of the fecal microbiome and metabolome | Trypanosoma cruzi parasites are the causative agents of Chagas disease. These parasites infect cardiac and gastrointestinal tissues, leading to local inflammation and tissue damage. Digestive Chagas disease is associated with perturbations in food absorption, intestinal traffic and defecation. However, the impact of T.... | Host-parasite interactions are usually studied as a binary system, without considering the role of the host microbiota. This work integrates microbiome research into the study of gastrointestinal Chagas disease. We show that T. cruzi infection perturbs the fecal microbiome and metabolome, indicating functional changes ... | Trypanosoma cruzi are protozoan parasites endemic to Central and South America. They cause a range of cardiac and gastrointestinal manifestations collectively known as Chagas disease. With increasing travel and immigration, infected individuals are also now found worldwide. Six to seven million people are T. cruzi-posi... |
10.1371/journal.ppat.1000147 | The Cysteine-Rich Interdomain Region from the Highly Variable Plasmodium falciparum Erythrocyte Membrane Protein-1 Exhibits a Conserved Structure | Plasmodium falciparum malaria parasites, living in red blood cells, express proteins of the erythrocyte membrane protein-1 (PfEMP1) family on the red blood cell surface. The binding of PfEMP1 molecules to human cell surface receptors mediates the adherence of infected red blood cells to human tissues. The sequences of ... | Malaria parasites express proteins of the erythrocyte membrane protein-1 family (PfEMP1) on the surfaces of the human red blood cells that they infect. These large proteins vary in sequence extensively, yet bind to host receptors to allow infected cells to adhere to host tissues. PfEMP1 proteins help parasites evade th... | Cycles of exponential parasite growth inside infected red blood cells (iRBCs), followed by lysis, and immediate re-invasion of uninfected RBCs are the hallmarks of malaria caused by P. falciparum. Though seemingly hidden from the human immune system inside the iRBC, P. falciparum expresses a number of proteins on the i... |
10.1371/journal.ppat.0030029 | TBK1 Protects Vacuolar Integrity during Intracellular Bacterial Infection | TANK-binding kinase-1 (TBK1) is an integral component of Type I interferon induction by microbial infection. The importance of TBK1 and Type I interferon in antiviral immunity is well established, but the function of TBK1 in bacterial infection is unclear. Upon infection of murine embryonic fibroblasts with Salmonella ... | Early control of invading microbial pathogens is an essential function of the host response to infection. Previous studies have shown that upon viral infection, a protein called TANK-binding kinase-1(TBK1) signals the induction of a program of protection that results in inhibition of viral replication. During infection... | Host organisms employ a multitude of innate defense mechanisms against invading microbial pathogens. Functions of the innate immune system include control and destruction of pathogens and instruction of the developing adaptive immune response through expression of cytokines, chemokines, and other proinflammatory molecu... |
10.1371/journal.ppat.1000483 | Connecting Quorum Sensing, c-di-GMP, Pel Polysaccharide, and Biofilm Formation in Pseudomonas aeruginosa through Tyrosine Phosphatase TpbA (PA3885) | With the opportunistic pathogen Pseudomonas aeruginosa, quorum sensing based on homoserine lactones was found to influence biofilm formation. Here we discern a mechanism by which quorum sensing controls biofilm formation by screening 5850 transposon mutants of P. aeruginosa PA14 for altered biofilm formation. This scre... | Most bacteria live in biofilms, which are complex communities of microorganisms attached to a surface via polysaccharides; these biofilms are responsible for most human bacterial diseases. The pathogen Pseudomonas aeruginosa is best-studied for biofilm formation. Currently, it is recognized that cell communication or q... | Pseudomonas aeruginosa, an opportunistic pathogen, is often used to elucidate how biofilms form because persistence of this bacterium is linked to its ability to form biofilms [1]. Biofilms are formed by the attachment of bacteria to submerged surfaces in aquatic environments through their production of microbial produ... |
10.1371/journal.pcbi.1001051 | Theoretical Analysis of the Stress Induced B-Z Transition in Superhelical DNA | We present a method to calculate the propensities of regions within a DNA molecule to transition from B-form to Z-form under negative superhelical stresses. We use statistical mechanics to analyze the competition that occurs among all susceptible Z-forming regions at thermodynamic equilibrium in a superhelically stress... | We present the SIBZ algorithm that calculates the equilibrium properties of the transition from right-handed B-form to left-handed Z-form in a DNA sequence that is subjected to imposed stresses. SIBZ calculates the probability of transition of each base pair in a user-defined sequence. By examining illustrative example... | DNA often occurs in an underwound, negatively superhelical topological state in vivo. In bacteria, gyrase enzymes act to generate negative supercoils, while topoisomerases dissipate them. The dynamic balance between these two processes determines a basal level of superhelicity that can change according to the environme... |
10.1371/journal.pntd.0007184 | Application of a targeted-enrichment methodology for full-genome sequencing of Dengue 1-4, Chikungunya and Zika viruses directly from patient samples | The frequency of epidemics caused by Dengue viruses 1–4, Zika virus and Chikungunya viruses have been on an upward trend in recent years driven primarily by uncontrolled urbanization, mobility of human populations and geographical spread of their shared vectors, Aedes aegypti and Aedes albopictus. Infections by these v... | Dengue viruses 1–4 (DENV1-4), Zika virus (ZIKV) and Chikungunya virus (CHIKV) are tropical and subtropical viruses that share a common arthropod vector, and have very similar clinical presentations that are difficult to distinguish. With the recent outbreaks of DENV, ZIKV and CHIKV globally, a single methodology able t... | Dengue viruses 1–4 (DENV1-4), Zika virus (ZIKV) and Chikungunya virus (CHIKV) are viruses spread by the Aedes aegypti and Aedes albopictus and are among the foremost arboviral threats to humans today [1]. DENV and ZIKV are flaviviruses with positive-sense, single-stranded RNA genomes of ~11 kb that encode for a single ... |
10.1371/journal.ppat.1005074 | A Novel Virus Causes Scale Drop Disease in Lates calcarifer | From 1992 onwards, outbreaks of a previously unknown illness have been reported in Asian seabass (Lates calcarifer) kept in maricultures in Southeast Asia. The most striking symptom of this emerging disease is the loss of scales. It was referred to as scale drop syndrome, but the etiology remained enigmatic. By using a... | Asian seabass or Lates calcarifer is a large, valuable fish kept in maricultures. Scale drop syndrome is an emerging disease in this species that currently results in significant economic losses for affected farms. Mortality rates can become as high as 50%, both in juvenile and adult fish. With the increasing maricultu... | Scale drop syndrome in Lates calcarifer, Asian seabass, was first reported in 1992 in Penang, Malaysia, and since then outbreaks have been seen in Indonesia and in the Strait of Malacca. The phenotypic symptoms and pathology of the syndrome were described in detail by Gibson-Kueh et al. [1]. Typically, affected fish ar... |
10.1371/journal.ppat.1000138 | Superior Immunogenicity of Inactivated Whole Virus H5N1 Influenza Vaccine is Primarily Controlled by Toll-like Receptor Signalling | In the case of an influenza pandemic, the current global influenza vaccine production capacity will be unable to meet the demand for billions of vaccine doses. The ongoing threat of an H5N1 pandemic therefore urges the development of highly immunogenic, dose-sparing vaccine formulations. In unprimed individuals, inacti... | The rise and spread of the highly pathogenic avian H5N1 influenza virus has seriously increased the risk of a new influenza pandemic. However, the number of vaccine doses that can be produced with today's production capacity will fall short of the demand in times of a pandemic. Use of inactivated whole virus (WIV) vacc... | The first cases of human infection with highly pathogenic avian influenza (HPAI) H5N1 virus occurred in 1997 during an outbreak in Hong Kong [1]. Since then HPAI H5N1 has spread across Asia, Europe, Africa and the Pacific, and has caused a cumulative number of 338 laboratory confirmed human cases of infection, with a f... |
10.1371/journal.pgen.1004843 | Recurrent Loss of Specific Introns during Angiosperm Evolution | Numerous instances of presence/absence variations for introns have been documented in eukaryotes, and some cases of recurrent loss of the same intron have been suggested. However, there has been no comprehensive or phylogenetically deep analysis of recurrent intron loss. Of 883 cases of intron presence/absence variatio... | The spliceosomal introns are nucleotide sequences that interrupt coding regions of eukaryotic genes and are removed by RNA splicing after transcription. Recent studies have reported several examples of possible recurrent intron loss or gain, i.e., introns that are independently removed from or inserted into the identic... | Spliceosomal introns (called introns hereafter) are noncoding DNA segments within eukaryotic genes that are removed after transcription. Although the presence of introns is one of the universal features of eukaryotes, and a large number of intron positions are highly conserved in orthologous genes across species, famil... |
10.1371/journal.pbio.1001810 | Dual PDF Signaling Pathways Reset Clocks Via TIMELESS and Acutely Excite Target Neurons to Control Circadian Behavior | Molecular circadian clocks are interconnected via neural networks. In Drosophila, PIGMENT-DISPERSING FACTOR (PDF) acts as a master network regulator with dual functions in synchronizing molecular oscillations between disparate PDF(+) and PDF(−) circadian pacemaker neurons and controlling pacemaker neuron output. Yet th... | Circadian clocks provide a mechanism for predicting and adapting behavioral and physiological processes to 24-hour rhythms in the environment. In animal nervous systems, cell-autonomous molecular oscillators are coupled via neural networks that control daily patterns of activity. A major neuropeptide synchronizing neur... | Circadian clocks endow organisms with the ability to predict and respond adaptively to daily changes in the environment. In many taxa, these clocks consist of cell-autonomous molecular feedback loops, producing ∼24-hour oscillations at the mRNA and protein levels. In insects and mammals these clocks are also connected ... |
10.1371/journal.ppat.1007578 | Oncogenic KSHV-encoded interferon regulatory factor upregulates HMGB2 and CMPK1 expression to promote cell invasion by disrupting a complex lncRNA-OIP5-AS1/miR-218-5p network | Kaposi’s sarcoma (KS), a highly disseminated tumor of hyperproliferative spindle endothelial cells, is the most common AIDS-associated malignancy caused by infection of Kaposi’s sarcoma-associated herpesvirus (KSHV). KSHV-encoded viral interferon regulatory factor 1 (vIRF1) is a viral oncogene but its role in KSHV-indu... | Kaposi's sarcoma-associated herpesvirus (KSHV) infection caused Kaposi’s sarcoma (KS), a highly disseminated tumor that frequently occurs in patients with AIDS. KSHV-encoded viral interferon regulatory factor 1 (vIRF1) is an oncogenic protein, which has been shown to be vital in KSHV evasion of innate antiviral respons... | Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is a double-stranded DNA virus, which belongs to γ-herpesvirus. KSHV was initially identified in an AIDS-associated Kaposi’s sarcoma (AIDS-KS) lesion, and has since been strongly linked to Kaposi’s sarcoma (KS), primary effusion ... |
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