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10.1371/journal.pgen.1007672 | The genomic basis of environmental adaptation in house mice | House mice (Mus musculus) arrived in the Americas only recently in association with European colonization (~400–600 generations), but have spread rapidly and show evidence of local adaptation. Here, we take advantage of this genetic model system to investigate the genomic basis of environmental adaptation in house mice... | The recent introduction of house mice into North America from Europe provides an opportunity to investigate environmental adaptation in an important genetic model system. We found that mice from different latitudes differed in body size and aspects of blood chemistry and behavior, and that those differences have a gene... | Understanding how organisms adapt to their environment is at the heart of evolutionary biology. The recent introduction of the western house mouse (Mus musculus domesticus) into North America from Europe provides a unique opportunity to study the genetic basis of environmental adaptation over short evolutionary timesca... |
10.1371/journal.pcbi.1004963 | Interplay between Graph Topology and Correlations of Third Order in Spiking Neuronal Networks | The study of processes evolving on networks has recently become a very popular research field, not only because of the rich mathematical theory that underpins it, but also because of its many possible applications, a number of them in the field of biology. Indeed, molecular signaling pathways, gene regulation, predator... | Many biological phenomena can be viewed as dynamical processes on a graph. Understanding coordinated activity of nodes in such a network is of some importance, as it helps to characterize the behavior of the complex system. Of course, the topology of a network plays a pivotal role in determining the level of coordinati... | Analyzing networks of interacting elements has become the tool of choice in many areas of biology. In recent years, network models have been used to study the interactions between predator and prey [1], gene interactions [2] and neural network dynamics [3, 4]. A fundamental question in the study of complex networks is ... |
10.1371/journal.pgen.1004102 | Comprehensive Functional Annotation of 77 Prostate Cancer Risk Loci | Genome-wide association studies (GWAS) have revolutionized the field of cancer genetics, but the causal links between increased genetic risk and onset/progression of disease processes remain to be identified. Here we report the first step in such an endeavor for prostate cancer. We provide a comprehensive annotation of... | In the following work we provide a complete summary annotation of functional hypotheses relating to risk identified by genome wide association studies of prostate cancer. In addition, we present new genome-wide profiles for H3K27-acetylation and TCF7L2 binding in LNCaP cells. We also introduce the concept of a risk enh... | The basic goal of research into human genetics is to connect variation at the genetic level with variation in organismal and cellular phenotype. Until recently, inferences about such connections have been limited to the kind associated with heritable disorders and developmental syndromes. Such variations often turn out... |
10.1371/journal.pgen.1001356 | Widespread Hypomethylation Occurs Early and Synergizes with Gene Amplification during Esophageal Carcinogenesis | Although a combination of genomic and epigenetic alterations are implicated in the multistep transformation of normal squamous esophageal epithelium to Barrett esophagus, dysplasia, and adenocarcinoma, the combinatorial effect of these changes is unknown. By integrating genome-wide DNA methylation, copy number, and tra... | The incidence of esophageal adenocarcinoma (EA) is increasing at an alarming pace in the United States. Distinct pathological stages of Barrett's metaplasia and low- and high-grade dysplasia can be seen preceding malignant transformation. These precursor lesions provide a unique in vivo model for deepening our understa... | The incidence of esophageal adenocarcinoma (EAC) is increasing at an alarming pace in the United States (>600% increase since 1975) [1]. Since most patients with EAC present at diagnosis with an advanced disease stage, the 5-year survival rate is a dismal 13% [2], underscoring the pressing need for early diagnostic bio... |
10.1371/journal.ppat.1001142 | Requirements for Receptor Engagement during Infection by Adenovirus Complexed with Blood Coagulation Factor X | Human adenoviruses from multiple species bind to coagulation factor X (FX), yet the importance of this interaction in adenovirus dissemination is unknown. Upon contact with blood, vectors based on adenovirus serotype 5 (Ad5) binds to FX via the hexon protein with nanomolar affinity, leading to selective uptake of the c... | Adenoviruses can infect many cell types and cause a range of illnesses in humans, including respiratory, ocular and gastrointestinal disorders. These illnesses are rarely fatal; however, in immunocompromised individuals, especially young children, disseminated adenovirus infections can cause serious and life-threatenin... | Adenoviruses are non-enveloped, icosahedral double-stranded DNA viruses of 70–90nm diameter. 54 different human serotypes have been identified to date and are classified into species based on their ability to agglutinate human, monkey or rat erythrocytes [1]. Adenoviruses cause a range of illnesses depending on the rou... |
10.1371/journal.pntd.0006782 | Improved methods to capture the total societal benefits of zoonotic disease control: Demonstrating the cost-effectiveness of an integrated control programme for Taenia solium, soil transmitted helminths and classical swine fever in northern Lao PDR | Control and elimination of zoonotic diseases requires robust information about their effect on both human and livestock health in order to enable policy formulation and the allocation of resources. This study aimed to evaluate the cost-effectiveness of controlling Taenia solium taeniasis/cysticercosis in both humans an... | A study was conducted in northern Lao PDR to ascertain the cost-effectiveness of controlling Taenia solium (T. solium taeniasis/cysticercosis) using five approaches namely: i) T. solium taeniasis/cysticercosis alone in the human population (the base comparator), ii) T. solium taeniasis/cysticercosis and soil transmitte... | Taenia solium taeniasis-cysticercosis complex is a zoonotic Neglected Tropical Disease (zNTD) found throughout many parts of Asia, Africa and Latin America, particularly where pigs and humans co-exist in areas of poor sanitation and hygiene [1–2]. Being the most important food-borne parasite worldwide and ranked fourth... |
10.1371/journal.pcbi.1005042 | Symbiotic Cell Differentiation and Cooperative Growth in Multicellular Aggregates | As cells grow and divide under a given environment, they become crowded and resources are limited, as seen in bacterial biofilms and multicellular aggregates. These cells often show strong interactions through exchanging chemicals, as evident in quorum sensing, to achieve mutualism and division of labor. Here, to achie... | Unicellular organisms, when aggregated under limited resources, often exhibit behaviors akin to multicellular organisms, possibly without advanced regulation mechanisms, as observed in biofilms and bacterial colonies. Cells in an aggregate have to differentiate into several types that are specialized for different task... | As unicellular organisms grow and divide, they often form a crowded aggregate. As exemplified by bacterial biofilms [1–3] and slime molds [4, 5], these aggregates are not merely crowded passively, but sometimes form a functional cell aggregate, in which cells strongly interact with each other by exchanging chemicals, a... |
10.1371/journal.pcbi.1004764 | Phenotypic Heterogeneity and the Evolution of Bacterial Life Cycles | Most bacteria live in colonies, where they often express different cell types. The ecological significance of these cell types and their evolutionary origin are often unknown. Here, we study the evolution of cell differentiation in the context of surface colonization. We particularly focus on the evolution of a ‘sticky... | In nature, most bacteria occur in surface-attached colonies. Inside these colonies, cells often express many different phenotypes. The significance of these phenotypes often remains unknown. We study the evolution of cell differentiation in the context of surface colonization. We particularly focus on the evolution of ... | In nature, most bacteria live in surface-attached colonies [1,2]. Inside these colonies, cells typically express a remarkable diversity of phenotypes [3,4]. This phenotypic heterogeneity can be induced by genetic mutations, inherent stochasticity or the environment [3–7]. For example, during colony growth in Pseudomona... |
10.1371/journal.pgen.1002119 | Specific SKN-1/Nrf Stress Responses to Perturbations in Translation Elongation and Proteasome Activity | SKN-1, the Caenorhabditis elegans Nrf1/2/3 ortholog, promotes both oxidative stress resistance and longevity. SKN-1 responds to oxidative stress by upregulating genes that detoxify and defend against free radicals and other reactive molecules, a SKN-1/Nrf function that is both well-known and conserved. Here we show tha... | The mechanisms through which organisms defend against environmental stresses are critical during diverse disease processes and are likely to be important for longevity. The nematode C. elegans is advantageous for genetic analysis of how stress defenses function and contribute to survival. The evolutionarily conserved C... | Maintenance of protein homeostasis is critical for organismal health, and protection against environmental challenges. Protein homeostasis depends upon the balance among the processes of protein synthesis, folding, and degradation. Disruptions in this balance result in accumulation of abnormal proteins, which over time... |
10.1371/journal.pgen.1004266 | Interaction between Two Timing MicroRNAs Controls Trichome Distribution in Arabidopsis | The miR156-targeted SQUAMOSA PROMOTER BINDING PROTEIN LIKE (SPL) transcription factors function as an endogenous age cue in regulating plant phase transition and phase-dependent morphogenesis, but the control of SPL output remains poorly understood. In Arabidopsis thaliana the spatial pattern of trichome is a hallmark ... | MicroRNAs are important aging regulators in many organisms. In Arabidopsis the miR156-targeted SQUAMOSA PROMOTER BINDING PROTEIN LIKE (SPL) transcription factors play important roles as an endogenous age cue in programming phase transition and phase-dependent morphogenesis, including trichome patterning. However, how t... | MicroRNA (miRNA) was first identified as the regulator of the juvenile-to-adult transition in Caenorhabditis elegans [1], and a similar function was later assigned to plant miRNA: miR156 and its target SQUAMOSA PROMOTER BINDING PROTEIN LIKE (SPL) genes define an endogenous aging and flowering pathway [2], [3]. The miR1... |
10.1371/journal.pgen.1006345 | Ontogeny of Unstable Chromosomes Generated by Telomere Error in Budding Yeast | DNA replication errors at certain sites in the genome initiate chromosome instability that ultimately leads to stable genomic rearrangements. Where instability begins is often unclear. And, early instability may form unstable chromosome intermediates whose transient nature also hinders mechanistic understanding. We rep... | Genomic instability forms unstable chromosomes that generate genomic rearrangements associated with human disease. Because unstable chromosomes are inherently dynamic and rarely observed, mechanisms of instability are often inferred from genomic sequencing of the end state. Longitudinal observation of events, from init... | Faithful replication of the genome prevents chromosome instability. Replication error causing chromosome instability results in a plethora of changes, including deletion, insertion, translocations, and loss. The multi-protein DNA replication complex, called the replisome, undergoes still untold changes, with unknown co... |
10.1371/journal.pntd.0002606 | Molecular Characterization of Severin from Clonorchis sinensis Excretory/Secretory Products and Its Potential Anti-apoptotic Role in Hepatocarcinoma PLC Cells | Clonorchiasis, caused by the infection of Clonorchis sinensis (C. sinensis), is a kind of neglected tropical disease, but it is highly related to cholangiocarcinoma and hepatocellular carcinoma (HCC). It has been well known that the excretory/secretory products of C. sinensis (CsESPs) play key roles in clonorchiasis as... | Clonorchis sinensis (C. sinensis) has afflicted more than 35 million people in world and approximately 15 million in China, creating a socio-economic burden in epidemic regions. The infection of C. sinensis is highly related to cholangiocarcinoma and hepatocellular carcinoma (HCC). It has been documented that excretory... | Clonorchis sinensis (C. sinensis) has been proven to be the causative agent of clonorchiasis, which is endemic in China, Korea and Vietnam [1], [2], [3]. As an important food-borne parasite, C. sinensis has afflicted more than 35 million people in world and approximately 15 million in China, creating a socio-economic b... |
10.1371/journal.pmed.1002660 | Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial | This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional ... | There are few licensed drug treatments for Alzheimer disease and none are effective in slowing the rate of disease progression.
Nilvadipine is a licensed blood pressure medication and has been shown to lower brain amyloid and improve memory function in animal models of Alzheimer disease.
If nilvadipine were shown to be... | Observational studies have suggested a benefit of certain blood pressure medications on reducing the risk of developing dementia [1]. Particular antihypertensive agents have also been shown to decrease Alzheimer disease pathology in the brains of people with hypertension, independently of blood pressure control, sugges... |
10.1371/journal.pmed.1002788 | Evaluation of a social protection policy on tuberculosis treatment outcomes: A prospective cohort study | Tuberculosis (TB) still represents a major public health problem in Latin America, with low success and high default rates. Poor adherence represents a major threat for TB control and promotes emergence of drug-resistant TB. Expanding social protection programs could have a substantial effect on the global burden of TB... | Tuberculosis (TB) still represents a major public health problem in many regions of the world, and although treatment is widely available and highly effective, it is long and burdensome to many patients, leading to suboptimal overall results due to low adherence to treatment.
Several strategies have been proposed to im... | Tuberculosis (TB) is still today a major global public health problem due to its high impact in terms of mortality and morbidity, particularly in economically active groups of low- and middle-income countries.
Despite being a disease with an effective and affordable therapy, treatment success rates are disappointingly... |
10.1371/journal.pgen.1002696 | Collapse of Telomere Homeostasis in Hematopoietic Cells Caused by Heterozygous Mutations in Telomerase Genes | Telomerase activity is readily detectable in extracts from human hematopoietic stem and progenitor cells, but appears unable to maintain telomere length with proliferation in vitro and with age in vivo. We performed a detailed study of the telomere length by flow FISH analysis in leukocytes from 835 healthy individuals... | Human blood cells all originate from a common precursor, the hematopoietic stem cell. Telomerase, the enzyme responsible for adding telomere repeats to chromosome ends, is active in human hematopoietic stem cells but appears unable to maintain a constant telomere length with age. We first document the telomere length o... | At least a few hundred nucleotides of telomere repeats must “cap” each chromosome end in order to suppress DNA damage signals and avoid the activation of DNA repair pathways [1]–[3]. Critically short or “uncapped” telomeres may be repaired by the enzyme telomerase [4] or by recombination [5]. However, the capacity of t... |
10.1371/journal.pmed.1002407 | Contemporary disengagement from antiretroviral therapy in Khayelitsha, South Africa: A cohort study | Retention in care is an essential component of meeting the UNAIDS “90-90-90” HIV treatment targets. In Khayelitsha township (population ~500,000) in Cape Town, South Africa, more than 50,000 patients have received antiretroviral therapy (ART) since the inception of this public-sector program in 2001. Disengagement from... | As of 2015, over 11 million people in sub-Saharan Africa were receiving antiretroviral therapy (ART) for treatment of HIV/AIDS, indicating the scale of patients who need lifelong treatment.
An important component in controlling the HIV/AIDS epidemic is retaining patients in lifelong care. In addition to keeping individ... | With the 2015 World Health Organization (WHO) guidelines recommending treatment for all HIV-infected individuals regardless of CD4 status and the continued high HIV incidence rates in endemic areas, there are increasing numbers of patients eligible for and starting lifelong antiretroviral therapy (ART). In order for he... |
10.1371/journal.pcbi.1005522 | Detecting similar binding pockets to enable systems polypharmacology | In the era of systems biology, multi-target pharmacological strategies hold promise for tackling disease-related networks. In this regard, drug promiscuity may be leveraged to interfere with multiple receptors: the so-called polypharmacology of drugs can be anticipated by analyzing the similarity of binding sites acros... | Traditionally, the fact that most drugs are promiscuous binders has been a major concern in pharmacology, due to the occurrence of undesired off-target clinical events. In the recent years, however, the realization that many diseases are the result of complex biological processes has encouraged rethinking of drug promi... | Multi-target strategies are a natural approach to tackling complex diseases. A fine way to achieve a multi-target effect is through drug polypharmacology, i.e. the simultaneous modulation of several targets by means of one single agent [1, 2], which poses pharmacokinetic advantages over drug combinations [3]. In the li... |
10.1371/journal.pgen.1001172 | Conserved Genes Act as Modifiers of Invertebrate SMN Loss of Function Defects | Spinal Muscular Atrophy (SMA) is caused by diminished function of the Survival of Motor Neuron (SMN) protein, but the molecular pathways critical for SMA pathology remain elusive. We have used genetic approaches in invertebrate models to identify conserved SMN loss of function modifier genes. Drosophila melanogaster an... | Spinal Muscular Atrophy (SMA) is a common, untreatable, and often fatal neuromuscular disease predominately caused by reduced Survival Motor Neuron (SMN) protein function. Here, we use invertebrate models to identify and validate conserved genes that play a critical role in SMN loss of function neuromuscular defects. D... | Decreased Survival of Motor Neuron (SMN) protein function underlies most Spinal Muscular Atrophy (SMA) cases [1]. The SMN protein is ubiquitously expressed [2], [3], yet SMA pathology is remarkably specific. Patients lose spinal α-motorneurons and experience muscular dysfunction with atrophy. Mild cases result in slowl... |
10.1371/journal.ppat.1000485 | Intravenous Inoculation of a Bat-Associated Rabies Virus Causes Lethal Encephalopathy in Mice through Invasion of the Brain via Neurosecretory Hypothalamic Fibers | The majority of rabies virus (RV) infections are caused by bites or scratches from rabid carnivores or bats. Usually, RV utilizes the retrograde transport within the neuronal network to spread from the infection site to the central nervous system (CNS) where it replicates in neuronal somata and infects other neurons vi... | Rabies virus (RV) infects mammalian neurons and cycles in regionally distinct animal populations such as the red fox in Europe, domestic canines in Asia, or raccoons, skunks and bats in Northern America. Although human rabies can be prevented by pre- and post-exposure prophylaxis, more than 50,000 people die annually f... | Rabies is a fatal central nervous system (CNS) disease in mammals, caused by rabies virus (RV), a neurotropic lyssavirus from the family of the rhabdoviridae [1]. Generally, RV is transmitted by scratches or bites of rabid animals, which results in the dissemination of virions into skin and muscle tissue. After initial... |
10.1371/journal.pbio.1002436 | Tracking Resilience to Infections by Mapping Disease Space | Infected hosts differ in their responses to pathogens; some hosts are resilient and recover their original health, whereas others follow a divergent path and die. To quantitate these differences, we propose mapping the routes infected individuals take through “disease space.” We find that when plotting physiological pa... | When we get sick, we long for recovery; thus, a major goal of medicine is to promote resilience—the ability of a host to return to its original health following an infection. While in the laboratory we can study the response to infection with precise knowledge of inoculation time and dose, sick patients in the clinic d... | As a field, we study infectious diseases to learn how to reduce their impact. One common method is to use antibiotics to limit pathogen growth. An alternative approach, which potentially avoids the risk of pathogen evolution of antibiotic resistance, is to limit the damage caused by the infection [1]. To study infectio... |
10.1371/journal.pcbi.1003517 | Long Non-Coding RNA and Alternative Splicing Modulations in Parkinson's Leukocytes Identified by RNA Sequencing | The continuously prolonged human lifespan is accompanied by increase in neurodegenerative diseases incidence, calling for the development of inexpensive blood-based diagnostics. Analyzing blood cell transcripts by RNA-Seq is a robust means to identify novel biomarkers that rapidly becomes a commonplace. However, there ... | Long non-coding RNAs (lncRNAs) comprise a novel, fascinating class of RNAs with largely unknown biological functions. Parkinson's-disease (PD) is the most frequent motor disorder, and Deep-brain-stimulation (DBS) treatment alleviates the symptoms, but early disease biomarkers are still unknown and new future genetic in... | Recent studies have identified conspicuous diversity in large intergenic long non-coding RNAs (lncRNAs) found across many species [1] [2]. LncRNAs are currently defined as transcripts of over 200 nucleotides [3]. Nonetheless, the GENCODE non-coding RNA set, the largest currently lncRNA database, contains currently as m... |
10.1371/journal.ppat.1002228 | Structural and Functional Studies on the Interaction of GspC and GspD in the Type II Secretion System | Type II secretion systems (T2SSs) are critical for secretion of many proteins from Gram-negative bacteria. In the T2SS, the outer membrane secretin GspD forms a multimeric pore for translocation of secreted proteins. GspD and the inner membrane protein GspC interact with each other via periplasmic domains. Three differ... | Many bacterial pathogens affecting humans, animals and plants export diverse proteins across the cell membranes into the medium surrounding the bacteria. Some of these secreted proteins are involved in pathogenesis. One example is cholera toxin secreted by the bacterium Vibrio cholerae, a causative agent of cholera. Th... | Many Gram-negative bacteria use a multi-protein type II secretion system (T2SS) to secrete a wide variety of exoproteins from the periplasm into the extra-cellular milieu [1], [2], [3], [4]. In Vibrio cholerae and enterotoxigenic Escherichia coli (ETEC), cholera toxin and the closely related heat-labile enterotoxin, in... |
10.1371/journal.pgen.1005619 | Transcriptional and Linkage Analyses Identify Loci that Mediate the Differential Macrophage Response to Inflammatory Stimuli and Infection | Macrophages display flexible activation states that range between pro-inflammatory (classical activation) and anti-inflammatory (alternative activation). These macrophage polarization states contribute to a variety of organismal phenotypes such as tissue remodeling and susceptibility to infectious and inflammatory dise... | Macrophages provide a first line of defense against invading pathogens and play an important role in the initiation and resolution of immune responses. When in contact with pathogens or immune factors, such as cytokines, macrophages assume activation states that range between pro-inflammatory (classical activation) and... | At the cellular level, innate immune cells, such as macrophages, are central to the development and prevention of infectious diseases. On engagement of surface signaling receptors or pattern recognition receptors (PRRs) such as toll-like receptors (TLRs), RIG-I-like receptors (RLRs) and the cytosolic NOD-like receptors... |
10.1371/journal.pbio.0060261 | Evolutionary Plasticity of Polycomb/Trithorax Response Elements in Drosophila Species | cis-Regulatory DNA elements contain multiple binding sites for activators and repressors of transcription. Among these elements are enhancers, which establish gene expression states, and Polycomb/Trithorax response elements (PREs), which take over from enhancers and maintain transcription states of several hundred deve... | The evolution of regulatory DNA plays a crucial role in making species different from one another. One way to study the evolution of regulatory DNA is by genome alignment, which assumes that elements with conserved function will be found in conserved pieces of DNA. Although conservation does imply function, it does not... | cis-Regulatory DNA elements are essential for the correct activation, repression, and maintenance of gene expression. These elements typically contain multiple short DNA motifs, which are recognised by sequence-specific DNA binding proteins, that either themselves act as activators and repressors of transcription, or r... |
10.1371/journal.pgen.1007892 | Exposure of Candida albicans β (1,3)-glucan is promoted by activation of the Cek1 pathway | Candida albicans is among the most common causes of human fungal infections and is an important source of mortality. C. albicans is able to diminish its detection by innate immune cells through masking of β (1,3)-glucan in the inner cell wall with an outer layer of heavily glycosylated mannoproteins (mannan). However, ... | Candida albicans causes fungal infections in the oral cavities and bloodstreams of patients with weakened immune function, such as AIDS or cancer patients. The immune system detects fungal infections, in part, by detecting the antigenic cell wall polysaccharide β (1,3)-glucan. The ability to mask β (1,3)-glucan from im... | Candida albicans is a human commensal that is part of the natural flora of the oral, genital and gastrointestinal tracts. Candida species are also the most common fungal pathogens of humans and cause diseases ranging from superficial infections of mucosal surfaces to severe systemic bloodstream infections in immune-com... |
10.1371/journal.pgen.1007321 | Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis | Hyperostosis Cranialis Interna (HCI) is a rare bone disorder characterized by progressive intracranial bone overgrowth at the skull. Here we identified by whole-exome sequencing a dominant mutation (L441R) in SLC39A14 (ZIP14). We show that L441R ZIP14 is no longer trafficked towards the plasma membrane and excessively ... | Osteoporosis is a skeletal disorder affecting hundreds of millions of people, and is characterized by a low bone mineral density (BMD) and increased susceptibility to fracture. Genetic factors are the greatest determinants of BMD, but only a small fraction of these have been identified through genome-wide association s... | Hyperostosis Cranialis Interna (HCI, OMIM 144755) is a rare bone disorder characterized by endosteal hyperostosis and osteosclerosis of the calvaria and the skull base. This results in the entrapment and dysfunction of cranial nerves I, II, V, VII and VIII, causing disturbances in smell, vision, sensation in the face, ... |
10.1371/journal.pgen.1008386 | In eubacteria, unlike eukaryotes, there is no evidence for selection favouring fail-safe 3’ additional stop codons | Errors throughout gene expression are likely deleterious, hence genomes are under selection to ameliorate their consequences. Additional stop codons (ASCs) are in-frame nonsense ‘codons’ downstream of the primary stop which may be read by translational machinery should the primary stop have been accidentally read throu... | In all organisms, gene expression is error-prone. One such error, translational read-through, occurs where the primary stop codon of an expressed gene is missed by the translational machinery. Failure to terminate is likely to be costly, hence genomes are under selection to prevent this from happening. One proposed err... | Errors throughout transcription, translation, and post-translational modification can, and do, happen all the time [1–5]. Whilst an invaluable source of novelty that drives evolution [6], the majority of these errors are likely deleterious [1–3, 6–8]. Genomes may therefore be under selection to mitigate their consequen... |
10.1371/journal.pgen.1002568 | Neurobeachin, a Regulator of Synaptic Protein Targeting, Is Associated with Body Fat Mass and Feeding Behavior in Mice and Body-Mass Index in Humans | Neurobeachin (Nbea) regulates neuronal membrane protein trafficking and is required for the development and functioning of central and neuromuscular synapses. In homozygous knockout (KO) mice, Nbea deficiency causes perinatal death. Here, we report that heterozygous KO mice haploinsufficient for Nbea have higher body w... | Body weight and energy balance are under very complex neural, endocrine, and metabolic control. Correspondingly, recent research suggests that hundreds of genes contribute to human obesity and that only a small proportion of them have as yet been identified. Neurobeachin (Nbea) is a protein specifically expressed in ne... | The BEACH (beige and Chediak-Higashi) domain protein family is implicated in the intracellular targeting of membrane proteins. Its members have been found in yeasts, amoebas, plants and animals, suggesting involvement in fundamental cellular functions. Mutations in BEACH domain proteins result in complex defects of cel... |
10.1371/journal.pgen.1004566 | Histone Methyltransferase MMSET/NSD2 Alters EZH2 Binding and Reprograms the Myeloma Epigenome through Global and Focal Changes in H3K36 and H3K27 Methylation | Overexpression of the histone methyltransferase MMSET in t(4;14)+ multiple myeloma patients is believed to be the driving factor in the pathogenesis of this subtype of myeloma. MMSET catalyzes dimethylation of lysine 36 on histone H3 (H3K36me2), and its overexpression causes a global increase in H3K36me2, redistributin... | Precise spatial and temporal gene expression is required for normal development, and aberrant regulation of gene expression is a common factor in many diseases, including cancer. Histone modifications contribute to the control of gene expression by altering chromatin structure and affecting the recruitment of transcrip... | Epigenetic control of gene expression plays a critical role in many biological processes and aberrant chromatin regulation is the driving factor in a multitude of diseases, including cancer. Through studies of chromosomal rearrangements, copy number changes, and more recently, sequencing of cancer genomes, it has becom... |
10.1371/journal.pgen.1002105 | Multiple Common Susceptibility Variants near BMP Pathway Loci GREM1, BMP4, and BMP2 Explain Part of the Missing Heritability of Colorectal Cancer | Genome-wide association studies (GWAS) have identified 14 tagging single nucleotide polymorphisms (tagSNPs) that are associated with the risk of colorectal cancer (CRC), and several of these tagSNPs are near bone morphogenetic protein (BMP) pathway loci. The penalty of multiple testing implicit in GWAS increases the at... | Genome-wide association studies (GWAS) have identified several colorectal cancer (CRC) susceptibility polymorphisms near genes that encode proteins in the bone morphogenetic protein (BMP) pathway. However, most of the inherited susceptibility to CRC remains unexplained. We investigated three of the best candidate BMP g... | Genome-wide association (GWA) studies of colorectal cancer (CRC) have so far identified 14 common, low-risk susceptibility variants [1]. Of these 14 variants, 3 are close to loci that are secreted members of the bone morphogenetic protein (BMP) signalling pathway: GREM1 (rs4779584); BMP4 (rs4444235); and BMP2 (rs961253... |
10.1371/journal.pmed.1002821 | College affirmative action bans and smoking and alcohol use among underrepresented minority adolescents in the United States: A difference-in-differences study | College affirmative action programs seek to expand socioeconomic opportunities for underrepresented minorities. Between 1996 and 2013, 9 US states—including California, Texas, and Michigan—banned race-based affirmative action in college admissions. Because economic opportunity is known to motivate health behavior, bann... | Between 1996 and 2013, 9 US states banned race-based affirmative action in college admissions.
Affirmative action bans may have adverse spillover effects on health behavior among students belonging to underrepresented minority groups (i.e., racial and ethnic minorities that are underrepresented in higher education) thr... | Socioeconomic factors have long been recognized as critical determinants of individual and population health [1–4]. In this vein, recent work has demonstrated a robust link between access to economic opportunities, health behaviors, and health outcomes [5–9]. Public policies that influence socioeconomic opportunities m... |
10.1371/journal.pntd.0000349 | Venezuelan Equine Encephalitis Virus in Iquitos, Peru: Urban Transmission of a Sylvatic Strain | Enzootic strains of Venezuelan equine encephalitis virus (VEEV) have been isolated from febrile patients in the Peruvian Amazon Basin at low but consistent levels since the early 1990s. Through a clinic-based febrile surveillance program, we detected an outbreak of VEEV infections in Iquitos, Peru, in the first half of... | Venezuelan equine encephalitis (VEE) is a mosquito-borne viral disease often causing grave illness and large outbreaks of disease in South America. In Iquitos, Peru, a city of 350,000 situated in the Amazon forest, we normally observe 10–14 VEE cases per year associated with people traveling to rural areas where strain... | Members of the Venezuelan equine encephalitis virus (VEEV) complex are arboviruses belonging to the Alphavirus genus of the Togaviridae family. First identified among equines in the 1930s [1], VEEV-associated human disease was not recognized until 1943 [2],[3] , although epidemiological data suggest that outbreaks may ... |
10.1371/journal.ppat.1002408 | Computational and Biochemical Analysis of the Xanthomonas Effector AvrBs2 and Its Role in the Modulation of Xanthomonas Type Three Effector Delivery | Effectors of the bacterial type III secretion system provide invaluable molecular probes to elucidate the molecular mechanisms of plant immunity and pathogen virulence. In this report, we focus on the AvrBs2 effector protein from the bacterial pathogen Xanthomonas euvesicatoria (Xe), the causal agent of bacterial spot ... | The bacterial pathogen Xanthomonas euvesicatoria (Xe) is the causal agent of bacterial leaf spot disease of pepper and tomato. This pathogen is capable of delivering more than 28 effector proteins to plant cells via the type three secretion and translocation system (TTSS). The AvrBs2 protein is a TTSS effector of Xe wi... | Plants have evolved sophisticated innate immune systems to counter the attack of various microbial pathogens through a combination of diverse molecular mechanisms [1]. Plant innate immunity is controlled by two overlapping signaling pathways. The first pathway, PAMP-Triggered Immunity (PTI), is a basal defense response... |
10.1371/journal.pgen.1001146 | Genetic Variants and Their Interactions in the Prediction of Increased Pre-Clinical Carotid Atherosclerosis: The Cardiovascular Risk in Young Finns Study | The relative contribution of genetic risk factors to the progression of subclinical atherosclerosis is poorly understood. It is likely that multiple variants are implicated in the development of atherosclerosis, but the subtle genotypic and phenotypic differences are beyond the reach of the conventional case-control de... | Although cardiovascular events, such as myocardial infarction and stroke, usually occur at later ages, it is known that the atherogenic process begins much earlier in life. Detection of subclinical atherosclerosis would therefore offer the means to identify individuals who are at increased risk of developing cardiovasc... | A major challenge of medical genetics is to determine an optimal set of genetic markers, typically in the form of single nucleotide polymorphisms (SNP), which when combined together with conventional risk factors, could be used in individual level risk prediction, classification and clinical decision-making. However, g... |
10.1371/journal.pntd.0002349 | Multi-Gene Detection and Identification of Mosquito-Borne RNA Viruses Using an Oligonucleotide Microarray | Arthropod-borne viruses are important emerging pathogens world-wide. Viruses transmitted by mosquitoes, such as dengue, yellow fever, and Japanese encephalitis viruses, infect hundreds of millions of people and animals each year. Global surveillance of these viruses in mosquito vectors using molecular based assays is c... | Approximately half of the world's population is at risk of viral, mosquito-borne illness such as dengue, yellow fever, Japanese encephalitis, Rift Valley fever, and chikungunya. In the past, these viruses have been regarded as pathogens of the tropics; however, they are emerging as global causes of illness. Very few ef... | Arthropod-borne viruses (arboviruses) are important human and veterinary pathogens that are biologically transmitted to vertebrates by hematophagous (blood feeding) arthropod vectors, such as female mosquitoes. The diverse group of mosquito-borne RNA viruses primarily includes flaviviruses (Flaviviridae: Flavivirus), a... |
10.1371/journal.pgen.1000921 | A Microarray-Based Genetic Screen for Yeast Chronological Aging Factors | Model organisms have played an important role in the elucidation of multiple genes and cellular processes that regulate aging. In this study we utilized the budding yeast, Saccharomyces cerevisiae, in a large-scale screen for genes that function in the regulation of chronological lifespan, which is defined by the numbe... | The aging process is associated with the onset of several age-associated diseases including diabetes and cancer. In rodent model systems, the dietary regimen known as caloric restriction (CR) is known to delay or prevent these diseases and to extend lifespan. As a result, there is a great deal of interest in understand... | Model eukaryotic organisms such as Drosophila and C. elegans have played important roles in the identification of genes and the molecular characterization of cellular and biochemical pathways that affect the aging process [1]. For example, large-scale systematic RNAi knockdown screens for lifespan extension with C. ele... |
10.1371/journal.pbio.1000216 | Single Molecule Imaging Reveals Differences in Microtubule Track Selection Between Kinesin Motors | Cells generate diverse microtubule populations by polymerization of a common α/β-tubulin building block. How microtubule associated proteins translate microtubule heterogeneity into specific cellular functions is not clear. We evaluated the ability of kinesin motors involved in vesicle transport to read microtubule het... | Eukaryotic cells assemble a variety of cytoskeletal structures from a set of highly conserved building blocks. For example, all microtubules are generated by the polymerization of a common α/β-tubulin subunit, yet cells can contain diverse, discrete populations of microtubule structures such as axonemes, spindles, and... | Understanding how cells generate intracellular structures and overall morphologies is one of the major goals of cell biology. For the cytoskeleton, strikingly different structures can be assembled from a set of highly conserved building blocks. For example, all microtubules are generated by the polymerization of a comm... |
10.1371/journal.pcbi.1005202 | Induced Fit in Protein Multimerization: The HFBI Case | Hydrophobins, produced by filamentous fungi, are small amphipathic proteins whose biological functions rely on their unique surface-activity properties. Understanding the mechanistic details of the multimerization process is of primary importance to clarify the interfacial activity of hydrophobins. We used free energy ... | Fungi proliferate by creating a complex hyphal network growing within a wet environment. However, for most fungi to colonize new territories, they must produce spores carried by aerial hyphae and spread them into the air. Aerial structures need to overcome the surface tension of the surrounding water in order to grow i... | Hydrophobins are small (7–15 kDa) proteins produced by filamentous fungi. They are globular and rigid proteins containing four disulfide bridges which stabilize the structure. Hydrophobins perform a variety of biological roles at interfaces that help fungi to adapt to their environment including adhesion and coatings o... |
10.1371/journal.pgen.1003352 | NODULE INCEPTION Directly Targets NF-Y Subunit Genes to Regulate Essential Processes of Root Nodule Development in Lotus japonicus | The interactions of legumes with symbiotic nitrogen-fixing bacteria cause the formation of specialized lateral root organs called root nodules. It has been postulated that this root nodule symbiosis system has recruited factors that act in early signaling pathways (common SYM genes) partly from the ancestral mycorrhiza... | Legumes produce nodules in roots as the endosymbiotic organs for nitrogen-fixing bacteria, collectively called rhizobia. The symbiotic relationship enables legumes to survive on soil with poor nitrogen sources. The rhizobial infection triggers cell division in the cortex to generate root nodule primordia. The root nodu... | The interactions of legume plants with their bacterial symbionts, collectively called “rhizobia,” cause the formation of specialized root lateral organs called root nodules. Unlike lateral roots, of which initiation is regulated by endogenous signals, activation of the mitotic cell cycle for root nodule organogenesis i... |
10.1371/journal.pcbi.1004754 | Application of Rigidity Theory to the Thermostabilization of Lipase A from Bacillus subtilis | Protein thermostability is a crucial factor for biotechnological enzyme applications. Protein engineering studies aimed at improving thermostability have successfully applied both directed evolution and rational design. However, for rational approaches, the major challenge remains the prediction of mutation sites and o... | Protein thermostability is a crucial factor for biotechnological enzyme applications. However, performance studies of computational approaches for predicting effects of mutations on protein (thermo)stability have suggested that there is still room for improvement. We describe and validate a novel and unique strategy to... | Thermostability is a crucial factor for a wealth of biotechnological enzyme applications [1,2]. Protein engineering aimed at improving thermostability is thus an important field of research in biotechnology [3,4]. There, methods of directed evolution are usually applied, which mimic natural evolution [5–8]. However, di... |
10.1371/journal.pcbi.1003007 | Cleavage Entropy as Quantitative Measure of Protease Specificity | A purely information theory-guided approach to quantitatively characterize protease specificity is established. We calculate an entropy value for each protease subpocket based on sequences of cleaved substrates extracted from the MEROPS database. We compare our results with known subpocket specificity profiles for indi... | Proteases show a broad range of cleavage specificities. Promiscuous proteases as digestive enzymes unspecifically degrade peptides, whereas highly specific proteases are involved in signaling cascades. As a quantitative index of substrate specificity was lacking, we introduce cleavage entropy as a measure of substrate ... | Proteases catalyze cleavage of peptide bonds and are involved in virtually all fundamental cellular processes [1] turning proteases into central drug targets [2]. Far over 500 proteases with unique substrate cleavage patterns have been identified in the human genome [3]. These patterns reach from specificity for a sing... |
10.1371/journal.pgen.1002647 | The C. elegans H3K27 Demethylase UTX-1 Is Essential for Normal Development, Independent of Its Enzymatic Activity | Epigenetic modifications influence gene expression and provide a unique mechanism for fine-tuning cellular differentiation and development in multicellular organisms. Here we report on the biological functions of UTX-1, the Caenorhabditis elegans homologue of mammalian UTX, a histone demethylase specific for H3K27me2/3... | Chromatin organization influences gene expression, and its regulation is crucial to achieve correct cellular differentiation and development in multicellular organisms. Histone demethylases are among several factors responsible for regulating chromatin dynamics. Here we report on the biological functions of UTX-1, the ... | The proper development of multicellular organisms requires strict regulation of cell-specific gene expression to ensure appropriate cell fate specification, cellular differentiation, and organogenesis. In addition to transcription factors, gene expression is controlled by chromatin organization, which is regulated by c... |
10.1371/journal.ppat.1005959 | Additive Promotion of Viral Internal Ribosome Entry Site-Mediated Translation by Far Upstream Element-Binding Protein 1 and an Enterovirus 71-Induced Cleavage Product | The 5' untranslated region (5' UTR) of the enterovirus 71 (EV71) RNA genome contains an internal ribosome entry site (IRES) that is indispensable for viral protein translation. Due to the limited coding capacity of their RNA genomes, EV71 and other picornaviruses typically recruit host factors, known as IRES trans-acti... | Many RNA viruses utilize internal ribosome entry sites (IRES) located in the 5’ untranslated region of genomic RNA to translate viral proteins in a cap-independent manner. Host proteins that are recruited to assist in viral IRES-driven translation are known as ITAFs (IRES trans-acting factors), of which far upstream el... | Enterovirus 71 (EV71), a cytoplasmic RNA virus of the Picornaviridae family, is known to infect both animals and humans, and can cause highly fatal neurological complications [1, 2]. During the infection process, EV71 binds to P-selectin glycoprotein ligand-1 (PSGL-1; CD162) [3] or scavenger receptor B2 (SCARB2) [4] on... |
10.1371/journal.pntd.0005100 | Atypical Manifestations of Cutaneous Leishmaniasis in a Region Endemic for Leishmania braziliensis: Clinical, Immunological and Parasitological Aspects | Atypical cutaneous leishmaniasis (ACL) has become progressively more frequent in Corte de Pedra, Northeast Brazil. Herein we characterize clinical presentation, antimony response, cytokine production and parasite strains prevailing in ACL.
Between 2005 and 2012, 51 ACL (cases) and 51 temporally matched cutaneous leishm... | Leishmania braziliensis is the main cause leishmaniasis that affects skin and upper airways mucosa in Brazil. Atypical cutaneous leishmaniasis (ACL) presentations are difficult to diagnose and treat, and do not fit the classical descriptions of the disease. It is not clear whether ACL share unique features or which are... | Tegumentary leishmaniasis is caused by protozoa of the genus Leishmania and presents a worldwide incidence of 0.7 to 1.2 million cases per year. Brazil, Colombia, Peru, Costa Rica, Algeria, North Sudan, Ethiopia, Syria, Iran and Afghanistan account for approximately 75% of the global incidence of disease [1]. In the Ne... |
10.1371/journal.pgen.1002997 | Plant Vascular Cell Division Is Maintained by an Interaction between PXY and Ethylene Signalling | The procambium and cambium are meristematic tissues from which vascular tissue is derived. Vascular initials differentiate into phloem towards the outside of the stem and xylem towards the inside. A small peptide derived from CLV-3/ESR1-LIKE 41 (CLE41) is thought to promote cell divisions in vascular meristems by signa... | Plants transport water and nutrients throughout their bodies using a specialised vascular system. Vascular tissue is also responsible for providing structural support to plants; for example, wood is made up of specialised vascular cells. Consequently, the vascular system constitutes the majority of plant biomass. Chemi... | Organised cell division and differentiation are required throughout nature for development of ordered body plans. The annual rings of trees which result from seasonal differences in radial growth are a widely recognisable example of the highly regulated nature of this process. Radial growth is achieved by generation of... |
10.1371/journal.ppat.1000548 | Two HIV-1 Variants Resistant to Small Molecule CCR5 Inhibitors Differ in How They Use CCR5 for Entry | HIV-1 variants resistant to small molecule CCR5 inhibitors recognize the inhibitor-CCR5 complex, while also interacting with free CCR5. The most common genetic route to resistance involves sequence changes in the gp120 V3 region, a pathway followed when the primary isolate CC1/85 was cultured with the AD101 inhibitor i... | Human immunodeficiency virus type 1 (HIV-1) is the causative agent of AIDS. HIV-1 entry into target cells is triggered by the interaction of the viral envelope glycoproteins with a cell-surface receptor (CD4) and a co-receptor (CCR5), and culminates in fusion of the viral and cell membranes. Small molecule inhibitors t... | Small molecule drugs or drug candidates bind to the cell surface CCR5 protein and prevent human immunodeficiency virus type 1 (HIV-1) from using it as a coreceptor for entry into CD4-positive target cells [1],[2]. These compounds, which include the licensed drug maraviroc (MVC) and the clinical candidate vicriviroc (VV... |
10.1371/journal.ppat.1000493 | Ebola Zaire Virus Blocks Type I Interferon Production by Exploiting the Host SUMO Modification Machinery | Ebola Zaire virus is highly pathogenic for humans, with case fatality rates approaching 90% in large outbreaks in Africa. The virus replicates in macrophages and dendritic cells (DCs), suppressing production of type I interferons (IFNs) while inducing the release of large quantities of proinflammatory cytokines. Althou... | Ebola Zaire virus causes severe hemorrhagic fever in humans that is fatal in almost 90% of cases. The rapid spread of the virus to macrophages and dendritic cells results in the release of high levels of inflammatory cytokines, causing shock and bleeding. The ability of Ebola virus to overwhelm host defenses is believe... | Ebola Zaire virus (EBOV) causes severe hemorrhagic fever in humans, with case fatality rates as high as 90% in large outbreaks in Africa [1]. Dendritic cells (DCs) and macrophages are the main initial targets of EBOV infection [2]–[4]. A series of studies have shown that EBOV inhibits the production of type I IFN by th... |
10.1371/journal.pntd.0007580 | Risk profiling of soil-transmitted helminth infection and estimated number of infected people in South Asia: A systematic review and Bayesian geostatistical Analysis | In South Asia, hundreds of millions of people are infected with soil-transmitted helminths (Ascaris lumbricoides, hookworm, and Trichuris trichiura). However, high-resolution risk profiles and the estimated number of people infected have yet to be determined. In turn, such information will assist control programs to id... | Hundreds of millions of people in South Asia are infected with parasitic worms, such as hookworm, roundworm, and whipworm. However, precise information on where these infections occur and the exact number of people affected is not available. Such information though is important to aid control programs, so that interven... | Soil-transmitted helminths (i.e., Ascaris lumbricoides, hookworm, and Trichuris trichiura) are widespread, particularly in resource-constrained settings and marginalized populations [1]. Indeed, soil-transmitted helminth infections are among the most prevalent of the neglected tropical diseases (NTDs), and they rank am... |
10.1371/journal.ppat.1006586 | Deletion of the rodent malaria ortholog for falcipain-1 highlights differences between hepatic and blood stage merozoites | Proteases have been implicated in a variety of developmental processes during the malaria parasite lifecycle. In particular, invasion and egress of the parasite from the infected hepatocyte and erythrocyte, critically depend on protease activity. Although falcipain-1 was the first cysteine protease to be characterized ... | Malaria affects hundreds of millions of people and is the cause of hundreds of thousands of deaths each year. Infection begins with the inoculation of sporozoites into the skin during the bite of an infected mosquito. Sporozoites subsequently travel to the liver, where they invade and replicate in hepatocytes, eventual... | Malaria, caused by parasites of the genus Plasmodium, continues to be a global health problem, causing significant morbidity and mortality particularly in resource poor settings [1]. Human infection begins with the injection of sporozoites into the skin where, using gliding motility, they find and enter the blood strea... |
10.1371/journal.pbio.1002393 | Signal Transduction at the Domain Interface of Prokaryotic Pentameric Ligand-Gated Ion Channels | Pentameric ligand-gated ion channels are activated by the binding of agonists to a site distant from the ion conduction path. These membrane proteins consist of distinct ligand-binding and pore domains that interact via an extended interface. Here, we have investigated the role of residues at this interface for channel... | The pentameric ligand-gated ion channels constitute a large family of membrane proteins that are expressed in animals and certain bacteria. Their molecular architecture and function is conserved throughout the family. In mammals, they operate as receptors of the neurotransmitters acetylcholine, serotonin, GABA, and gly... | During activation of a pentameric ligand-gated ion channel (pLGIC), the binding of agonists promotes the opening of a selective ion conduction pore at a distance of more than 50 Å away from the binding sites [1,2]. This process has been described by means of the Monod Weyman Changeux (MWC) mechanism of allosteric prote... |
10.1371/journal.pgen.1001167 | Genetic Association Study Identifies HSPB7 as a Risk Gene for Idiopathic Dilated Cardiomyopathy | Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopath... | Dilated cardiomyopathy is a severe disease of the heart muscle and often leads to chronic heart failure, eventually with the consequence of cardiac transplantation. Identification of genetic disease markers in at-risk persons could play an important role in preventive health care. Several mutations in familial forms of... | Dilated cardiomyopathy (DCM) is a common form of heart muscle disease with a prevalence of 1∶2,500 in the general population. It represents a major cause of cardiovascular morbidity and mortality and is characterized by systolic dysfunction as well as dilation and impaired contraction of the ventricles, often leading t... |
10.1371/journal.pntd.0000655 | Using the Prevalence of Individual Species of Intestinal Nematode Worms to Estimate the Combined Prevalence of Any Species | To assess if a probabilistic model could be used to estimate the combined prevalence of infection with any species of intestinal nematode worm when only the separate prevalence of each species is reported, and to estimate the extent to which simply taking the highest individual species prevalence underestimates the com... | Mixed infections with roundworm, whipworm and hookworm are common, but survey reports often give only the separate prevalence of each type. However, the combined prevalence is important to estimate accurately the number of individuals who would benefit from control programmes and to make decisions about the frequency o... | The World Health Organization (WHO) estimates that intestinal nematode worms, also known as soil-transmitted helminths, are currently endemic in 130 countries in the world [1]. These worms include the common roundworm Ascaris lumbricoides, the whipworm Trichuris trichiura and the hookworms Ancylostoma duodenale and Nec... |
10.1371/journal.pntd.0003665 | Genetic Recombination between Human and Animal Parasites Creates Novel Strains of Human Pathogen | Genetic recombination between pathogens derived from humans and livestock has the potential to create novel pathogen strains, highlighted by the influenza pandemic H1N1/09, which was derived from a re-assortment of swine, avian and human influenza A viruses. Here we investigated whether genetic recombination between su... | Genetic recombination allows transfer of harmful traits between different strains of the same pathogen and enables the emergence of genetically novel pathogen strains that the host population has not previously encountered. This can be particularly important when a pathogen acquires a virulence trait that allows it to ... | Genetic recombination can generate new pathogen strains to which host populations have no prior immunity. This can have disastrous consequences; for example, the human population is at risk of an influenza pandemic caused by recombination between viruses derived from humans and domestic livestock. Microbial genetic rec... |
10.1371/journal.pgen.1004935 | Partially Redundant Enhancers Cooperatively Maintain Mammalian Pomc Expression Above a Critical Functional Threshold | Cell-specific expression of many genes is conveyed by multiple enhancers, with each individual enhancer controlling a particular expression domain. In contrast, multiple enhancers drive similar expression patterns of some genes involved in embryonic development, suggesting regulatory redundancy. Work in Drosophila has ... | The stability of animal form and function in the face of genetic and environmental variation relies on consistent gene expression. Multiple enhancers, each specifying a unique regulatory domain, control the precise spatiotemporal expression of many genes. However, in some genes apparently redundant enhancers regulate e... | Precise quantitative and spatiotemporal control of protein-coding gene expression is essential for normal development and cellular function. Cis-regulatory genomic elements, including enhancers, play pivotal roles in this control and are extensively utilized by metazoan genomes[1,2]. Although the entire repertoire of t... |
10.1371/journal.pgen.1002235 | The Evolutionarily Conserved Longevity Determinants HCF-1 and SIR-2.1/SIRT1 Collaborate to Regulate DAF-16/FOXO | The conserved DAF-16/FOXO transcription factors and SIR-2.1/SIRT1 deacetylases are critical for diverse biological processes, particularly longevity and stress response; and complex regulation of DAF-16/FOXO by SIR-2.1/SIRT1 is central to appropriate biological outcomes. Caenorhabditis elegans Host Cell Factor 1 (HCF-1... | The nematode C. elegans has been instrumental in identifying and characterizing genetic components that influence aging. Studies in worms have been successfully extended to complex mammalian organisms allowing for the identification of genetic factors that impact longevity in mammals. DAF-16/FOXO transcription factors ... | The Insulin/Insulin-like Growth Factor-1(IGF-1) signaling (IIS) cascade is one of the most highly conserved and best characterized longevity pathways in eukaryotes. When stimulated, the insulin/IGF-1 like receptors initiate a kinase cascade that leads to the phosphorylation, and cytoplasmic retention of the main downst... |
10.1371/journal.pcbi.1006199 | Learning the sequence of influenza A genome assembly during viral replication using point process models and fluorescence in situ hybridization | Within influenza virus infected cells, viral genomic RNA are selectively packed into progeny virions, which predominantly contain a single copy of 8 viral RNA segments. Intersegmental RNA-RNA interactions are thought to mediate selective packaging of each viral ribonucleoprotein complex (vRNP). Clear evidence of a spec... | Influenza virus consists of eight viral ribonucleoproteins (vRNPs) that are assembled by infected cells to produce new virions. The process by which all eight vRNPs are assembled is not yet understood. We therefore used images from a previous study in which up to four vRNPs had been visualized in the same cell to const... | Influenza A virus, part of the orthomyxoviridae family, has a segmented genome of eight distinct viral RNA segments coding at least 11 major proteins and several auxiliary peptides. Most notable of the 11 viral proteins are hemagglutinin (HA) and neurominidase (NA), the canonical H and N in influenza strain designation... |
10.1371/journal.pgen.1000296 | Disruption of AP1S1, Causing a Novel Neurocutaneous Syndrome, Perturbs Development of the Skin and Spinal Cord | Adaptor protein (AP) complexes regulate clathrin-coated vesicle assembly, protein cargo sorting, and vesicular trafficking between organelles in eukaryotic cells. Because disruption of the various subunits of the AP complexes is embryonic lethal in the majority of cases, characterization of their function in vivo is st... | We describe a novel genetic syndrome that we named MEDNIK, to designate a disease characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis and keratodermia. This syndrome was found in four French-Canadian families with a common ancestor and is caused by a mutation in the AP1S1 gene.... | Protein trafficking between organelles in eukaryotic cells is mainly mediated by clathrin-coated vesicles and their assembly requires adaptor protein (AP) complexes [1],[2]. The AP complexes also determine protein cargo selection for transport between the trans-Golgi network (TGN), endosomes, lysosomes and the plasma m... |
10.1371/journal.pgen.1006386 | The QTL GNP1 Encodes GA20ox1, Which Increases Grain Number and Yield by Increasing Cytokinin Activity in Rice Panicle Meristems | Cytokinins and gibberellins (GAs) play antagonistic roles in regulating reproductive meristem activity. Cytokinins have positive effects on meristem activity and maintenance. During inflorescence meristem development, cytokinin biosynthesis is activated via a KNOX-mediated pathway. Increased cytokinin activity leads to... | Grain number per panicle, a valuable agronomic trait for rice yield improvement, is profoundly affected by reproductive meristem activity. This activity, in turn, is controlled by transcriptional and plant hormone regulators, especially KNOX proteins and cytokinins. However, little is known about the roles of GAs in th... | Rice panicle architecture, a valuable composite agronomic trait that includes grain number per panicle (GNP), panicle length and so on, is strongly associated with rice grain yield. GNP is one of the most important agronomic characteristics of ideal plant architecture [1]. To improve rice grain yields to meet the needs... |
10.1371/journal.pcbi.1002254 | Significance of Input Correlations in Striatal Function | The striatum is the main input station of the basal ganglia and is strongly associated with motor and cognitive functions. Anatomical evidence suggests that individual striatal neurons are unlikely to share their inputs from the cortex. Using a biologically realistic large-scale network model of striatum and cortico-st... | The striatum is the main input station of the basal ganglia and plays a crucial role in multiple motor and cognitive functions. Striatum is a recurrently connected network of GABAergic medium spiny neurons (MSNs), which receive strong feedforward inhibition from the fast spiking interneurons and massive excitatory affe... | The striatum is the main input stage of the basal ganglia and plays an important role in various cognitive and motor functions [1]–[5]. With its involvement in multiple behavioral tasks, the computational role of the striatum is of crucial interest. The presence of recurrent inhibitory projections among the main consti... |
10.1371/journal.pcbi.1002719 | Predictive Dynamics of Human Pain Perception | While the static magnitude of thermal pain perception has been shown to follow a power-law function of the temperature, its dynamical features have been largely overlooked. Due to the slow temporal experience of pain, multiple studies now show that the time evolution of its magnitude can be captured with continuous onl... | We propose a model of thermal pain perception that accounts for its dynamical behavior, and can be used to predict subjective responses to thermal stimulation on individual subjects with high accuracy, close to 90% averaged over subjects (over 65% for the null hypothesis). The model is based on behavioral consideration... | Any scientific or philosophical examination of human perception invariably must take into consideration the long-lasting notion of the subjectivity of pain. Plato, Aristotle, Galen, and Darwin excluded pain from other sensory modalities and instead classified it with emotions. Avicenna (or Ibn Sina), the 11th century A... |
10.1371/journal.ppat.1007893 | The fatty acid oleate is required for innate immune activation and pathogen defense in Caenorhabditis elegans | Fatty acids affect a number of physiological processes, in addition to forming the building blocks of membranes and body fat stores. In this study, we uncover a role for the monounsaturated fatty acid oleate in the innate immune response of the nematode Caenorhabditis elegans. From an RNAi screen for regulators of inna... | The evolution of multicellular organisms has been shaped by their interactions with pathogenic microorganisms. The microscopic nematode C. elegans eats bacteria for food and has evolved inducible immune defenses toward ingested pathogens that are coordinated within intestinal epithelial cells. C. elegans, therefore, pr... | Fatty acids are the key structural components of phospholipids and triglycerides, and thereby affect nearly every facet of eukaryotic physiology. In addition to forming the building blocks of membranes and functioning as a currency of energy storage, fatty acid molecules promote health in a diverse number of ways. For ... |
10.1371/journal.pcbi.1004867 | An Introduction to Programming for Bioscientists: A Python-Based Primer | Computing has revolutionized the biological sciences over the past several decades, such that virtually all contemporary research in molecular biology, biochemistry, and other biosciences utilizes computer programs. The computational advances have come on many fronts, spurred by fundamental developments in hardware, so... | Contemporary biology has largely become computational biology, whether it involves applying physical principles to simulate the motion of each atom in a piece of DNA, or using machine learning algorithms to integrate and mine “omics” data across whole cells (or even entire ecosystems). The ability to design algorithms ... | Datasets of unprecedented volume and heterogeneity are becoming the norm in science, and particularly in the biosciences. High-throughput experimental methodologies in genomics [1], proteomics [2], transcriptomics [3], metabolomics [4], and other “omics” [5–7] routinely yield vast stores of data on a system-wide scale.... |
10.1371/journal.pbio.1001861 | The Kinase Regulator Mob1 Acts as a Patterning Protein for Stentor Morphogenesis | Morphogenesis and pattern formation are vital processes in any organism, whether unicellular or multicellular. But in contrast to the developmental biology of plants and animals, the principles of morphogenesis and pattern formation in single cells remain largely unknown. Although all cells develop patterns, they are m... | Cells have the ability to develop complex morphologies, but the mechanisms that determine these varied shapes are not well understood. Cell shape determination can be challenging to study in multicellular organisms because it can be difficult to know whether shape changes are determined internally within an individual ... | The ability to develop and regenerate complex morphologies from a simpler starting point is among the properties that set living organisms apart from inanimate matter. Although these processes are most often considered in the context of embryos and multicellular organisms, even individual cells need to develop and rege... |
10.1371/journal.ppat.1004909 | Phosphatidic Acid Produced by Phospholipase D Promotes RNA Replication of a Plant RNA Virus | Eukaryotic positive-strand RNA [(+)RNA] viruses are intracellular obligate parasites replicate using the membrane-bound replicase complexes that contain multiple viral and host components. To replicate, (+)RNA viruses exploit host resources and modify host metabolism and membrane organization. Phospholipase D (PLD) is ... | All characterized eukaryotic positive-strand RNA [(+)RNA] viruses replicate their genomes using the viral replication complexes (VRCs), which contain multiple viral and host components, on intracellular membranes. Phospholipids are major constituents of cellular membranes; however, the function(s) of phospholipids in g... | Positive-strand RNA [(+)RNA] viruses are the most abundant plant viruses, and include many viruses economically important in agriculture. (+)RNA plant viruses have a limited coding capacity. To replicate and achieve successful infection in their hosts, they need to use host proteins, membranes, lipids, and metabolites.... |
10.1371/journal.pcbi.1000741 | Flow-Based Cytometric Analysis of Cell Cycle via Simulated Cell Populations | We present a new approach to the handling and interrogating of large flow cytometry data where cell status and function can be described, at the population level, by global descriptors such as distribution mean or co-efficient of variation experimental data. Here we link the “real” data to initialise a computer simulat... | One of the key challenges facing cell biologists today is understanding the influence of molecular controls in shaping and controlling cell growth and proliferation. There is growing recognition that abnormal progression through the cell cycle and the associated effects on the growth of cell populations has a major imp... | Multiparameter flow cytometry is widely used to study the cell cycle and its perturbation in the context of both basic research and in routine clinical analysis [1]–[6]. Such analyses may use a wide range of fluorescent reporters that correlate to the expression of key molecular components of the cell cycle, such as cy... |
10.1371/journal.pcbi.1005639 | A curated genome-scale metabolic model of Bordetella pertussis metabolism | The Gram-negative bacterium Bordetella pertussis is the causative agent of whooping cough, a serious respiratory infection causing hundreds of thousands of deaths annually worldwide. There are effective vaccines, but their production requires growing large quantities of B. pertussis. Unfortunately, B. pertussis has rel... | Metabolic flux models have been used to understand how organisms adapt their metabolism under different growth conditions, and are finding increasing application in synthetic biology and biotechnology. One barrier to progress in this field is the construction and curation of metabolic flux models for new organisms. Her... | B. pertussis is a Gram-negative bacterium that causes whooping cough, a respiratory infection responsible for significant annual mortality worldwide [1, 2], especially among infants and young children. B. pertussis is described as a fastidious organism. It does not metabolise sugars as carbon source as it does not poss... |
10.1371/journal.pgen.1007824 | Anisotropic Crb accumulation, modulated by Src42A, is coupled to polarised epithelial tube growth in Drosophila | The control of the size of internal tubular organs, such as the lungs or vascular system, is critical for proper physiological activity and to prevent disease or malformations. This control incorporates the intrinsic physical anisotropy of tubes to generate proportionate organs that match their function. The exact mech... | The regulation of the size of tubular organs is critical to ensure their physiological activity and to prevent disease and malformations. Here we use the Drosophila tracheal system as a suitable model to investigate the mechanisms underlying size regulation of tubular organs. Different mechanisms were known to control ... | Tubes are physically anisotropic, with a curved circumferential axis and a flat longitudinal one. This physical property confers orientation and polarisation to tubes, critical for their physiological activity in biological systems. Many vital organs, such as the lungs, vascular system or mammary glands, are internal t... |
10.1371/journal.ppat.1007669 | FOXO1 transcription factor plays a key role in T cell—HIV-1 interaction | HIV-1 is dependent on the host cell for providing the metabolic resources for completion of its viral replication cycle. Thus, HIV-1 replicates efficiently only in activated CD4+ T cells. Barriers preventing HIV-1 replication in resting CD4+ T cells include a block that limits reverse transcription and also the lack of... | HIV-1 is controlled by host restriction factors that interfere with its life cycle. However, the virus has equipped itself to counter these strategies. We report a new interplay between HIV-1 and human T lymphocytes through the FOXO1 transcription factor. By using AS1842856, a drug targeting FOXO1, we found that FOXO1 ... | As other viruses, HIV-1 is an obligate intracellular pathogen strictly dependent on a suitable host cell machinery for most of the steps of its life cycle, a machinery that is hijacked by the virus to generate its progeny. In the case of human CD4+ T lymphocytes, the permissiveness to HIV-1 infection depends on their c... |
10.1371/journal.pgen.1002630 | Regulation of Budding Yeast Mating-Type Switching Donor Preference by the FHA Domain of Fkh1 | During Saccharomyces cerevisiae mating-type switching, an HO endonuclease-induced double-strand break (DSB) at MAT is repaired by recombining with one of two donors, HMLα or HMRa, located at opposite ends of chromosome III. MATa cells preferentially recombine with HMLα; this decision depends on the Recombination Enhanc... | Mating-type gene switching occurs by a DSB–initiated gene conversion event using one of two donors, HML or HMR. MATa cells preferentially recombine with HML whereas MATα cells choose HMR. Donor preference is governed by the Recombination Enhancer (RE), located about 17 kb from HML. RE is repressed in MATα cells, wherea... | Saccharomyces mating-type switching occurs through a DSB-initiated intrachromosomal gene conversion event at MAT, using one of two donors on chromosome III, HML and HMR (Figure 1A) [1]–[3]. Switching is initiated by expression of the site-specific HO endonuclease that cleaves only one site in the yeast genome, MATa or ... |
10.1371/journal.pcbi.1002338 | Macro-level Modeling of the Response of C. elegans Reproduction to Chronic Heat Stress | A major goal of systems biology is to understand how organism-level behavior arises from a myriad of molecular interactions. Often this involves complex sets of rules describing interactions among a large number of components. As an alternative, we have developed a simple, macro-level model to describe how chronic temp... | Dynamic response to changing conditions in the environment is an essential property of all biological systems. Whereas extensive research over the last several decades has elucidated numerous molecular responses to environmental stress, there is much less known how these translate into organismal-level responses. Two t... | Much of modern biology is inherently reductionist, seeking to enumerate interactions and components to elucidate the inner workings of cells and organisms. However, phenotypes often cannot be explained simply as the sum of the properties of the micro-components. Emergent phenomena [1] are not unique to biology; physica... |
10.1371/journal.pntd.0005798 | Epidemiology of enteroaggregative Escherichia coli infections and associated outcomes in the MAL-ED birth cohort | Enteroaggregative E. coli (EAEC) have been associated with mildly inflammatory diarrhea in outbreaks and in travelers and have been increasingly recognized as enteric pathogens in young children with and without overt diarrhea. We examined the risk factors for EAEC infections and their associations with environmental e... | Enteroaggregative E. coli (EAEC) are pathogens that infect the intestine and can cause diarrhea. They are also commonly identified among young children in low-resource settings, who can carry the pathogen without symptomatic diarrhea. We examined the risk factors for EAEC infections and their associations with child he... | Enteroaggregative Escherichia coli (EAEC) infections have been increasingly recognized as important enteropathogens since their initial discovery by patterns of adherence to HEp-2 cells in E. coli isolates from Chilean children with diarrhea [1]. EAEC have since been associated with foodborne outbreaks of diarrhea [2],... |
10.1371/journal.pntd.0005456 | Neutropenia induced by high-dose intravenous benzylpenicillin in treating neurosyphilis: Does it really matter? | Prompt therapy with high-dose intravenous benzylpenicillin for a prolonged period is critical for neurosyphilis patients to avoid irreversible sequelae. However, life-threatening neutropenia has been reported as a complication of prolonged therapy with high doses of benzylpenicillin when treating other diseases. This s... | High-dose intravenous benzylpenicillin is an effective treatment for neurosyphilis although it can cause potentially life-threatening drug-induced neutropenia. We investigated the incidence, presentation, management and prognosis of benzylpenicillin-induced neutropenia among neurosyphilis patients treated over a three ... | Neutropenia is a condition marked by an absolute neutrophil count (ANC) below 1.5×109/L in adults [1], which can be further categorized as mild (1×109/L≤ANC<1.5×109/L), moderate (0.5×109/L≤ANC<1×109/L) and severe type (ANC<0.5×109/L) [1, 2]. There are many causes including drug-induced neutropenia [2, 3]. Benzylpenicil... |
10.1371/journal.pgen.1006324 | Prion Aggregates Are Recruited to the Insoluble Protein Deposit (IPOD) via Myosin 2-Based Vesicular Transport | Aggregation of amyloidogenic proteins is associated with several neurodegenerative diseases. Sequestration of misfolded and aggregated proteins into specialized deposition sites may reduce their potentially detrimental properties. Yeast exhibits a distinct deposition site for amyloid aggregates termed “Insoluble PrOtei... | The occurrence of large inclusions of aggregated amyloidogenic proteins is a hallmark of several neurodegenerative diseases. The most toxic species are believed to represent smaller units such as oligomers, whereas larger amyloid depositions are viewed rather cell protective. Therefore, it is important to understand ho... | Protein aggregation occurs through coalescence of misfolded protein species. The cause for acquisition of an aberrant fold can be very diverse ranging from thermal, oxidative or metabolic stress, translational errors, subunit imbalance or mutations to spontaneous or induced conformational rearrangement of intrinsically... |
10.1371/journal.pntd.0000488 | Feasibility, Drug Safety, and Effectiveness of Etiological Treatment Programs for Chagas Disease in Honduras, Guatemala, and Bolivia: 10-Year Experience of Médecins Sans Frontières | Chagas disease (American trypanosomiasis) is a zoonotic or anthropozoonotic disease caused by the parasite Trypanosoma cruzi. Predominantly affecting populations in poor areas of Latin America, medical care for this neglected disease is often lacking. Médecins Sans Frontières/Doctors Without Borders (MSF) has provided ... | Chagas disease was discovered 100 years ago by the Brazilian physician Carlos Chagas. Predominantly affecting poor populations throughout Latin America, recognition and treatment of this parasitic disease are often neglected. Since 1999, the international medical humanitarian aid organization Médecins Sans Frontières (... | Discovered 100 years ago in 1909, Chagas disease (American trypanosomiasis) is an endemic disease of the Americas, caused by infection with the protozoan parasite Trypanosoma cruzi. According to varying estimates, there are about 10–15 million existing cases, 50,000 new annual infections, and 14,000 deaths per year [1]... |
10.1371/journal.pgen.1008215 | XBP1 signalling is essential for alleviating mutant protein aggregation in ER-stress related skeletal disease | The unfolded protein response (UPR) is a conserved cellular response to the accumulation of proteinaceous material in endoplasmic reticulum (ER), active both in health and disease to alleviate cellular stress and improve protein folding. Multiple epiphyseal dysplasia (EDM5) is a genetic skeletal condition and a classic... | A significant proportion of genetic skeletal diseases result from misfolding of structural proteins within the endoplasmic reticulum (ER) of cartilage cells (chondrocytes). Interestingly, these diseases often share transcriptomic changes with non-skeletal conditions such as Alzheimer’s disease and diabetes and include ... | The unfolded protein response (UPR) is one of the canonical cellular stress pathways that is triggered by unfolded proteins accumulating in the ER lumen. The pathway is active in both health and disease and many secretory cells have a highly active UPR to allow a greater secretory output [1]. Over the recent years, the... |
10.1371/journal.ppat.1007560 | Influenza-induced immune suppression to methicillin-resistant Staphylococcus aureus is mediated by TLR9 | Bacterial lung infections, particularly with methicillin-resistant Staphylococcus aureus (MRSA), increase mortality following influenza infection, but the mechanisms remain unclear. Here we show that expression of TLR9, a microbial DNA sensor, is increased in murine lung macrophages, dendritic cells, CD8+ T cells and e... | Influenza-associated secondary bacterial infections, particularly with methicillin-resistant Staphylococcus aureus (MRSA), are a major cause of morbidity and mortality, and better therapeutic strategies are needed. Stimulation of TLR2 has shown promise for improving health in influenza-bacteria dual-infected animals. H... | Influenza viruses are single-stranded RNA viruses with a segmented genome capable of undergoing mutagenesis to evade host immunity and they cause seasonal outbreaks leading to over a half million deaths per year worldwide (World Health Organization, 2016)[1]. Influenza viruses can overcome traditional vaccine strategie... |
10.1371/journal.ppat.1002438 | Synergistic Roles of Eukaryotic Translation Elongation Factors 1Bγ and 1A in Stimulation of Tombusvirus Minus-Strand Synthesis | Host factors are recruited into viral replicase complexes to aid replication of plus-strand RNA viruses. In this paper, we show that deletion of eukaryotic translation elongation factor 1Bgamma (eEF1Bγ) reduces Tomato bushy stunt virus (TBSV) replication in yeast host. Also, knock down of eEF1Bγ level in plant host dec... | RNA viruses recruit numerous host proteins to facilitate their replication and spread. Among the identified host proteins are RNA-binding proteins (RBPs), such as ribosomal proteins, translation factors and RNA-modifying enzymes. In this paper, the authors show that deletion of eukaryotic translation elongation factor ... | Plus-stranded (+)RNA viruses recruit numerous host proteins to facilitate their replication and spread [1], [2]. Among the identified host proteins are RNA-binding proteins (RBPs), such as ribosomal proteins, translation factors and RNA-modifying enzymes [1]–[5]. The subverted host proteins likely affect several steps ... |
10.1371/journal.pgen.1007189 | The non-classical nuclear import carrier Transportin 1 modulates circadian rhythms through its effect on PER1 nuclear localization | Circadian clocks are molecular timekeeping mechanisms that allow organisms to anticipate daily changes in their environment. The fundamental cellular basis of these clocks is delayed negative feedback gene regulation with PERIOD and CRYPTOCHROME containing protein complexes as main inhibitory elements. For a correct ci... | Circadian clocks are endogenous timekeeping mechanisms allowing organisms to anticipate daily changes in their environment. In mammals, the fundamental mechanism of these clocks is a delayed negative feedback loop, in which timely auto-repression of clock components is essential. This repression occurs at a transcripti... | Circadian clocks are endogenous oscillators that have evolved in almost all eukaryotes to anticipate daily rhythms in their environment. In mammals, circadian rhythm generation is a cell-autonomous process with transcriptional-translational feedback loops as fundamental mechanism [1]. A key step is the rhythmic inhibit... |
10.1371/journal.pbio.1001576 | Self-Renewal of Single Mouse Hematopoietic Stem Cells Is Reduced by JAK2V617F Without Compromising Progenitor Cell Expansion | Recent descriptions of significant heterogeneity in normal stem cells and cancers have altered our understanding of tumorigenesis, emphasizing the need to understand how single stem cells are subverted to cause tumors. Human myeloproliferative neoplasms (MPNs) are thought to reflect transformation of a hematopoietic st... | Recent descriptions of the existence of significant heterogeneity in normal stem cells and cancers have altered our understanding of tumorigenesis, emphasizing the need to understand how single stem cells are subverted to cause tumours. In this study, we focus on understanding the stem cell defect that results from a m... | The hematopoietic system produces multiple types of specialized blood cells and its lifelong maintenance relies upon hematopoietic stem cells (HSCs) [1]. One of their most intriguing characteristics is the execution of balanced fate choices in order to maintain themselves and to provide the correct numbers and types of... |
10.1371/journal.pcbi.1002104 | Decelerating Spread of West Nile Virus by Percolation in a Heterogeneous Urban Landscape | Vector-borne diseases are emerging and re-emerging in urban environments throughout the world, presenting an increasing challenge to human health and a major obstacle to development. Currently, more than half of the global population is concentrated in urban environments, which are highly heterogeneous in the extent, d... | Current theory of the spatial spread of pathogens predicts travelling waves at constant or increasing speed in homogeneous environments. However, in urban environments, increasing and often unregulated development produces a highly heterogeneous landscape. Such heterogeneity affects pathogens spread by insect vectors p... | Urbanization, due to both population growth in cities and immigration from rural communities, now concentrates almost half of the global human population (3.3 out of 6.8 billion people) into urban centres where crowding promotes the spread of infectious diseases [1]. Transmission of vector-borne diseases in urban envir... |
10.1371/journal.pgen.1007117 | Development of a tissue-specific ribosome profiling approach in Drosophila enables genome-wide evaluation of translational adaptations | Recent advances in next-generation sequencing approaches have revolutionized our understanding of transcriptional expression in diverse systems. However, measurements of transcription do not necessarily reflect gene translation, the process of ultimate importance in understanding cellular function. To circumvent this l... | Recent advances in next-generation sequencing approaches have revolutionized our understanding of transcriptional expression in diverse systems. However, transcriptional expression alone does not necessarily report gene translation, the process of ultimate importance in understanding cellular function. Ribosome profili... | Recent advances in next-generation sequencing such as RNA-seq have revolutionized the measurement and quantification of genome-wide changes in transcriptional expression, without pre-existing knowledge of gene identity, at unprecedented resolution [1, 2]. In addition, biochemical tagging of ribosomes has emerged as a p... |
10.1371/journal.pgen.1004565 | The MAP Kinase p38 Is Part of Drosophila melanogaster's Circadian Clock | All organisms have to adapt to acute as well as to regularly occurring changes in the environment. To deal with these major challenges organisms evolved two fundamental mechanisms: the p38 mitogen-activated protein kinase (MAPK) pathway, a major stress pathway for signaling stressful events, and circadian clocks to pre... | The circadian and the stress system are two distinct physiological systems that help the organism to adapt to environmental challenges. While the latter elicits reactive responses to acute environmental changes, the circadian system predicts daily occurring alterations and prepares the organism in advance. However, the... | Circadian clocks provide a key advantage to organism allowing them to prepare in advance for daily environmental changes. They control daily rhythms in physiology and behavior, as locomotor activity, sleep-wake cycles and hormonal secretion. A hallmark feature of these clocks is that they oscillate with free-running pe... |
10.1371/journal.pntd.0007187 | Increasing incidence of invasive nontyphoidal Salmonella infections in Queensland, Australia, 2007-2016 | Nontyphoidal Salmonella is a major contributor to the global burden of foodborne disease, with invasive infections contributing substantially to illnesses and deaths. We analyzed notifiable disease surveillance data for invasive nontyphoidal Salmonella disease (iNTS) in Queensland, Australia. We used Poisson regression... | We identified increasing incidence of invasive infections due to nontyphoidal Salmonella in Queensland with particularly high rates of disease among males, infants, elderly people, and cases infected with Salmonella serotype Virchow. Salmonella serotypes Choleraesuis, Dublin, and Panama had the highest proportion of in... | Nontyphoidal Salmonella (NTS) infections are a serious public health concern globally. In high-income settings, NTS predominantly causes a self-limiting diarrhoeal illness with low case fatality risk [1]. NTS may also invade beyond the gastrointestinal tract and cause severe disease, including bacteremia and infection ... |
10.1371/journal.pntd.0003093 | The Effect of (-)-Epigallocatechin 3-O - Gallate In Vitro and In Vivo in Leishmania braziliensis: Involvement of Reactive Oxygen Species as a Mechanism of Action | Leishmaniasis is a parasitic disease associated with extensive mortality and morbidity. The treatment for leishmaniasis is currently based on pentavalent antimonials and amphotericin B; however, these drugs result in numerous adverse side effects. Natural compounds have been used as novel treatments for parasitic disea... | Leishmaniasis is a parasitic disease that is endemic in 88 countries, primarily located in tropical and subtropical regions, that affects more than 12 million people worldwide. Leishmaniasis treatments are currently based on pentavalent antimonials and amphotericin B; however, these drugs result in numerous adverse sid... | Leishmaniasis is a parasitic disease that is caused by protozoa of the genus Leishmania and is associated with extensive mortality and morbidity. This disease is endemic in 98 countries, mainly in tropical and subtropical regions, and affects more than 12 million people worldwide. Leishmaniasis has an annual incidence ... |
10.1371/journal.ppat.1003845 | Suppression of Interferon Lambda Signaling by SOCS-1 Results in Their Excessive Production during Influenza Virus Infection | Innate cytokine response provides the first line of defense against influenza virus infection. However, excessive production of cytokines appears to be critical in the pathogenesis of influenza virus. Interferon lambdas (IFN-λ) have been shown to be overproduced during influenza virus infection, but the precise pathoge... | Influenza virus infection triggers innate immune responses. However, aberrant host immune responses such as excessive production of cytokines contribute to the pathogenesis of influenza virus. Type III interferons (IFN-λ) constitute the major innate immune response to influenza virus infection, but the precise pathogen... | Influenza A virus (IAV), a highly infectious respiratory pathogen, causes worldwide annual epidemics and occasional pandemics. Therefore, IAV has continued to be a top global public health threat. The host cytokine immune response provides the first line of defense against IAV infection. A variety of cell types in the ... |
10.1371/journal.pcbi.1004592 | Learning of Chunking Sequences in Cognition and Behavior | We often learn and recall long sequences in smaller segments, such as a phone number 858 534 22 30 memorized as four segments. Behavioral experiments suggest that humans and some animals employ this strategy of breaking down cognitive or behavioral sequences into chunks in a wide variety of tasks, but the dynamical pri... | Because chunking is a hallmark of the brain’s organization, efforts to understand its dynamics can provide valuable insights into the brain and its disorders. For identifying the dynamical principles of chunking learning, we hypothesize that perceptual sequences can be learned and stored as a chain of metastable fixed ... | Sequence learning is a critical component of human intelligence. The ability to recognize and produce ordered sequences is a defining feature of the brain and a key component of many cognitive performances. Sequence learning and production is a hierarchical process, such as in speech organization, behavioral sequences,... |
10.1371/journal.pcbi.1005315 | Novel Models of Visual Topographic Map Alignment in the Superior Colliculus | The establishment of precise neuronal connectivity during development is critical for sensing the external environment and informing appropriate behavioral responses. In the visual system, many connections are organized topographically, which preserves the spatial order of the visual scene. The superior colliculus (SC)... | In order to process sensory stimuli, precise connections must be established between sensory neurons during development. In the visual system, many connections are organized topographically, such that neighboring neurons monitor adjacent regions of space. In the superior colliculus (SC), converging topographic inputs m... | Processing sensory information is a critical task of the central nervous system, requiring the establishment of precisely ordered synaptic connectivity during development. In the visual system, image-forming regions are organized into topographics maps, such that neighboring neurons monitor adjacent regions of visual s... |
10.1371/journal.pcbi.1006840 | Modeling differentiation-state transitions linked to therapeutic escape in triple-negative breast cancer | Drug resistance in breast cancer cell populations has been shown to arise through phenotypic transition of cancer cells to a drug-tolerant state, for example through epithelial-to-mesenchymal transition or transition to a cancer stem cell state. However, many breast tumors are a heterogeneous mixture of cell types with... | Some classes of breast cancer tumors are composed of cells with different sets of observable traits, or phenotypes. The phenotype corresponds to particular cellular functionality and can arise due to the genetic/epigenetic code inside the cell, the environment outside the cell, and the genotype-environment interaction.... | Heterogeneity of phenotypic states in cancer cell populations is likely driven by both genetic [1] [2] [3] and epigenetic [4] [5] [3] mechanisms, and is linked to the aggressiveness of cancer and its response to therapy. In particular, different phenotypic states of breast cancer cells within a tumor are associated wit... |
10.1371/journal.pntd.0003779 | Prevalence and Transmission of Trypanosoma cruzi in People of Rural Communities of the High Jungle of Northern Peru | Vector-borne transmission of Trypanosoma cruzi is seen exclusively in the Americas where an estimated 8 million people are infected with the parasite. Significant research in southern Peru has been conducted to understand T. cruzi infection and vector control, however, much less is known about the burden of infection a... | Chagas disease causes significant morbidity and mortality throughout Central and South America. The epidemiology and control of this disease is subject to unique regional particularities, including the behavior and ecology of the local insect vector species. Significant resources have been allocated towards research an... | Chagas disease is caused by the protozoan parasite Trypanosoma cruzi, and is primarily transmitted by triatomine vectors. Chagas disease is endemic to poor rural regions of Central and South America and is responsible for the largest public health burden of any parasitic infection in the Western Hemisphere [1]. An esti... |
10.1371/journal.ppat.1000722 | Type I Interferon Induction Is Detrimental during Infection with the Whipple's Disease Bacterium, Tropheryma whipplei | Macrophages are the first line of defense against pathogens. Upon infection macrophages usually produce high levels of proinflammatory mediators. However, macrophages can undergo an alternate polarization leading to a permissive state. In assessing global macrophage responses to the bacterial agent of Whipple's disease... | Innate immune cells are sentinels allowing the host to sense invading pathogens. Among them, macrophages are highly microbicidal and are able to kill microorganisms. However, several pathogens have evolved strategies to hijack macrophage responses in order to survive or replicate. Tropheryma whipplei is the agent of Wh... | Over the past decades, activated macrophages were mainly considered as cells that secrete inflammatory mediators and kill intracellular pathogens. However, studies have now revealed activated macrophages as a continuum of cells with phenotypic and functional heterogeneity [1],[2]. Schematically, macrophages exposed to ... |
10.1371/journal.pcbi.1002804 | Modelling Hair Follicle Growth Dynamics as an Excitable Medium | The hair follicle system represents a tractable model for the study of stem cell behaviour in regenerative adult epithelial tissue. However, although there are numerous spatial scales of observation (molecular, cellular, follicle and multi follicle), it is not yet clear what mechanisms underpin the follicle growth cycl... | Although the molecular interactions that regulate the follicle growth cycle have begun to be uncovered, the fundamental interactions that regulate periodicity remain elusive. In this study we develop a model in which we neglect biophysical effects (and hence morphological changes) by treating each follicle as a functio... | Hair is a characteristic feature of mammals and performs a variety of roles, such as thermal insulation, physical protection, camouflage, social interaction and sensory perception [1]. The relative importance of the different functions of hair depend on a host of factors (e.g. local environment) and it is often crucial... |
10.1371/journal.pcbi.1002918 | Evidence for Model-based Computations in the Human Amygdala during Pavlovian Conditioning | Contemporary computational accounts of instrumental conditioning have emphasized a role for a model-based system in which values are computed with reference to a rich model of the structure of the world, and a model-free system in which values are updated without encoding such structure. Much less studied is the possib... | A hot topic in the neurobiology of learning is the idea that there may be two distinct mechanisms for learning in the brain: a model-based learning system in which predictions are made with respect to a rich internal model of the learning environment, versus a “model-free” mechanism in which trial-and-error learning oc... | Neural computations mediating instrumental conditioning are suggested to depend on two distinct mechanisms: a model-based reinforcement learning system, in which the value of actions are computed on the basis of a rich knowledge of the states of the world and the nature of the transitions between states, and a “model-f... |
10.1371/journal.ppat.1006324 | A quorum sensing-independent path to stumpy development in Trypanosoma brucei | For persistent infections of the mammalian host, African trypanosomes limit their population size by quorum sensing of the parasite-excreted stumpy induction factor (SIF), which induces development to the tsetse-infective stumpy stage. We found that besides this cell density-dependent mechanism, there exists a second p... | African trypanosomes escape the mammalian host’s immune system by antigenic variation of their variant surface glycoprotein (VSG) coat. VSGs are expressed from a specialized region in the genome, the expression site (ES), that contains essential expression site associated genes (ESAGs). So far, it was assumed that only... | Pathogenic bacteria and protozoan parasites often employ a coat of surface molecules to protect themselves from host immune attack. These surface coats are sometimes variable and hence, not only act as a physical shield but have evolved as an efficient camouflage strategy. The surface-exposed proteins are mostly member... |
10.1371/journal.pgen.1000030 | The Mating-Type Chromosome in the Filamentous Ascomycete Neurospora tetrasperma Represents a Model for Early Evolution of Sex Chromosomes | We combined gene divergence data, classical genetics, and phylogenetics to study the evolution of the mating-type chromosome in the filamentous ascomycete Neurospora tetrasperma. In this species, a large non-recombining region of the mating-type chromosome is associated with a unique fungal life cycle where self-fertil... | In fungi, mating occurs between individuals of alternative mating-types and there is no dichotomy of individuals into two morphologically different sexes. Nevertheless, in this paper we show that chromosomal regions controlling mating-type identity in fungi share features with the more complex sex chromosomes found in ... | Many diverse systems for sex determination have evolved in plants and animals [1]–[3]. One involves physically distinct sex chromosomes, a system thought to have evolved independently many times by suppression of recombination around the sex determination genes, followed by differentiation and degeneration of the non-r... |
10.1371/journal.ppat.1004286 | A Screen of Coxiella burnetii Mutants Reveals Important Roles for Dot/Icm Effectors and Host Autophagy in Vacuole Biogenesis | Coxiella burnetii is an intracellular pathogen that replicates in a lysosome-derived vacuole. The molecular mechanisms used by this bacterium to create a pathogen-occupied vacuole remain largely unknown. Here, we conducted a visual screen on an arrayed library of C. burnetii NMII transposon insertion mutants to identif... | Coxiella burnetii is the causative agent of the human disease Q fever. This bacterium uses the Dot/Icm type IV secretion system to deliver effectors into the cytosol of host cells. The Dot/Icm system is required for intracellular replication of C. burnetii. To determine the contribution of individual proteins to the es... | Coxiella burnetii is a highly infectious human pathogen responsible for a global zoonotic disease called Q fever. Inhalation of contaminated aerosols by humans can lead to an acute systemic illness or a more serious chronic infection that commonly presents as endocarditis [1], [2]. The animal reservoirs for C. burnetii... |
10.1371/journal.pcbi.1005277 | Morphological Transformation and Force Generation of Active Cytoskeletal Networks | Cells assemble numerous types of actomyosin bundles that generate contractile forces for biological processes, such as cytokinesis and cell migration. One example of contractile bundles is a transverse arc that forms via actomyosin-driven condensation of actin filaments in the lamellipodia of migrating cells and exerts... | Contractile networks and bundles generate mechanical forces required for various cellular processes, particularly cell division and migration. In many of these processes, networks are structurally reorganized into bundles by the activity of molecular motors. During this morphological transformation, filaments constitut... | The actin cytoskeleton plays an important role in various cellular processes, such as changes in cell shape, cytokinesis, and cell migration [1]. Much of the mechanical forces required for these processes are generated by interactions between actin filaments (F-actin) and myosin II motors [2]. Actomyosin contractility ... |
10.1371/journal.pcbi.1005122 | Macromolecular Crowding Regulates the Gene Expression Profile by Limiting Diffusion | We seek to elucidate the role of macromolecular crowding in transcription and translation. It is well known that stochasticity in gene expression can lead to differential gene expression and heterogeneity in a cell population. Recent experimental observations by Tan et al. have improved our understanding of the functio... | The cellular nucleus is packed with macromolecules such as DNAs and proteins, which leaves limited space for other molecules to move around. Recent experimental results by C. Tan et al. have shown that macromolecular crowding can regulate gene expression, resulting in a more homogenous cell population. We introduce a c... | Even in an isogenic cell population under constant environmental conditions, significant variability in molecular content can be observed. This variability plays an important role in stem cell differentiation [1], cellular adaptation to a fluctuating environment [2], variations in cellular response to sudden stress [3]... |
10.1371/journal.pntd.0005252 | A Multi-Host Agent-Based Model for a Zoonotic, Vector-Borne Disease. A Case Study on Trypanosomiasis in Eastern Province, Zambia | This paper presents a new agent-based model (ABM) for investigating T. b. rhodesiense human African trypanosomiasis (rHAT) disease dynamics, produced to aid a greater understanding of disease transmission, and essential for development of appropriate mitigation strategies.
The ABM was developed to model rHAT incidence ... | African trypanosomiasis is a parasitic disease which affects humans and other animals in 36 sub-Saharan African countries. The disease is transmitted by the tsetse fly, and the human form of the diseases is known as sleeping sickness. Infectious disease transmission has traditionally been modelled using techniques that... | Human African trypanosomiasis (HAT), also known as sleeping sickness, is a parasitic disease which poses a significant disease burden in affected communities living in HAT foci across sub-Saharan Africa [1, 2]. HAT is caused by two sub-species of the protozoan parasite Trypanosoma brucei s.l.: T. b. rhodesiense, in eas... |
10.1371/journal.pcbi.1003801 | Revealing Molecular Mechanisms by Integrating High-Dimensional Functional Screens with Protein Interaction Data | Functional genomics screens using multi-parametric assays are powerful approaches for identifying genes involved in particular cellular processes. However, they suffer from problems like noise, and often provide little insight into molecular mechanisms. A bottleneck for addressing these issues is the lack of computatio... | Genome-scale functional genomics screens are important tools for investigating the function of genes. Technological progress allows for the simultaneous measurement of multiple parameters quantifying the response of cells to gene perturbations such as RNA interference. Such multi-dimensional screens provide rich data, ... | Genome-scale functional genetics screens using technologies such as RNA interference (RNAi) have recently started to generate high-dimensional datasets by measuring either the same parameter in different cell lines [1], [2] or different features in the same cell line [3]–[5].
Such high-dimensionality improves the phen... |
10.1371/journal.ppat.1001256 | HCMV Spread and Cell Tropism are Determined by Distinct Virus Populations | Human cytomegalovirus (HCMV) can infect many different cell types in vivo. Two gH/gL complexes are used for entry into cells. gH/gL/pUL(128,130,131A) shows no selectivity for its host cell, whereas formation of a gH/gL/gO complex only restricts the tropism mainly to fibroblasts. Here, we describe that depending on the ... | gH/gL complexes of herpesviruses are supposed to promote fusion of the viral envelope with cellular membranes. The gH/gL core complex associates with additional proteins which define the tropism for certain cell types by promoting binding to specific receptors. Two alternative gH/gL complexes of human cytomegalovirus (... | Human cytomegalovirus (HCMV) is ubiquitously distributed in the human population. In immunocompetent adults infections are mainly asymptomatic, but in immunocompromised patients like transplant recipients or AIDS patients life threatening infections occur at a high rate. HCMV is also the leading cause of birth defects ... |
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