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10.1371/journal.ppat.1002129 | The Impact of Recombination on dN/dS within Recently Emerged Bacterial Clones | The development of next-generation sequencing platforms is set to reveal an unprecedented level of detail on short-term molecular evolutionary processes in bacteria. Here we re-analyse genome-wide single nucleotide polymorphism (SNP) datasets for recently emerged clones of methicillin resistant Staphylococcus aureus (M... | As bacteria diversify, many of the nucleotide changes that emerge will render the cell slightly less competitive, and these mutations will tend to be removed by natural selection. However, this purging process does not happen instantaneously, and this delay allows deleterious mutations to survive in the population long... | The populations of many pathogenic bacterial species exist as a collection of discrete clonal complexes, many of which have emerged recently and exhibit specific resistance or virulence attributes. For example, molecular techniques such as multilocus sequence typing (MLST) [1] have identified a small number of widely d... |
10.1371/journal.pgen.1000527 | A Network of Conserved Damage Survival Pathways Revealed by a Genomic RNAi Screen | Damage initiates a pleiotropic cellular response aimed at cellular survival when appropriate. To identify genes required for damage survival, we used a cell-based RNAi screen against the Drosophila genome and the alkylating agent methyl methanesulphonate (MMS). Similar studies performed in other model organisms report ... | Cellular damage is known to elicit a pleiotropic response, but the relative importance of the constituent components in cell survival is poorly understood. To provide an unbiased identification of the proteins utilized in damage survival, we performed an RNAi survival screen in fly cells with methyl methanesulfonate (M... | Cellular damage is a normal component of life, with constant damage exposure from both endogenous and exogenous sources. Damage to DNA is considered to be the most biologically relevant lesion with the potential of mutagenic results, though most exogenous agents have the potential to damage many components of the cell.... |
10.1371/journal.pgen.1003439 | Mouse Oocyte Methylomes at Base Resolution Reveal Genome-Wide Accumulation of Non-CpG Methylation and Role of DNA Methyltransferases | DNA methylation is an epigenetic modification that plays a crucial role in normal mammalian development, retrotransposon silencing, and cellular reprogramming. Although methylation mainly occurs on the cytosine in a CG site, non-CG methylation is prevalent in pluripotent stem cells, brain, and oocytes. We previously id... | Methylation of cytosine bases in DNA is an epigenetic modification crucial for normal development, retrotransposon silencing, and cellular reprogramming. In mammals, the vast majority of 5-methylcytosine occurs at CG dinucleotides, and thus most studies to date have focused on this dinucleotide. However, recent studies... | DNA methylation is a well-characterized epigenetic modification crucial for normal mammalian development, retrotransposon silencing, and cellular reprogramming [1], [2]. In mammals, a high proportion of 5-methylcytosines (mCs) occurs at CG dinucleotides, and thus studies on DNA methylation so far have focused on this d... |
10.1371/journal.pntd.0006154 | MAIT cells are activated in acute Dengue virus infection and after in vitro Zika virus infection | Dengue virus (DENV) and Zika virus (ZIKV) are members of the Flaviviridae and are predominantly transmitted via mosquito bites. Both viruses are responsible for a growing number of infections in tropical and subtropical regions. DENV infection can cause lethargy with severe morbidity and dengue shock syndrome leading t... | Dengue virus (DENV) and Zika virus (ZIKV) are responsible for a growing number of infections in tropical and subtropical regions. DENV infection can cause dengue shock syndrome leading to death in some cases, while ZIKV is now linked with Guillain-Barré syndrome and congenital anomalies including microcephaly. The prot... | Dengue virus (DENV) and Zika virus (ZIKV) are members of Flaviviridae and both are transmitted mostly via mosquito bites. It is estimated that around 400 million people are infected with DENV annually[1]. DENV infection symptoms range from mild disease, to dengue fever, dengue hemorrhagic fever, and dengue shock syndro... |
10.1371/journal.pntd.0000447 | Strong Host-Feeding Preferences of the Vector Triatoma infestans Modified by Vector Density: Implications for the Epidemiology of Chagas Disease | Understanding the factors that affect the host-feeding preferences of triatomine bugs is crucial for estimating transmission risks and predicting the effects of control tactics targeting domestic animals. We tested whether Triatoma infestans bugs prefer to feed on dogs vs. chickens and on dogs vs. cats and whether vect... | Chagas disease is a complex zoonosis with more than 150 mammalian host species, nearly a dozen blood-sucking triatomine species as main vectors, and 9–11 million people infected with Trypanosoma cruzi (its causal agent) in the Americas. Triatoma infestans, a highly domesticated species and one of the main vectors, feed... | Host choice of hematophagous insects mainly depends on relative host abundance and proximity, host defensive behavior, the density of blood-sucking insects, and the spatial and temporal concurrence of hosts and insects [1],[2]. Examples of innate (genetically determined) host-feeding preferences are few, and convincing... |
10.1371/journal.ppat.1001333 | A New Model to Produce Infectious Hepatitis C Virus without the Replication Requirement | Numerous constraints significantly hamper the experimental study of hepatitis C virus (HCV). Robust replication in cell culture occurs with only a few strains, and is invariably accompanied by adaptive mutations that impair in vivo infectivity/replication. This problem complicates the production and study of authentic ... | Two decades after its identification, hepatitis C virus (HCV) remains a leading cause of serious liver diseases worldwide. The poor in vitro propagation of patient isolates has impaired their study. Conversely, viral strains of the most prevalent (∼70% of total infections) and clinically problematic (∼45% cured with th... | HCV infects 2–3% of the world population. A majority of infected people fail to clear the virus and are at risk for developing serious liver complications (reviewed in [1]). HCV belongs to the genus Hepacivirus in the Flaviviridæ family, and at least six genotypes have been identified so far [2]. Greater than two third... |
10.1371/journal.pmed.1002652 | Risk of adverse outcomes following urinary tract infection in older people with renal impairment: Retrospective cohort study using linked health record data | Few studies have investigated the risk of adverse outcomes in older people with renal impairment presenting to primary care with a urinary tract infection (UTI). The aim of this study was to determine the risk of adverse outcomes in patients aged ≥65 years presenting to primary care with a UTI, by estimated glomerular ... | It is not known if older adults with impaired kidney function are at increased risk of hospitalisation or death following a urinary tract infection (UTI).
Nitrofurantoin is an antibiotic used to treat UTI but is not recommended in people with impaired kidney function. However, the evidence supporting this recommendatio... | The Kidney Disease Improving Global Outcomes working group defines degrees of renal impairment using the glomerular filtration rate (GFR) [1]. GFRs <60 mL/minute/1.73 m2 are split into four groups and reflect worsening renal function, from mild impairment to renal failure. Around 6% of adults in the United Kingdom have... |
10.1371/journal.pcbi.1005860 | Fragmentation modes and the evolution of life cycles | Reproduction is a defining feature of living systems. To reproduce, aggregates of biological units (e.g., multicellular organisms or colonial bacteria) must fragment into smaller parts. Fragmentation modes in nature range from binary fission in bacteria to collective-level fragmentation and the production of unicellula... | Mode of reproduction is a defining trait of all organisms, including colonial bacteria and multicellular organisms. To produce offspring, aggregates must fragment by splitting into two or more groups. The particular way that a given group fragments defines the life cycle of the organism. For instance, insect colonies c... | A requirement for evolution—and a defining feature of life—is reproduction [1–4]. Perhaps the simplest mode of reproduction is binary fission in unicellular bacteria, whereby a single cell divides and produces two offspring cells. In more complex organisms, such as colonial bacteria, reproduction involves fragmentation... |
10.1371/journal.pgen.1007374 | Role of heterotrimeric Gα proteins in maize development and enhancement of agronomic traits | Plant shoot systems derive from the shoot apical meristems (SAMs), pools of stems cells that are regulated by a feedback between the WUSCHEL (WUS) homeobox protein and CLAVATA (CLV) peptides and receptors. The maize heterotrimeric G protein α subunit COMPACT PLANT2 (CT2) functions with CLV receptors to regulate meriste... | Maize is one of the most important cereal crops worldwide. Optimizing its yields requires fine tuning of development. Therefore, it is critical to understand the developmental signaling mechanisms to provide basic knowledge to maximize productivity. The heterotrimeric G proteins transmit signals from cell surface recep... | The plant shoot system is derived from the SAMs, pools of stems cells that have the ability of self-renewal, while initiating new leaves and axillary meristems [1]. The CLV-WUS negative feedback loop has been identified as the key pathway to regulate SAM proliferation and differentiation in Arabidopsis, and is widely c... |
10.1371/journal.pgen.1004107 | Cell-Cycle Dependent Expression of a Translocation-Mediated Fusion Oncogene Mediates Checkpoint Adaptation in Rhabdomyosarcoma | Rhabdomyosarcoma is the most commonly occurring soft-tissue sarcoma in childhood. Most rhabdomyosarcoma falls into one of two biologically distinct subgroups represented by alveolar or embryonal histology. The alveolar subtype harbors a translocation-mediated PAX3:FOXO1A fusion gene and has an extremely poor prognosis.... | Rare childhood cancers can be paradigms from which important new principles can be discerned. The childhood muscle cancer rhabdomyosarcoma is no exception, having been the focus of the original 1969 description by Drs. Li and Fraumeni of a syndrome now know to be commonly caused by underlying p53 tumor suppressor loss-... | Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. Historically, RMS has been thought to arise from muscle because of the expression of myogenic markers. Most childhood RMS falls into one of two biologically distinct subgroups: alveolar (aRMS) or embryonal (eRMS). aRMS is the more aggressive varia... |
10.1371/journal.ppat.1006518 | Hijacking of the O-GlcNAcZYME complex by the HTLV-1 Tax oncoprotein facilitates viral transcription | The viral Tax oncoprotein plays a key role in both Human T-cell lymphotropic virus type 1 (HTLV-1)-replication and HTLV-1-associated pathologies, notably adult T-cell leukemia. Tax governs the transcription from the viral 5’LTR, enhancing thereby its own expression, via the recruitment of dimers of phosphorylated CREB ... | Human T-cell lymphotropic virus type 1 (HTLV-1) is the only human retrovirus associated to a cancer. Indeed, HTLV-1 is responsible for adult T-cell leukemia, an aggressive malignant proliferation of CD4+ T lymphocytes. The regulatory protein Tax governs HTLV-1 transcription from the 5’LTR, driving expression of all vir... | Human T-lymphotropic virus type 1 (HTLV-1) is the only retrovirus associated to a cancer in humans. HTLV-1 is indeed the etiologic agent of adult T-cell leukemia/lymphoma (ATLL), a very aggressive malignant proliferation of CD4+ T lymphocytes, which appears in 2–5% of infected individuals (reviewed in [1]). In addition... |
10.1371/journal.ppat.1007441 | Quantitative RNAseq analysis of Ugandan KS tumors reveals KSHV gene expression dominated by transcription from the LTd downstream latency promoter | KSHV is endemic in Uganda and the HIV epidemic has dramatically increased the incidence of Kaposi sarcoma (KS). To investigate the role of KSHV in the development of KS, we obtained KS biopsies from ART-naïve, HIV-positive individuals in Uganda and analyzed the tumors using RNAseq to globally characterize the KSHV tran... | Kaposi’s sarcoma (KS) is among the world’s most common AIDS-associated malignancies. The Kaposi sarcoma-associated herpesvirus (KSHV) was first identified in KS tumors and is now known to be the causative agent of all forms of KS, including classical, endemic, iatrogenic and HIV-associated. KSHV is endemic to sub-Sahar... | Since its discovery in 1994, the Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8 (HHV-8), has been identified as the etiologic cause of all types of Kaposi sarcoma (KS), and is etiologically associated with primary effusion lymphoma (PEL) and multicentric Castleman Disease (MCD)[1]. The ... |
10.1371/journal.pmed.1002885 | Integrating preexposure prophylaxis delivery in routine family planning clinics: A feasibility programmatic evaluation in Kenya | Young women account for a disproportionate fraction of new HIV infections in Africa and are a priority population for HIV prevention, including implementation of preexposure prophylaxis (PrEP). The overarching goal of this project was to demonstrate the feasibility of integrating PrEP delivery within routine family pla... | Adolescent girls and young women (AGYW) in Africa are disproportionately affected by HIV infections because of cultural, structural, biological, and behavior factors.
Preexposure prophylaxis (PrEP), as a highly potent and recommended discreet user-controlled HIV prevention strategy, has the potential to substantially r... | Young women in HIV high-burden settings are a priority population for HIV prevention because they account for a disproportionate fraction of new HIV infections [1]. Preexposure prophylaxis (PrEP) is a safe and highly potent intervention when taken daily and has the potential to substantially reduce new infections if de... |
10.1371/journal.pgen.1000144 | Patterns of Positive Selection in Six Mammalian Genomes | Genome-wide scans for positively selected genes (PSGs) in mammals have provided insight into the dynamics of genome evolution, the genetic basis of differences between species, and the functions of individual genes. However, previous scans have been limited in power and accuracy owing to small numbers of available geno... | Populations evolve as mutations arise in individual organisms and, through hereditary transmission, gradually become “fixed” (shared by all individuals) in the population. Many mutations have essentially no effect on organismal fitness and can become fixed only by the stochastic process of neutral drift. However, some ... | Positive darwinian selection is an important source of evolutionary innovation and a major force behind the divergence of species. The Neutralist-Selectionist debate of the past 30 years has gradually given way to a general consensus that both neutral drift and positive selection play major roles in evolutionary change... |
10.1371/journal.pbio.1000334 | Sequestration of the Aβ Peptide Prevents Toxicity and Promotes Degradation In Vivo | Protein aggregation, arising from the failure of the cell to regulate the synthesis or degradation of aggregation-prone proteins, underlies many neurodegenerative disorders. However, the balance between the synthesis, clearance, and assembly of misfolded proteins into neurotoxic aggregates remains poorly understood. He... | Alzheimer's disease is thought to be a result of neuronal damage caused by toxic aggregated forms of the Aβ peptide in the brain. There is no cure and existing treatments are ineffective in reversing or preventing disease progression. Here we describe a novel strategy that makes use of an engineered “Affibody” protein ... | Of the neurodegenerative disorders that have been linked to protein misfolding and aggregation [1], Alzheimer's disease (AD) is the most common [2],[3]. Transgenic animal models have shown that aggregation of the Alzheimer β-peptide (Aβ) causes memory impairment [4],[5] and cognitive deficits [6] similar to those seen ... |
10.1371/journal.pgen.1004747 | It's All in Your Mind: Determining Germ Cell Fate by Neuronal IRE-1 in C. elegans | The C. elegans germline is pluripotent and mitotic, similar to self-renewing mammalian tissues. Apoptosis is triggered as part of the normal oogenesis program, and is increased in response to various stresses. Here, we examined the effect of endoplasmic reticulum (ER) stress on apoptosis in the C. elegans germline. We ... | Cells in the C. elegans germline undergo programmed cell death as part of the normal developmental program and in response to various stresses. Here, we discovered that more germ cells undergo programmed cell death under stress conditions associated with the accumulation of misfolded proteins in the endoplasmic reticul... | Apoptosis, also known as programed cell death (PCD), is a highly conserved fundamental cellular process that provides a self-elimination mechanism for the removal of unwanted cells. PCD is critical for organ development, tissue remodeling, cellular homeostasis and elimination of abnormal and damaged cells [1], [2]. The... |
10.1371/journal.pntd.0002831 | Distribution and Clinical Manifestations of Cryptosporidium Species and Subtypes in HIV/AIDS Patients in Ethiopia | Cryptosporidiosis is an important cause for chronic diarrhea and death in HIV/AIDS patients. Among common Cryptosporidium species in humans, C. parvum is responsible for most zoonotic infections in industrialized nations. Nevertheless, the clinical significance of C. parvum and role of zoonotic transmission in cryptosp... | The disease burden of Cryptosporidium parvum and role of zoonotic transmission in cryptosporidiosis epidemiology are poorly understood in developing countries. In this study, we examined the distribution and clinical manifestations of Cryptosporidium species and subtypes in HIV/AIDS patients in Addis Ababa, Ethiopia. U... | Cryptosporidium is an important protozoan parasite affecting HIV/AIDS patients, causing diarrhea, wasting syndrome, and reduced life quality [1]. Since specific therapy or vaccine for the control of this parasite is not yet available, preventing infections depends on avoiding exposure to the parasite and maintaining im... |
10.1371/journal.ppat.1004115 | Phosphorylation of KasB Regulates Virulence and Acid-Fastness in Mycobacterium tuberculosis | Mycobacterium tuberculosis bacilli display two signature features: acid-fast staining and the capacity to induce long-term latent infections in humans. However, the mechanisms governing these two important processes remain largely unknown. Ser/Thr phosphorylation has recently emerged as an important regulatory mechanis... | Acid-fast staining has been used since 1882 as the hallmark diagnostic test for detecting Mycobacterium tuberculosis, the causative agent of tuberculosis. It has been attributed to the presence of a waxy cell envelope, and primarily to its key components, mycolic acids. Here, we report a new mechanism of regulation in ... | Mycobacterium tuberculosis (Mtb) is an extraordinarily versatile pathogen that can exist in two distinct states in the host, leading to asymptomatic latent infection in which bacilli are present in a non-replicating dormant form, or to active tuberculosis (TB), characterized by actively replicating organisms. Establish... |
10.1371/journal.ppat.1002216 | Th2-polarised PrP-specific Transgenic T-cells Confer Partial Protection against Murine Scrapie | Several hurdles must be overcome in order to achieve efficient and safe immunotherapy against conformational neurodegenerative diseases. In prion diseases, the main difficulty is that the prion protein is tolerated as a self protein, which prevents powerful immune responses. Passive antibody therapy is effective only d... | It is generally accepted that prion-specific antibodies can protect against mouse scrapie infection. However, passive antibody therapy is limited to the lymphoinvasion stage of the disease. Active immunization has been attempted but the results have been disappointing. There is therefore a need for developing analytica... | Prion diseases, also termed transmissible spongiform encephalopathies (TSE), are fatal neurodegenerative disorders against which no treatment is available yet. The key pathogenic event is the conversion of the cellular prion protein (PrPc), a ubiquitous, host-encoded glycoprotein, into a misfolded protein, PrP scrapie ... |
10.1371/journal.pgen.1007432 | A conserved role for Syntaxin-1 in pre- and post-commissural midline axonal guidance in fly, chick, and mouse | Axonal growth and guidance rely on correct growth cone responses to guidance cues. Unlike the signaling cascades that link axonal growth to cytoskeletal dynamics, little is known about the crosstalk mechanisms between guidance and membrane dynamics and turnover. Recent studies indicate that whereas axonal attraction re... | Syntaxin-1 is a core factor in tethering synaptic vesicles and mediating their fusion to the cell membrane at the synapse. Thus, Syntaxin-1 mediates neurotransmission in the adult nervous system. Here we show that this protein is also involved in axonal guidance in the CNS of vertebrates and invertebrates during the de... | Axonal growth and guidance are responsible for the correct formation of neural circuits. These processes rely on the tightly regulated response of the growth cone to both diffusible and membrane-bound guidance cues. In response to such cues, several intracellular signaling cascades are activated within the growth cone,... |
10.1371/journal.ppat.1002304 | Discovery of an Ebolavirus-Like Filovirus in Europe | Filoviruses, amongst the most lethal of primate pathogens, have only been reported as natural infections in sub-Saharan Africa and the Philippines. Infections of bats with the ebolaviruses and marburgviruses do not appear to be associated with disease. Here we report identification in dead insectivorous bats of a genet... | A novel filovirus, provisionally named Lloviu virus (LLOV), was detected during the investigation of Miniopterus schreibersii die-offs in Cueva del Lloviu in southern Europe. LLOV is genetically distinct from other marburgviruses and ebolaviruses and is the first filovirus detected in Europe that was not imported from ... | Filoviruses cause lethal hemorrhagic fever in humans and nonhuman primates. The family Filoviridae includes two genera: Marburgvirus, comprising various strains of the Lake Victoria marburgvirus (MARV); and Ebolavirus (EBOVs), comprising four species including Sudan ebolavirus (SEBOV), Zaire ebolavirus (ZEBOV), Ivory C... |
10.1371/journal.ppat.1007746 | Regulation of arginine transport by GCN2 eIF2 kinase is important for replication of the intracellular parasite Toxoplasma gondii | Toxoplasma gondii is a prevalent protozoan parasite that can infect any nucleated cell but cannot replicate outside of its host cell. Toxoplasma is auxotrophic for several nutrients including arginine, tryptophan, and purines, which it must acquire from its host cell. The demands of parasite replication rapidly deplete... | Parasites that live inside a host cell must develop strategies to ensure sufficient delivery of nutrients required for survival and replication. After invasion, Toxoplasma rapidly usurps the supply of its essential amino acid arginine from the host cell. Sensing low levels of arginine, the host cell initiates a nutrien... | Toxoplasma gondii is an obligate intracellular protozoan parasite that can infect any nucleated cell. Toxoplasma resides and replicates within a non-fusogenic parasitophorous vacuole that functions to siphon nutrients from its host cell [1]. As an intracellular pathogen, Toxoplasma is auxotrophic for a range of nutrien... |
10.1371/journal.pntd.0000641 | Genotyping of Human Lice Suggests Multiple Emergences of Body Lice from Local Head Louse Populations | Genetic analyses of human lice have shown that the current taxonomic classification of head lice (Pediculus humanus capitis) and body lice (Pediculus humanus humanus) does not reflect their phylogenetic organization. Three phylotypes of head lice A, B and C exist but body lice have been observed only in phylotype A. He... | While being phenotypically and physiologically different, human head and body lice are indistinguishable based on mitochondrial and nuclear genes. As protein-coding genes are too conserved to provide significant genetic diversity, we performed strain-typing of a large collection of human head and body lice using variab... | Lice are extremely well-adapted ectoparasites that are usually host-specific [1]. Three recognized taxa of lice feed on humans: head lice (Pediculus humanus capitis), body lice (Pediculus humanus humanus), and pubic lice (Pthirius pubis), feed on humans. As one of the most intimate parasites of humans, lice have been w... |
10.1371/journal.ppat.1004692 | The Epigenetic Regulator G9a Mediates Tolerance to RNA Virus Infection in Drosophila | Little is known about the tolerance mechanisms that reduce the negative effects of microbial infection on host fitness. Here, we demonstrate that the histone H3 lysine 9 methyltransferase G9a regulates tolerance to virus infection by shaping the response of the evolutionary conserved Jak-Stat pathway in Drosophila. G9a... | Multicellular organisms deploy various strategies to fight microbial infections. Invading pathogens may be eradicated directly by antimicrobial effectors of the immune system. Another strategy consists of increasing the tolerance of the host to infection, for example, by limiting the adverse effects of the immune respo... | Efficient immunity against pathogens requires the coordinated activation and repression of genes within multiple signaling networks. Insufficient immune activation results in high microbial burden, severe pathogenesis, and high mortality from infection; overly strong immune responses may lead to tissue damage, immunopa... |
10.1371/journal.pgen.0030188 | Unexpected Novel Relational Links Uncovered by Extensive Developmental Profiling of Nuclear Receptor Expression | Nuclear receptors (NRs) are transcription factors that are implicated in several biological processes such as embryonic development, homeostasis, and metabolic diseases. To study the role of NRs in development, it is critically important to know when and where individual genes are expressed. Although systematic express... | NRs are key molecules controlling development, metabolism, and reproduction in metazoans. Since NRs are implicated in many human diseases such as cancer, metabolic syndrome, and hormone resistance, they are important pharmaceutical targets and are under intense scrutiny to better understand their biological functions. ... | Diverse processes such as reproduction, development, metabolism, and cancer are genetically regulated to a large extent by nuclear hormone receptors (NRs), a prominent transcription factor superfamily [1]. Several small lipophilic molecules, including steroids, thyroid hormones, and retinoids, function by binding membe... |
10.1371/journal.pntd.0005009 | Plasmodium vivax VIR Proteins Are Targets of Naturally-Acquired Antibody and T Cell Immune Responses to Malaria in Pregnant Women | P. vivax infection during pregnancy has been associated with poor outcomes such as anemia, low birth weight and congenital malaria, thus representing an important global health problem. However, no vaccine is currently available for its prevention. Vir genes were the first putative virulent factors associated with P. v... | Naturally-acquired antibody responses to novel recombinant proteins and synthetic peptides based on sequences from P. vivax VIR antigens were evaluated in women from five distinct geographical regions endemic for malaria, during and after pregnancy. Levels of IgG to VIR antigens were indicative of cumulative malaria ex... | Neglected for a long time, P. vivax malaria is raising more attention lately due to the increased recognition of its burden [1–4] and the renewed call for malaria elimination in endemic areas where P. vivax is an important source of malaria. Firstly, P. vivax is the most widely-spread of the human malaria parasites, wi... |
10.1371/journal.pntd.0006580 | The impact of the Ebola virus disease (EVD) epidemic on agricultural production and livelihoods in Liberia | There is unequivocal evidence in the literature that epidemics adversely affect the livelihoods of individuals, households and communities. However, evidence in the literature is dominated by the socioeconomic impacts of HIV/AIDS and malaria, while evidence on the impact of the Ebola virus disease (EVD) on households’ ... | Epidemics such as HIV/AIDS, malaria and Ebola virus disease (EVD) may adversely impact the livelihoods of the society affected by the epidemics. Nonetheless, the mechanism behind the effects of the epidemics may differ depending on different factors, such as the transmission mechanisms, latency, and mortality rates ass... | There is a plethora of evidence in the literature that epidemics such as HIV/AIDS and malaria have profound implications for the livelihoods of the affected society. The impact of HIV/AIDS on livelihoods has been intensively investigated and there is universal consensus that HIV/AIDS adversely affects the livelihoods o... |
10.1371/journal.pgen.1006946 | Plant microRNAs in larval food regulate honeybee caste development | The major environmental determinants of honeybee caste development come from larval nutrients: royal jelly stimulates the differentiation of larvae into queens, whereas beebread leads to worker bee fate. However, these determinants are not fully characterized. Here we report that plant RNAs, particularly miRNAs, which ... | How caste has formed in honeybees is an enduring puzzle. The prevailing view is that royal jelly stimulates the differentiation of larvae into queen. Here, we uncover a new mechanism that plant miRNAs in worker bee’s food postpone larval development, thereby inducing sterile worker bees. Thus, the theories about honeyb... | Caste development in social insects represents a major transition from one level of organization to another in evolution and is believed to be central to the ecological success of social insects [1]. How castes evolved is an enduring puzzle that has long fascinated scientists but currently has no satisfactory answers. ... |
10.1371/journal.pgen.1003285 | Drosophila Yemanuclein and HIRA Cooperate for De Novo Assembly of H3.3-Containing Nucleosomes in the Male Pronucleus | The differentiation of post-meiotic spermatids in animals is characterized by a unique reorganization of their nuclear architecture and chromatin composition. In many species, the formation of sperm nuclei involves the massive replacement of nucleosomes with protamines, followed by a phase of extreme nuclear compaction... | Chromosome organization relies on a basic functional unit called the nucleosome, in which DNA is wrapped around a core of histone proteins. However, during male gamete formation, the majority of histones are replaced by sperm-specific proteins that are adapted to sexual reproduction but incompatible with the formation ... | Assembly of octameric nucleosomes in eukaryotic chromatin is a stepwise process where deposition of a histone H3-H4 heterotetramer precedes incorporation of two H2A-H2B dimers [1]. While the bulk of de novo chromatin assembly occurs during genome replication and mainly involves canonical histone H3, alternative, replic... |
10.1371/journal.pntd.0002906 | Cytokine Production but Lack of Proliferation in Peripheral Blood Mononuclear Cells from Chronic Chagas' Disease Cardiomyopathy Patients in Response to T. cruzi Ribosomal P Proteins | Trypanosoma cruzi ribosomal P proteins, P2β and P0, induce high levels of antibodies in patients with chronic Chagas' disease Cardiomyopathy (CCC). It is well known that these antibodies alter the beating rate of cardiomyocytes and provoke apoptosis by their interaction with β1-adrenergic and M2-muscarinic cardiac rece... | Chronic Chagas' disease Cardiomyopathy (CCC) is the most frequent and severe consequence of the chronic infection by protozoan parasite T. cruzi. Patients with CCC develop high levels of antibodies against ribosomal P proteins of T. cruzi, called P2β and P0. These antibodies can cross-react with, and stimulate, the β1-... | Trypanosoma cruzi, the etiological agent of Chagas' disease, affects approximately 8–10 million people, and its infection is one of the major human health problems in Central and South America, being extended now to Europe (especially Spain and Portugal), the United States, Canada, Japan and Australia [1], [2], [3]. Up... |
10.1371/journal.pgen.1002824 | Genome-Wide Association Analysis in Asthma Subjects Identifies SPATS2L as a Novel Bronchodilator Response Gene | Bronchodilator response (BDR) is an important asthma phenotype that measures reversibility of airway obstruction by comparing lung function (i.e. FEV1) before and after the administration of a short-acting β2-agonist, the most common rescue medications used for the treatment of asthma. BDR also serves as a test of β2-a... | Bronchodilator response (BDR) is an important asthma phenotype that measures reversibility of airway obstruction by comparing lung function before and after the administration of short-acting β2-agonists, common medications used for asthma treatment. We performed a genome-wide association study of BDR with 1,644 white ... | Asthma is a chronic respiratory disease that affects over 20 million Americans and 300 million people worldwide [1], [2]. A hallmark characteristic of asthma is reversible airway obstruction, which is commonly measured via a bronchodilator response (BDR) test, in which the reduction of bronchoconstriction after adminis... |
10.1371/journal.pgen.1003742 | Type I-E CRISPR-Cas Systems Discriminate Target from Non-Target DNA through Base Pairing-Independent PAM Recognition | Discriminating self and non-self is a universal requirement of immune systems. Adaptive immune systems in prokaryotes are centered around repetitive loci called CRISPRs (clustered regularly interspaced short palindromic repeat), into which invader DNA fragments are incorporated. CRISPR transcripts are processed into sm... | CRISPR loci and their associated genes form a diverse set of adaptive immune systems that are widespread among prokaryotes. In these systems, the CRISPR-associated genes (cas) encode for proteins that capture fragments of invading DNA and integrate these sequences between repeat sequences of the host's CRISPR locus. Th... | There are several prokaryotic defense systems that confer innate immunity against invading mobile genetic elements, such as receptor masking, blocking DNA injection, restriction/modification (R-M) and abortive infection (reviewed in [1]–[3]). In addition, half of the bacteria, and most of the archaea, contain CRISPR-Ca... |
10.1371/journal.pcbi.1003957 | Live Imaging-Based Model Selection Reveals Periodic Regulation of the Stochastic G1/S Phase Transition in Vertebrate Axial Development | In multicellular organism development, a stochastic cellular response is observed, even when a population of cells is exposed to the same environmental conditions. Retrieving the spatiotemporal regulatory mode hidden in the heterogeneous cellular behavior is a challenging task. The G1/S transition observed in cell cycl... | Cell cycle progression is considered to involve a cellular time-counting machinery for proper morphogenesis and patterning of tissues. Therefore, it is important to understand the regulatory mode of cell cycle progression during physiological and pathological tissue growth, which will benefit tissue engineering therapy... | The development of multicellular organisms is a highly coordinated process, in which cell proliferation and sequential changes in cellular identities are spatiotemporally regulated, through which patterned tissues and organs are ultimately formed. As a system to ensure the precision and reproducibility of the developme... |
10.1371/journal.pntd.0004417 | Climate and the Timing of Imported Cases as Determinants of the Dengue Outbreak in Guangzhou, 2014: Evidence from a Mathematical Model | As the world’s fastest spreading vector-borne disease, dengue was estimated to infect more than 390 million people in 2010, a 30-fold increase in the past half century. Although considered to be a non-endemic country, mainland China had 55,114 reported dengue cases from 2005 to 2014, of which 47,056 occurred in 2014. F... | Dengue has not been considered to be a major problem in China since it is recognized as an imported disease and only 8,058 cases were reported from 2005 to 2013. However, in 2014 alone, 47,056 new cases were reported. In this study, a mathematical model was developed to determine the possible cause of this outbreak. Th... | Dengue is a febrile illness caused by the dengue virus which is further classified into 4 serotypes (DENV 1–4), and transmitted by Aedes aegypti and Aedes albopictus mosquitoes. Classically, dengue virus infection produces mild flu-like fevers but can also result in lethal dengue hemorrhagic fever (DHF) and dengue shoc... |
10.1371/journal.pgen.1002877 | The Burkholderia bcpAIOB Genes Define Unique Classes of Two-Partner Secretion and Contact Dependent Growth Inhibition Systems | Microbes have evolved many strategies to adapt to changes in environmental conditions and population structures, including cooperation and competition. One apparently competitive mechanism is contact dependent growth inhibition (CDI). Identified in Escherichia coli, CDI is mediated by Two–Partner Secretion (TPS) pathwa... | Contact dependent growth inhibition (CDI) is a phenomenon discovered in Escherichia coli in which CDI+ bacteria inhibit the growth of CDI− bacteria upon cell-to-cell contact. CDI is mediated by large toxic “exoproteins” present on the bacterial cell surface. An ‘immunity’ protein protects CDI+ cells from killing themse... | Microbes rarely live alone. Whether free in the environment or in close association with eukaryotic hosts, microbes typically share their living space with other viral, prokaryotic, and/or eukaryotic microorganisms. Survival under these conditions requires mechanisms for sensing, responding to, and cooperating or compe... |
10.1371/journal.ppat.1005344 | The Epstein-Barr Virus BART miRNA Cluster of the M81 Strain Modulates Multiple Functions in Primary B Cells | The Epstein-Barr virus (EBV) is a B lymphotropic virus that infects the majority of the human population. All EBV strains transform B lymphocytes, but some strains, such as M81, also induce spontaneous virus replication. EBV encodes 22 microRNAs (miRNAs) that form a cluster within the BART region of the virus and have ... | The Epstein-Barr virus (EBV) infects more than 90% of the human adult population. Although EBV usually causes an asymptomatic infection, it is oncogenic in a small proportion of infected individuals. EBV produces a large number of microRNAs, a type of RNA that controls the production of their proteins though multiple m... | The Epstein-Barr virus (EBV) is a strongly B lymphotropic virus that infects the majority of the world human population and is associated with the development of malignant tumors, mainly lymphomas and carcinomas of the nasopharynx (NPC) and of the stomach [1]. Shortly after infection, B cells start to divide and genera... |
10.1371/journal.ppat.1006129 | Respiration of Microbiota-Derived 1,2-propanediol Drives Salmonella Expansion during Colitis | Intestinal inflammation caused by Salmonella enterica serovar Typhimurium increases the availability of electron acceptors that fuel a respiratory growth of the pathogen in the intestinal lumen. Here we show that one of the carbon sources driving this respiratory expansion in the mouse model is 1,2-propanediol, a micro... | Salmonella enterica serovar Typhimurium induces intestinal inflammation to induce the generation of host-derived respiratory electron acceptors, thereby driving a respiratory pathogen expansion, which aids infectious transmission by the fecal oral route. However, the identity of nutrients serving as electron donors to ... | Salmonella enterica serovar Typhimurium (S. Typhimurium) is a common cause of food poisoning. Upon ingestion, the pathogen enters the intestinal epithelium using the invasion-associated type III secretion system (T3SS-1) [1] and deploys a second type III secretion system (T3SS-2) to survive in host tissue [2]. This vir... |
10.1371/journal.pcbi.1004705 | Systems-Wide Prediction of Enzyme Promiscuity Reveals a New Underground Alternative Route for Pyridoxal 5’-Phosphate Production in E. coli | Recent insights suggest that non-specific and/or promiscuous enzymes are common and active across life. Understanding the role of such enzymes is an important open question in biology. Here we develop a genome-wide method, PROPER, that uses a permissive PSI-BLAST approach to predict promiscuous activities of metabolic ... | Many enzymes can perform secondary functions at low affinities or rates, but such ‘promiscuous’ functions have never been predicted on a genome-wide scale. Here, we present the first genome-wide method to predict promiscuous functions of metabolic genes, which we apply to E. coli. Notably, we predict and validate sever... | Enzymes have traditionally been associated with discrete activities [1]. Clear-cut annotations populate well-known enzyme databases such as KEGG and Uniprot, and foster an implicit assumption that gene activities are specific. However, recent advancements in our understanding of evolution and enzyme activity have cast ... |
10.1371/journal.ppat.1007672 | Increased mucosal neutrophil survival is associated with altered microbiota in HIV infection | Gastrointestinal (GI) mucosal dysfunction predicts and likely contributes to non-infectious comorbidities and mortality in HIV infection and persists despite antiretroviral therapy. However, the mechanisms underlying this dysfunction remain incompletely understood. Neutrophils are important for containment of pathogens... | HIV infection results in chronic immune activation that leads to increased risk of other diseases and premature death, and this has been linked to gastrointestinal tract (GI) damage in infected individuals. In this study, we investigated neutrophils, a cell involved in the immune response to pathogens, in colorectal ti... | Gastrointestinal (GI) mucosal damage and immune dysfunction drive chronic inflammation and microbial translocation in HIV infection, which predict and likely contribute to non-infectious comorbidities and mortality[1–5]. Although long-term antiretroviral therapy (ART) partially restores mucosal damage, a degree of muco... |
10.1371/journal.pmed.1002101 | Assessment of Adverse Events in Protocols, Clinical Study Reports, and Published Papers of Trials of Orlistat: A Document Analysis | Little is known about how adverse events are summarised and reported in trials, as detailed information is usually considered confidential. We have acquired clinical study reports (CSRs) from the European Medicines Agency through the Freedom of Information Act. The CSRs describe the results of studies conducted as part... | Most drugs have adverse effects, or harms, that may become evident in clinical trials.
Pharmaceutical companies seeking to market a new drug must report adverse effects observed in trial participants in the Clinical Study Reports (CSRs), which they provide to regulatory authorities.
Additionally, investigators may repo... | Randomised trials generally underreport harms, which according to Consolidated Standards of Reporting Trials (CONSORT) is the totality of adverse events [1]. In 14% of 185 randomised trials published in major medical journals in 1997, adverse reactions were not mentioned at all, and in 32% they were not shown for each ... |
10.1371/journal.pgen.1007112 | In vivo zebrafish morphogenesis shows Cyp26b1 promotes tendon condensation and musculoskeletal patterning in the embryonic jaw | Integrated development of diverse tissues gives rise to a functional, mobile vertebrate musculoskeletal system. However, the genetics and cellular interactions that drive the integration of muscle, tendon, and skeleton are poorly understood. In the vertebrate head, neural crest cells, from which cranial tendons derive,... | Mobility requires that muscles form appropriate attachments via tendon. The genes regulating this attachment are poorly understood. This is especially true in the head where mesoderm and neural crest cells generate muscle and tendon, respectively. We show that the gene cyp26b1 is critical for muscle tendon attachment i... | The movements and functions of the human head depend on 150 individual muscles, and loss of tendon or of tendon-muscle interactions has been implicated in human craniofacial syndromes with muscle defects. Vertebrate craniofacial development is a complex process involving communication between muscles, tendons, cartilag... |
10.1371/journal.pcbi.1006025 | Gap junction plasticity as a mechanism to regulate network-wide oscillations | Cortical oscillations are thought to be involved in many cognitive functions and processes. Several mechanisms have been proposed to regulate oscillations. One prominent but understudied mechanism is gap junction coupling. Gap junctions are ubiquitous in cortex between GABAergic interneurons. Moreover, recent experimen... | Oscillations of neural activity emerge when many neurons repeatedly activate together and are observed in many brain regions, particularly during sleep and attention. Their functional role is still debated, but could be associated with normal cognitive processes such as memory formation or with pathologies such as schi... | Oscillatory patterns of neuronal activity are reported in many brains regions with frequencies ranging from less than one Hertz to hundreds of Hertz. These oscillations are often associated with cognitive phenomena such as sleep or attention. Local field potential measurements in the neocortex and thalamus show the pre... |
10.1371/journal.pcbi.1003975 | Heterogeneity and Convergence of Olfactory First-Order Neurons Account for the High Speed and Sensitivity of Second-Order Neurons | In the olfactory system of male moths, a specialized subset of neurons detects and processes the main component of the sex pheromone emitted by females. It is composed of several thousand first-order olfactory receptor neurons (ORNs), all expressing the same pheromone receptor, that contact synaptically a few tens of s... | Understanding how sensory signals are optimally encoded by nervous systems is of strong interest to neuroscientists, and also to engineers as it may lead to more efficient artificial detection systems. This is particularly relevant to olfaction, because the current electronic noses are far outperformed by their biologi... | In insects and vertebrates the first two neuronal layers of the olfactory system present the same organization where many ORNs in the first layer converge to a small number of output neurons in the second layer – PNs in insects and mitral cells in vertebrates [1], [2]. The ORNs that project onto a single glomerulus exp... |
10.1371/journal.ppat.1004310 | Determinants of Influenza Transmission in South East Asia: Insights from a Household Cohort Study in Vietnam | To guide control policies, it is important that the determinants of influenza transmission are fully characterized. Such assessment is complex because the risk of influenza infection is multifaceted and depends both on immunity acquired naturally or via vaccination and on the individual level of exposure to influenza i... | Influenza causes an estimated three to five million severe illnesses worldwide each year. In order to guide control policies it is important to determine the key risk factors for transmission. This is often done by studying transmission in households but in the past, analysis of such data has suffered from important si... | Three to five millions severe illnesses and 250,000 to 500,000 deaths worldwide are due to the influenza virus each year [1]. To guide control policies, it is important that the determinants of influenza transmission are fully characterized. Such assessment is complex because the risk of influenza infection is multifac... |
10.1371/journal.ppat.1000611 | A Granulin-Like Growth Factor Secreted by the Carcinogenic Liver Fluke, Opisthorchis viverrini, Promotes Proliferation of Host Cells | The human liver fluke, Opisthorchis viverrini, infects millions of people throughout south-east Asia and is a major cause of cholangiocarcinoma, or cancer of the bile ducts. The mechanisms by which chronic infection with O. viverrini results in cholangiocarcinogenesis are multi-factorial, but one such mechanism is the ... | The oriental liver fluke is endemic through South-East Asia and is the major cause of cause of liver cancer in north-eastern Thailand. The molecules that are secreted by the parasite cause cells to multiply quicker than they normally would, and excessive cell growth is a key stage in the initiation of many cancers. We ... | Cholangiocarcinoma (CCA), or cancer of the bile ducts, is prevalent in people from Thailand and Laos whose staple diet includes uncooked fish which harbour the liver fluke, Opisthorchis viverrini, the main risk factor for this cancer in the region [1]. There is no stronger link between a parasite and cancer than that b... |
10.1371/journal.pgen.1000049 | Cell-to-Cell Stochastic Variation in Gene Expression Is a Complex Genetic Trait | The genetic control of common traits is rarely deterministic, with many genes contributing only to the chance of developing a given phenotype. This incomplete penetrance is poorly understood and is usually attributed to interactions between genes or interactions between genes and environmental conditions. Because many ... | Although most inter-individual phenotypic variabilities are largely attributable to DNA differences, a wealth of examples illustrate how a single biological system can vary stochastically over time and between individuals. Identical twins are not identical, and similarly, clonal microbial cells differ in many aspects e... | Two fascinating area of research on gene expression have been conducted intensively and independently during the past couple of years. A large community of geneticists has contributed to the identification of genetic sources underlying expression differences between individuals. Such expression Quantitative Trait Loci ... |
10.1371/journal.pgen.1003121 | Reciprocal Signaling between the Ectoderm and a Mesendodermal Left-Right Organizer Directs Left-Right Determination in the Sea Urchin Embryo | During echinoderm development, expression of nodal on the right side plays a crucial role in positioning of the rudiment on the left side, but the mechanisms that restrict nodal expression to the right side are not known. Here we show that establishment of left-right asymmetry in the sea urchin embryo relies on recipro... | Asymmetries between the left and the right sides of the body are an essential feature of most bilaterian animals, and failure to establish these asymmetries can result in pathological disorders in humans. Left-right asymmetries are established during early development by the asymmetric activity of a signaling pathway i... | Left-right (L/R) asymmetry is an essential feature of development in most bilaterian animals. In vertebrates, the morphology and positioning of many internal organs as well as development of the nervous system is left-right asymmetric and failure to establish these asymmetries can result in pathological disorders [1]–[... |
10.1371/journal.pntd.0004144 | Copulation Activity, Sperm Production and Conidia Transfer in Aedes aegypti Males Contaminated by Metarhizium anisopliae: A Biological Control Prospect | Dengue is the most prevalent arboviral disease transmitted by Aedes aegypti worldwide, whose chemical control is difficult, expensive, and of inconsistent efficacy. Releases of Metarhizium anisopliae—exposed Ae. aegypti males to disseminate conidia among female mosquitoes by mating represents a promising biological con... | Dengue virus (four serotypes) is transmitted primarily by the mosquitoes Aedes aegypti and currently 2.5 billion people are in risk of being infected. The incidence of this neglected disease is increasing in developing countries where communities have not been able to effectively remove mosquito sources and their econo... | Aedes aegypti is the principal vector of the four dengue (DENV) virus serotypes [1]. Although its control through larval source removal is effective, the only rapid but inconsistent way to interrupt epidemic transmission is by chemical insecticides [2,3]. The scarcity of natural enemies of Ae. aegypti [4,5] has led to ... |
10.1371/journal.pcbi.1005178 | Individual Differences in Dynamic Functional Brain Connectivity across the Human Lifespan | Individual differences in brain functional networks may be related to complex personal identifiers, including health, age, and ability. Dynamic network theory has been used to identify properties of dynamic brain function from fMRI data, but the majority of analyses and findings remain at the level of the group. Here, ... | Complex patterns of activity in each individual human brain generate the unique range of thoughts and behaviors that person experiences. Individual differences in ability, age, state of mind, and other characteristics are tied to differences in brain activity, but determination of the exact nature of these relationship... | Functional connectivity (FC) analyses based on fMRI data are effective tools for quantifying and characterizing interactions between brain regions. Many approaches borrow methods from the field of graph theory, in which FC is used to build graphs that model the brain as a complex network, treating brain regions as node... |
10.1371/journal.pbio.1001255 | Development and Function of Invariant Natural Killer T Cells Producing TH2- and TH17-Cytokines | There is heterogeneity in invariant natural killer T (iNKT) cells based on the expression of CD4 and the IL-17 receptor B (IL-17RB), a receptor for IL-25 which is a key factor in TH2 immunity. However, the development pathway and precise function of these iNKT cell subtypes remain unknown. IL-17RB+ iNKT cells are prese... | T cells are a diverse group of immune cells involved in cell-mediated acquired immunity. One subset of T cells is the innate-like invariant natural killer T (iNKT) cells that recognize glycolipid ligands on target cells instead of peptides. We know that functionally distinct subtypes of iNKT cells are involved in speci... | Natural killer T (NKT) cells, unlike conventional T cells bearing diverse antigen receptors, are characterized by the expression of an invariant T cell receptor (TCR), Vα14Jα18 paired with Vβ8, Vβ7, or Vβ2 in mice [1] and the Vα24Jα18/Vβ11 pair in humans [2],[3], that recognizes glycolipid antigens in conjunction with ... |
10.1371/journal.pcbi.1000006 | Multi-Scale Simulations Provide Supporting Evidence for the Hypothesis of Intramolecular Protein Translocation in GroEL/GroES Complexes | The biological function of chaperone complexes is to assist the folding of non-native proteins. The widely studied GroEL chaperonin is a double-barreled complex that can trap non-native proteins in one of its two barrels. The ATP-driven binding of a GroES cap then results in a major structural change of the chamber whe... | Chaperonin complexes capture proteins that have not yet reached their functional (“native”) state. Non-native proteins cannot perform their function correctly and threaten the survival of the cell. The chaperonins help these proteins to reach their native state. The prokaryotic GroEL-GroES chaperonin is an ellipsoidal ... | Proteins that have not yet folded to their native state may interfere with the machinery of the cell. For this reason, prokaryotic and eukaryotic cells have evolved special macro-molecular “chaperone” complexes that capture and refold partially folded proteins, thereby preventing them from indulging in cellular mischie... |
10.1371/journal.pbio.1000518 | Non-Canonical NF-κB Activation and Abnormal B Cell Accumulation in Mice Expressing Ubiquitin Protein Ligase-Inactive c-IAP2 | Chromosomal translocations between loci encoding MALT1 and c-IAP2 are common in MALT lymphomas. The resulting fusion proteins lack the c-IAP2 RING domain, the region responsible for its ubiquitin protein ligase (E3) activity. Ectopic expression of the fusion protein activates the canonical NF-κB signaling cascade, but ... | MALT (mucosal associated lymphoid tissue) lymphomas commonly express a mutant protein that contains a portion of the ubiquitin protein ligase cellular Inhibitor of Apoptosis 2 (c-IAP2) and a portion of the paracaspase MALT1. Expression of this fusion protein activates the anti-apoptotic transcription factor NF-κB, but ... | The defining characteristic of the IAP (Inhibitor of Apoptosis) gene family is the presence of one or more baculovirus IAP repeats (BIRs) (reviewed in [1]). These ∼70 amino acid regions mediate protein-protein interactions, and in the context of adjacent sequences are responsible for the association of certain IAP fami... |
10.1371/journal.pbio.2006357 | Evolutionary diversification of the HAP2 membrane insertion motifs to drive gamete fusion across eukaryotes | HAPLESS2 (HAP2) is a broadly conserved, gamete-expressed transmembrane protein that was shown recently to be structurally homologous to viral class II fusion proteins, which initiate fusion with host cells via insertion of fusion loops into the host membrane. However, the functional conformation of the HAP2 fusion loop... | The fusion of gamete plasma membranes is the fundamental cellular event that brings two parental cells together to form a new individual, yet we know surprisingly little about this process at the molecular level. HAPLESS 2 (HAP2) is a conserved sperm plasma membrane protein that is essential for gamete fusion in a dive... | The fusion of gamete plasma membranes to form a zygote is central to sexual reproduction, yet a molecular mechanism for this fundamental process has only very recently been proposed. The crystal structure of the C. reinhardtii HAPLESS 2 (HAP2) ectodomain (CrHAP2e) [1] revealed that this broadly conserved, gamete-expres... |
10.1371/journal.ppat.1006707 | Structural basis of glycan specificity of P[19] VP8*: Implications for rotavirus zoonosis and evolution | Recognition of specific cell surface glycans, mediated by the VP8* domain of the spike protein VP4, is the essential first step in rotavirus (RV) infection. Due to lack of direct structural information of virus-ligand interactions, the molecular basis of ligand-controlled host ranges of the major human RVs (P[8] and P[... | Rotaviruses (RVs) are diverse, infecting humans and/or animals. Significant advances in understanding ligand-associated RV host ranges have been made but how such host ligands drive RV evolution leading to the diverse genotypes/genogroups already identified remains unclear. In this study, through solving crystal struct... | Rotaviruses (RVs) are a major cause of severe gastroenteritis in children under the age of 5, causing 200,000 deaths[1–3]and account for 2 million childhood hospital admissions with an estimated cost of over 1 billion US dollars per year[4, 5]. It has been shown that RV attachment to cell surface carbohydrates, mediate... |
10.1371/journal.pbio.2005069 | The zinc transporter ZIPT-7.1 regulates sperm activation in nematodes | Sperm activation is a fascinating example of cell differentiation, in which immotile spermatids undergo a rapid and dramatic transition to become mature, motile sperm. Because the sperm nucleus is transcriptionally silent, this transition does not involve transcriptional changes. Although Caenorhabditis elegans is a le... | Sperm are specialized cells with transcriptionally silent DNA that has been packaged for delivery into the egg. In their final step of development, immature sperm undergo a rapid transition from nonmotile cells to mature, motile sperm capable of fertilization. The signals that trigger this change are not clearly unders... | In animals, each differentiated cell type expresses a unique set of genes, resulting in the characteristic array of proteins that together confer its identity. These proteins equip the cell for the specific functions it needs to perform its role within a complex animal. Sperm provide a fascinating example of how multip... |
10.1371/journal.pcbi.1000585 | Predicting Protein Ligand Binding Sites by Combining Evolutionary Sequence Conservation and 3D Structure | Identifying a protein's functional sites is an important step towards characterizing its molecular function. Numerous structure- and sequence-based methods have been developed for this problem. Here we introduce ConCavity, a small molecule binding site prediction algorithm that integrates evolutionary sequence conserva... | Protein molecules are ubiquitous in the cell; they perform thousands of functions crucial for life. Proteins accomplish nearly all of these functions by interacting with other molecules. These interactions are mediated by specific amino acid positions in the proteins. Knowledge of these “functional sites” is crucial fo... | Proteins' functions are determined to a large degree by their interactions with other molecules. Identifying which residues participate in these interactions is an important component of functionally characterizing a protein. Many computational approaches based on analysis of protein sequences or structures have been d... |
10.1371/journal.pgen.1006696 | Lethality of mice bearing a knockout of the Ngly1-gene is partially rescued by the additional deletion of the Engase gene | The cytoplasmic peptide:N-glycanase (Ngly1 in mammals) is a de-N-glycosylating enzyme that is highly conserved among eukaryotes. It was recently reported that subjects harboring mutations in the NGLY1 gene exhibited severe systemic symptoms (NGLY1-deficiency). While the enzyme obviously has a critical role in mammals, ... | Ngly1 is a cytoplasmic de-N-glycosylating enzyme that is ubiquitously found in eukaryotes. This enzyme is involved in a process referred to as endoplasmic reticulum-associated degradation (ERAD), one of the quality control mechanisms for newly synthesized proteins. A genetic disorder, NGLY1-deficiency, caused by mutati... | The endoplasmic reticulum (ER) is the organelle responsible for the biosynthesis of proteins that pass through the secretory pathway. This organelle has an efficient protein quality control or homeostasis system, in which abnormal or excess proteins are targeted for destruction [1–3]. In such systems, cytoplasmic prote... |
10.1371/journal.ppat.1006878 | The fungal pathogen Magnaporthe oryzae suppresses innate immunity by modulating a host potassium channel | Potassium (K+) is required by plants for growth and development, and also contributes to immunity against pathogens. However, it has not been established whether pathogens modulate host K+ signaling pathways to enhance virulence and subvert host immunity. Here, we show that the effector protein AvrPiz-t from the rice b... | Plant nutritional status can greatly influence plant immunity in response to pathogen invasion. Rice blast, a devastating rice disease caused by the hemibiotrophic fungus Magnaporthe oryzae, causes a significant reduction in yield and affects food security. In this study, we demonstrate that the M. oryzae secreted prot... | Potassium (K+) plays important roles in many fundamental processes in plants, including enzyme activation, cellular homeostasis, membrane transport, osmoregulation and immunoreaction [1, 2]. The uptake and translocation of K+ in plants relies on a number of K+ channels and transporters. In the model plant Arabidopsis (... |
10.1371/journal.pgen.1003445 | Smaug/SAMD4A Restores Translational Activity of CUGBP1 and Suppresses CUG-Induced Myopathy | We report the identification and characterization of a previously unknown suppressor of myopathy caused by expansion of CUG repeats, the mutation that triggers Myotonic Dystrophy Type 1 (DM1). We screened a collection of genes encoding RNA–binding proteins as candidates to modify DM1 pathogenesis using a well establish... | Myotonic dystrophy type 1 (DM1) is the most common among the muscular dystrophies causing muscle weakness and wasting in adults, and it is triggered by expansion of an untranslated CUG repeat. To identify potential therapeutic approaches, we used a Drosophila DM1 model to screen for genes capable of suppressing CUG-ind... | Myotonic Dystrophy type 1 (DM1) is a multisystemic neuromuscular disorder that has become a paradigm of a class of diseases caused by RNA toxicity. DM1 arises from expansion of a CTG triplet repeat in the 3′ untranslated region of the DMPK gene, and it accounts for the majority of adult cases of muscular dystrophy [1]–... |
10.1371/journal.pgen.1003706 | The Architecture of a Prototypical Bacterial Signaling Circuit Enables a Single Point Mutation to Confer Novel Network Properties | Even a single mutation can cause a marked change in a protein's properties. When the mutant protein functions within a network, complex phenotypes may emerge that are not intrinsic properties of the protein itself. Network architectures that enable such dramatic changes in function from a few mutations remain relativel... | A mutation can cause significant changes to a protein's function. Since proteins often act together in genetic circuits to control various cellular processes, mutant proteins can lead to unexpected consequences for system-level behavior. In this study, we describe a remarkable example of this phenomenon in a mutant of ... | A few mutations can lead to significant changes in a protein's functional properties. Examples include mutations that change the absorption and emission spectra of a fluorescent protein [1], the substrate specificity of an enzyme [2], or the allosteric control of a transcription factor [3]. In all of these examples, th... |
10.1371/journal.pgen.1005698 | Developmental Dynamics of X-Chromosome Dosage Compensation by the DCC and H4K20me1 in C. elegans | In Caenorhabditis elegans, the dosage compensation complex (DCC) specifically binds to and represses transcription from both X chromosomes in hermaphrodites. The DCC is composed of an X-specific condensin complex that interacts with several proteins. During embryogenesis, DCC starts localizing to the X chromosomes arou... | In many animals, males have a single X and females have two X chromosomes, creating an X chromosomal gene dosage imbalance between sexes. This imbalance is corrected by dosage compensation mechanisms, which are essential for development in mammals, flies and worms. The timing and the molecular mechanisms of dosage comp... | Dosage compensation equalizes X chromosome gene expression between sexes. Different animals use different strategies of dosage compensation by co-opting diverse mechanisms of gene regulation to the X chromosome [1]. In mammals, dosage compensation transcriptionally inactivates one of the two X chromosomes in XX females... |
10.1371/journal.pcbi.1007063 | Modeling visual performance differences ‘around’ the visual field: A computational observer approach | Visual performance depends on polar angle, even when eccentricity is held constant; on many psychophysical tasks observers perform best when stimuli are presented on the horizontal meridian, worst on the upper vertical, and intermediate on the lower vertical meridian. This variation in performance ‘around’ the visual f... | A fundamental goal in computational neuroscience is to link known facts from biology with behavior. Here, we considered visual behavior, specifically the fact that people are better at visual tasks performed to the left or right of the center of gaze, compared to above or below at the same distance from gaze. We sought... | Psychophysical performance is not uniform across the visual field. The largest source of this non-uniformity is eccentricity: acuity is much higher in the central visual field (fovea), limiting many recognition tasks such as reading and face recognition to only a relatively small portion of the retina. As a result, cen... |
10.1371/journal.pcbi.1002577 | Quantifying the Contribution of the Liver to Glucose Homeostasis: A Detailed Kinetic Model of Human Hepatic Glucose Metabolism | Despite the crucial role of the liver in glucose homeostasis, a detailed mathematical model of human hepatic glucose metabolism is lacking so far. Here we present a detailed kinetic model of glycolysis, gluconeogenesis and glycogen metabolism in human hepatocytes integrated with the hormonal control of these pathways b... | Glucose is an indispensable fuel for all cells and organs, but at the same time leads to problems at high concentrations. As a consequence, blood glucose is controlled in a narrow range to guarantee constant supply and on the other hand avoid damages associated with elevated glucose levels. The liver is the main organ ... | The human plasma glucose is kept in a narrow range between minimum values of ∼3 mM after prolonged fasting or extensive muscle activity and maximum values of ∼9 mM reached postprandially [1], [2]. Homoeostasis of plasma glucose is crucial for the organism: Hyperglycemia results in non-enzymatic glycosylation (glycation... |
10.1371/journal.pntd.0006300 | No evidence for association between APOL1 kidney disease risk alleles and Human African Trypanosomiasis in two Ugandan populations | Human African trypanosomiasis (HAT) manifests as an acute form caused by Trypanosoma brucei rhodesiense (Tbr) and a chronic form caused by Trypanosoma brucei gambiense (Tbg). Previous studies have suggested a host genetic role in infection outcomes, particularly for APOL1. We have undertaken candidate gene association ... | Human African Trypanosomiasis (HAT) occurs in two distinct disease forms; the acute form and the chronic form which are caused by microscopically indistinguishable hemo-parasites, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense respectively. Uganda is the only country where both forms of the disease are... | The tsetse transmitted African trypanosomes are flagellated protozoa, a range of which cause disease in animals (known as Nagana) and humans (Human African Trypanosomiasis, HAT, also known as sleeping sickness). These diseases are responsible for significant morbidity and mortality [1–3] and therefore directly impact o... |
10.1371/journal.pntd.0005439 | GOST: A generic ordinal sequential trial design for a treatment trial in an emerging pandemic | Conducting clinical trials to assess experimental treatments for potentially pandemic infectious diseases is challenging. Since many outbreaks of infectious diseases last only six to eight weeks, there is a need for trial designs that can be implemented rapidly in the face of uncertainty. Outbreaks are sudden and unpre... | Since many outbreaks of infectious diseases last only six to eight weeks, there is a need for trial designs that can be implemented rapidly in the face of uncertainty. The Generic Ordinal Sequential Trial (GOST) is a flexible statistical design for a randomised clinical trial comparing an experimental treatment for an ... | The 2013–15 Ebola virus disease epidemic in West Africa highlighted the need to be able to develop treatment trial protocols in a matter of weeks, rather than the months or even years that are more usually taken. Clinical research on epidemic infectious diseases has to take place when new cases are occurring. Urgency a... |
10.1371/journal.pntd.0000918 | Responses of Human Endothelial Cells to Pathogenic and Non-Pathogenic Leptospira Species | Leptospirosis is a widespread zoonotic infection that primarily affects residents of tropical regions, but causes infections in animals and humans in temperate regions as well. The agents of leptospirosis comprise several members of the genus Leptospira, which also includes non-pathogenic, saprophytic species. Leptospi... | Leptospirosis is a widespread zoonotic infection that primarily affects residents of tropical regions, but is seen occasionally in temperate regions as well. Leptospirosis can vary in severity from a mild, non-specific illness to severe disease that includes multi-organ failure and widespread endothelial damage and hem... | Leptospirosis is a geographically widespread zoonosis that has emerged as a significant public health problem in urban slums, particularly in the tropics. The infection is caused by species of spirochetes belonging to the genus Leptospira. There are more than 200 serovars of Leptospira distributed among both pathogenic... |
10.1371/journal.pcbi.1006960 | Modeling the temporal dynamics of the gut microbial community in adults and infants | Given the highly dynamic and complex nature of the human gut microbial community, the ability to identify and predict time-dependent compositional patterns of microbes is crucial to our understanding of the structure and functions of this ecosystem. One factor that could affect such time-dependent patterns is microbial... | The ability to characterize and predict temporal trajectories of the microbial community in the human gut is crucial to our understanding of the structure and functions of this ecosystem. In this study we develop MTV-LMM, a method for modeling time-series microbial community data. Using MTV-LMM we find that in contrast... | There is increasing recognition that the human gut microbiome is a contributor to many aspects of human physiology and health including obesity, non-alcoholic fatty liver disease, inflammatory diseases, cancer, metabolic diseases, aging, and neurodegenerative disorders [1–14]. This suggests that the human gut microbiom... |
10.1371/journal.pcbi.1000271 | Efficient Network Reconstruction from Dynamical Cascades Identifies
Small-World Topology of Neuronal Avalanches | Cascading activity is commonly found in complex systems with directed
interactions such as metabolic networks, neuronal networks, or disease spreading
in social networks. Substantial insight into a system's organization
can be obtained by reconstructing the un... | In many complex systems found across disciplines, such as biological cells and
organisms, social networks, economic systems, and the Internet, individual
elements interact with each other, thereby forming large networks whose
structure is often not known. In t... | Cascade-like dynamics is characterized by the succession of events, or processes,
that are causally related, and is frequently encountered in many complex systems
(networks) across disciplines. For example, single cells in living organisms
maintain metabolic, protein and ... |
10.1371/journal.pbio.0060231 | Rice XB15, a Protein Phosphatase 2C, Negatively Regulates Cell Death and XA21-Mediated Innate Immunity | Perception of extracellular signals by cell surface receptors is of central importance to eukaryotic development and immunity. Kinases that are associated with the receptors or are part of the receptors themselves modulate signaling through phosphorylation events. The rice (Oryza sativa L.) XA21 receptor kinase is a ke... | Resistance to pathogens is critical to plant and animal survival. Plants, unlike animals, lack an adaptive immune system and instead rely on the innate immune response to protect against infection. To elucidate the molecular mechanism of plant innate immunity, we are studying the signaling cascade mediated by the rice ... | Protein kinases regulate most cellular signal transduction pathways including cell growth and proliferation, cellular differentiation, morphogenesis, gene transcription, and immunity [1–3]. Adaptive immunity, restricted to vertebrates, is characterized by the creation of antigen-specific receptors through somatic recom... |
10.1371/journal.pntd.0005951 | Pre-clinical antigenicity studies of an innovative multivalent vaccine for human visceral leishmaniasis | The notion that previous infection by Leishmania spp. in endemic areas leads to robust anti-Leishmania immunity, supports vaccination as a potentially effective approach to prevent disease development. Nevertheless, to date there is no vaccine available for human leishmaniasis. We optimized and assessed in vivo the saf... | Although vaccination is accepted as a potentially effective approach to prevent leishmaniasis, to date there is no vaccine available for human disease. The research on the topic is therefore extremely important, and the design and testing of new vaccine approaches, as well as non-traditional immunization schemes contin... | Leishmaniasis is a spectrum of pathological outcomes caused by different Leishmania spp., intracellular parasites with a complex life cycle requiring a susceptible host and a permissive vector [1]. Visceral leishmaniasis, the most severe form of the disease, fatal if untreated, is caused by L. donovani and L. infantum,... |
10.1371/journal.pcbi.1000264 | Developmental Robustness by Obligate Interaction of Class B Floral Homeotic Genes and Proteins | DEF-like and GLO-like class B floral homeotic genes encode closely related MADS-domain transcription factors that act as developmental switches involved in specifying the identity of petals and stamens during flower development. Class B gene function requires transcriptional upregulation by an autoregulatory loop that ... | The development of organs, their position, and boundaries in multicellular organisms are defined by genes that can sustain their own activation over long periods of time, termed genetic switches. A good case in point is provided by the genetic machinery controlling the development of flowers in higher plants. In Arabid... | Depending on the nature of the interactions of their constituents, gene regulatory circuits can display a variety of dynamical behaviors ranging from simple steady states, to switching and multistability, to oscillations. Temporal or spatial patterning during development requires activation of genes at a particular tim... |
10.1371/journal.pntd.0003084 | Suppressing Dengue-2 Infection by Chemical Inhibition of Aedes aegypti Host Factors | Dengue virus host factors (DENV HFs) that are essential for the completion of the infection cycle in the mosquito vector and vertebrate host represent potent targets for transmission blocking. Here we investigated whether known mammalian DENV HF inhibitors could influence virus infection in the arthropod vector A. aegy... | Arboviruses utilize homologous host factors of the mammalian and insect cellular machinery to complete the infection cycle. Studies in both mammalian and insect cell lines have shown that virus infection can be suppressed through inhibition of host factors by chemical compounds that therefore could be developed into tr... | From a global health perspective, dengue virus (DENV) is currently the most important arbovirus transmitted by mosquitoes. Approximately 3.6 billion people are at risk of DENV infection, and 100 million people are infected annually [1]. Given the lack of registered antivirals or vaccines against DENV, a major effort to... |
10.1371/journal.pntd.0005962 | Quantitative multiplexed proteomics of Taenia solium cysts obtained from the skeletal muscle and central nervous system of pigs | In human and porcine cysticercosis caused by the tapeworm Taenia solium, the larval stage (cysts) can infest several tissues including the central nervous system (CNS) and the skeletal muscles (SM). The cyst’s proteomics changes associated with the tissue localization in the host tissues have been poorly studied. Quant... | Human and porcine cysticercosis caused by Taenia solium is a parasite disease still endemic in developing countries. The cysts can be located in different host tissues, including different organs of the central nervous system and the skeletal muscles. The molecular mechanisms associated with the tissue localization of ... | Human and porcine cysticercosis caused by the larval stage of Taenia solium, is acquired by the ingestion of this parasite’s eggs. After activation by several gastrointestinal agents, the oncospheres penetrating the intestinal wall later establish in different tissues and organs including the skeletal muscles (SM) and ... |
10.1371/journal.pntd.0000350 | Mefloquine—An Aminoalcohol with Promising Antischistosomal Properties in Mice | The treatment and control of schistosomiasis, an often neglected tropical disease that exacerbates poverty, depends on a single drug, praziquantel. The large-scale use of praziquantel might select for drug-resistant parasites, hence there is a need to develop new antischistosomal compounds. Here, we report that the ant... | Schistosomiasis is a chronic and debilitating disease that occurs in tropical and subtropical areas. The disease is caused by an infection with a parasitic worm and affects over 200 million people. The treatment and control of schistosomiasis relies on a single drug, praziquantel. This drug is increasingly used, and he... | Schistosomiasis is a chronic and debilitating disease that exacerbates poverty [1],[2]. Although close to 800 million individuals are at risk of contracting the disease and over 200 million people are thought to be infected, schistosomiasis is often neglected [3],[4]. The causative agent is a digenetic trematode of the... |
10.1371/journal.ppat.1003370 | Crosstalk between the Circadian Clock and Innate Immunity in Arabidopsis | The circadian clock integrates temporal information with environmental cues in regulating plant development and physiology. Recently, the circadian clock has been shown to affect plant responses to biotic cues. To further examine this role of the circadian clock, we tested disease resistance in mutants disrupted in CCA... | Plants are frequently challenged by various pathogens. The circadian clock, which is the internal time measuring machinery, has been implicated in regulating plant responses to biotic cues. To better understand the role of the circadian clock in defense control, we tested disease resistance with Arabidopsis mutants dis... | Plants are challenged by various pathogens on a daily basis. Accumulating evidence implicates a role of the circadian clock in regulating plant innate immunity. The circadian clock is the internal time measuring machinery important for plant growth and development. However, our understanding of the molecular basis of h... |
10.1371/journal.pcbi.1000370 | Representation of Time-Varying Stimuli by a Network Exhibiting Oscillations on a Faster Time Scale | Sensory processing is associated with gamma frequency oscillations (30–80 Hz) in sensory cortices. This raises the question whether gamma oscillations can be directly involved in the representation of time-varying stimuli, including stimuli whose time scale is longer than a gamma cycle. We are interested in the ability... | Sensory processing of time-varying stimuli, such as speech, is associated with high-frequency oscillatory cortical activity, the functional significance of which is still unknown. One possibility is that the oscillations are part of a stimulus-encoding mechanism. Here, we investigate a computational model of such a mec... | In recent years, there has been a growing interest in understanding how temporal information of sensory stimuli is encoded by sensory corticies (see, e.g., [1]–[8]). It has been shown that information about the features of the external stimulus is encoded in the fine temporal structure of the neural response (see, e.g.... |
10.1371/journal.pntd.0005587 | A nonsense mutation in TLR5 is associated with survival and reduced IL-10 and TNF-α levels in human melioidosis | Melioidosis, caused by the flagellated bacterium Burkholderia pseudomallei, is a life-threatening and increasingly recognized emerging disease. Toll-like receptor (TLR) 5 is a germline-encoded pattern recognition receptor to bacterial flagellin. We evaluated the association of a nonsense TLR5 genetic variant that trunc... | Melioidosis is a high-mortality infectious disease in Southeast Asia and northern Australia caused by Burkholderia pseudomallei, which is a flagellated, rod-shaped Gram-negative bacterium. Understanding protective host immune responses to melioidosis is fundamental for effective vaccine development. A previous study de... | Melioidosis is caused by the Gram-negative, flagellated bacillus and environmental saprophyte, Burkholderia pseudomallei, which the US Centers for Disease Control and Prevention (CDC) have identified as a Tier 1 bioterrorism agent. Clinical presentations of melioidosis range from acute sepsis to chronic and persistent ... |
10.1371/journal.ppat.1002496 | Viral Cyclins Mediate Separate Phases of Infection by Integrating Functions of Distinct Mammalian Cyclins | Gammaherpesvirus cyclins have expanded biochemical features relative to mammalian cyclins, and promote infection and pathogenesis including acute lung infection, viral persistence, and reactivation from latency. To define the essential features of the viral cyclin, we generated a panel of knock-in viruses expressing va... | Many viruses encode homologs of human oncogenes, including the gammaherpesvirus viral cyclin genes. These viruses cause lifelong infection associated with chronic diseases, including malignancies, which are exacerbated in immune deficiency. The conserved viral cyclins were first recognized nearly two decades ago, and d... | Gammaherpesviruses are oncogenic viruses that establish lifelong infection of the host. Primary gammaherpesvirus infection of healthy adult hosts results in an acute stage of lytic virus replication which is then cleared, with lifelong latent infection established primarily in B lymphocytes. A transient mononucleosis-l... |
10.1371/journal.pbio.1000278 | Coherence Potentials: Loss-Less, All-or-None Network Events in the Cortex | Transient associations among neurons are thought to underlie memory and behavior. However, little is known about how such associations occur or how they can be identified. Here we recorded ongoing local field potential (LFP) activity at multiple sites within the cortex of awake monkeys and organotypic cultures of corte... | Perception and behavior are thought to arise from transient associations among sub-groups of nerve cells in the brain. However, identifying which of the many active neurons are associated at any given time and how poses a challenge. Here we show that when the composite activity of a local group of cortical neurons, mea... | Since its introduction by Hebb [1], the transient formation of cell assemblies has been one of the most fundamental and provocative hypotheses to understand cortex function. The existence and identification of such assemblies, however, has been extremely difficult as it requires a criterion that separates the activitie... |
10.1371/journal.ppat.1002405 | Kaposi's Sarcoma Herpesvirus microRNAs Target Caspase 3 and Regulate Apoptosis | Kaposi's sarcoma herpesvirus (KSHV) encodes a cluster of twelve micro (mi)RNAs, which are abundantly expressed during both latent and lytic infection. Previous studies reported that KSHV is able to inhibit apoptosis during latent infection; we thus tested the involvement of viral miRNAs in this process. We found that b... | MiRNAs are small, non-coding RNAs that regulate gene expression post-transcriptionally via binding to complementary sites in target mRNAs. This evolutionary conserved regulatory system is present in most eukaryotes, and it has recently been shown that certain viruses have evolved to express their own miRNAs. Due to the... | The development of cancer is linked to six major hallmarks that explain how cells transgress from a normal to a neoplastic state, including (i) sustained proliferative signaling, (ii) evasion of growth suppression, (iii) activated invasion and metastasis, (iv) enabled replicative immortality, (v) induced angiogenesis a... |
10.1371/journal.ppat.1001174 | Tyrosine Sulfation of the Amino Terminus of PSGL-1 Is Critical for Enterovirus 71 Infection | Enterovirus 71 (EV71) is one of the major causative agents of hand, foot, and mouth disease, a common febrile disease in children; however, EV71 has been also associated with various neurological diseases including fatal cases in large EV71 outbreaks particularly in the Asia Pacific region. Recently we identified human... | Enterovirus 71 (EV71) is a major causative agent of hand, foot, and mouth disease and a diverse array of neurological diseases, including fatal encephalitis, in children. EV71 has increasingly caused large outbreaks of hand, foot, and mouth disease particularly in the Asia-Pacific region. Recently, we identified human ... | Enterovirus 71 (EV71) is a small, nonenveloped, positive-stranded RNA virus that belongs to human enterovirus species A of the genus Enterovirus in the family Picornaviridae. EV71 is a major causative agent of hand, foot, and mouth disease (HFMD), a common febrile disease affecting mainly young children. HFMD is charac... |
10.1371/journal.pcbi.1006115 | Age density patterns in patients medical conditions: A clustering approach | This paper presents a data analysis framework to uncover relationships between health conditions, age and sex for a large population of patients. We study a massive heterogeneous sample of 1.7 million patients in Brazil, containing 47 million of health records with detailed medical conditions for visits to medical faci... | Age and sex of a patient can be directly related to susceptibilities to certain medical conditions. We present a method to generate clusters of human phenotype, based on the age of the population. This method helps extract knowledge on age and sex from the data. The age and sex correlations with disease conditions can ... | Studies of groups of diseases occurring together, or disease comorbidities, have traditionally focused on studies of small groups of diseases using techniques of hypothesis-testing [1–6]. The repeated existence of particular comorbidities is important to diagnoses and better index diseases [7, 8]. Databases of electron... |
10.1371/journal.ppat.1005763 | Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond | A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of infor... | Malaria leads to the loss of over 440,000 lives annually; accelerating research to discover new candidate drugs is a priority. Medicines for Malaria Venture (MMV) has distilled over 25,000 compounds that kill malaria parasites in vitro into a group of 400 representative compounds, called the "Malaria Box". These Malari... | Preclinical development for drugs in neglected diseases remains a slow process due to a lack of access to compounds, and legal complications over intellectual property ownership. One way to accelerate drug discovery is to provide open access to bioactive molecules with public disclosure of the resulting biological data... |
10.1371/journal.pntd.0006636 | The current epidemiological status of urogenital schistosomiasis among primary school pupils in Katsina State, Nigeria: An imperative for a scale up of water and sanitation initiative and mass administration of medicines with Praziquantel | Human schistosomiasis, a debilitating and chronic disease, is among a set of 17 neglected tropical infectious diseases of poverty that is currently posing a threat to the wellbeing of 2 billion people in the world. The SHAWN/WASH and MAM programmes in the study area require epidemiological data to enhance their effecti... | In 1851, human schistosomiasis was discovered in Egypt by a German surgeon named Theodor Bilharz. Therefore, it is alternatively called ‘bilharziasis’. Being a disease that is closely associated with poverty in the tropics, chiefly the sub-Saharan Africa, Urinary Schistosomiasis is transmitted to humans who source for ... | Human schistosomiasis, though less fatal, but debilitating and chronic in nature, is among a set of 17 neglected tropical infectious diseases of poverty that is currently posing a threat to the wellbeing of 2 billion people in the world [1]. The aetiological agent of urogenital schistosomiasis is the infective stage (c... |
10.1371/journal.pgen.1001367 | 14-3-3 Proteins Regulate Exonuclease 1–Dependent Processing of Stalled Replication Forks | Replication fork integrity, which is essential for the maintenance of genome stability, is monitored by checkpoint-mediated phosphorylation events. 14-3-3 proteins are able to bind phosphorylated proteins and were shown to play an undefined role under DNA replication stress. Exonuclease 1 (Exo1) processes stalled repli... | Stalling and collapse of DNA replication forks is an important source of genome instability and has been implicated in early steps of carcinogenesis. The maintenance of stable intermediates upon stalled replication requires the coordinated action of a number of proteins and proper inhibitory control of dangerous enzyma... | DNA lesions can cause stalling and collapse of the replication fork and lead to chromosome breaks, mutations, genome rearrangements and eventually cancer [1]. To prevent this, a replication checkpoint has evolved as surveillance mechanism to control components of the replisome [2] and to allow coordinating replication ... |
10.1371/journal.pgen.1005636 | Single Strand Annealing Plays a Major Role in RecA-Independent Recombination between Repeated Sequences in the Radioresistant Deinococcus radiodurans Bacterium | The bacterium Deinococcus radiodurans is one of the most radioresistant organisms known. It is able to reconstruct a functional genome from hundreds of radiation-induced chromosomal fragments. Our work aims to highlight the genes involved in recombination between 438 bp direct repeats separated by intervening sequences... | Deinococcus radiodurans is known for its exceptional ability to tolerate exposure to DNA damaging agents and, in particular, to very high doses of ionizing radiation. This exceptional radioresistance results from many features including efficient DNA double strand break repair. Here, we examine genome stability in D. r... | The extreme resistance of the bacterium D. radiodurans to DNA-fragmenting treatments, such as ionizing radiation or desiccation, is correlated with the ability to reconstruct a functional genome from hundreds of chromosomal fragments. The rapid reconstitution of an intact genome is thought to occur through an extended ... |
10.1371/journal.pcbi.1000223 | Quantification of Local Morphodynamics and Local GTPase Activity by Edge Evolution Tracking | Advances in time-lapse fluorescence microscopy have enabled us to directly observe dynamic cellular phenomena. Although the techniques themselves have promoted the understanding of dynamic cellular functions, the vast number of images acquired has generated a need for automated processing tools to extract statistical i... | Morphological change is a key indicator of various cellular functions such as migration and construction of specific structures. Time-lapse image microscopy permits the visualization of changes in morphology and spatio-temporal protein activity related to dynamic cellular functions. However, an unsolved problem is the ... | Cell morphological change is a key process in the development and homeostasis of multicellular organisms [1],[2]. Various types of morphological change appear during migration and differentiation; essential events occurring as part of these processes usually accompany morphologically different phenotypes. Therefore, ce... |
10.1371/journal.pntd.0007343 | Zika viruses of African and Asian lineages cause fetal harm in a mouse model of vertical transmission | Congenital Zika virus (ZIKV) infection was first linked to birth defects during the American outbreak in 2015/2016. It has been proposed that mutations unique to the Asian/American-genotype explain, at least in part, the ability of Asian/American ZIKV to cause congenital Zika syndrome (CZS). Recent studies identified m... | Zika virus (ZIKV) was first discovered in Uganda in 1947, and is thought to have spread from Africa through equatorial Asia in the middle of the 20th century. Along the way the virus diversified, so that now two genetic lineages, African and Asian/American, are recognized. Congenital Zika syndrome (CZS), the set of fet... | Zika virus causes adverse pregnancy outcomes including fetal loss, developmental abnormalities, and neurological damage, collectively termed congenital Zika syndrome (CZS) [1–4]. Why does CZS seem like a new complication when ZIKV has been circulating in Africa and Asia for decades? A provocative explanation for the re... |
10.1371/journal.ppat.1002792 | Hyperthermia Stimulates HIV-1 Replication | HIV-infected individuals may experience fever episodes. Fever is an elevation of the body temperature accompanied by inflammation. It is usually beneficial for the host through enhancement of immunological defenses. In cultures, transient non-physiological heat shock (42–45°C) and Heat Shock Proteins (HSPs) modulate HI... | Fever is a complex reaction triggered in response to pathogen infection. It induces diverse effects on the human body and especially on the immune system. The functions of immune cells are positively affected by fever, helping them to fight infection. Fever consists in a physiological elevation of temperature and in in... | Fever is a physiological process induced by endogenous pyretics (IL-6, IL-1β, TNFα) in response to stresses such as pathogen infection. It consists in hyperthermia, an elevation of the body temperature to 38–40°C, associated with an inflammatory state. Fever is generally beneficial for the host, triggering multiple eve... |
10.1371/journal.pntd.0000982 | Evaluation of Cost-Effective Strategies for Rabies Post-Exposure Vaccination in Low-Income Countries | Prompt post-exposure prophylaxis (PEP) is essential in preventing the fatal onset of disease in persons exposed to rabies. Unfortunately, life-saving rabies vaccines and biologicals are often neither accessible nor affordable, particularly to the poorest sectors of society who are most at risk and upon whom the largest... | Rapid delivery of post-exposure vaccination is essential for preventing the fatal onset of rabies in persons bitten by rabid animals. But for communities most at risk of exposure to rabies (in resource poor countries where domestic dog rabies is still common), post-exposure vaccines are often not affordable and are onl... | Rabies is invariably fatal once clinical signs appear but can be readily prevented after exposure with prompt and appropriate post-exposure prophylaxis (PEP) [1]. PEP is therefore the most critical life-saving intervention essential for the prevention of rabies in humans after exposure [2]. In reality, most of the esti... |
10.1371/journal.pgen.1004484 | Common Transcriptional Mechanisms for Visual Photoreceptor Cell Differentiation among Pancrustaceans | A hallmark of visual rhabdomeric photoreceptors is the expression of a rhabdomeric opsin and uniquely associated phototransduction molecules, which are incorporated into a specialized expanded apical membrane, the rhabdomere. Given the extensive utilization of rhabdomeric photoreceptors in the eyes of protostomes, here... | Visual systems are populated by one of two fundamental types of photoreceptors, ciliary and rhabdomeric. Each photoreceptor type is defined by the opsin molecule expressed and the final morphological form adapted to house the phototransduction machinery. Here we address whether a common transcriptional mechanisms exist... | Rhabdomeric (r) photoreceptors are one of two fundamental types of photoreceptors that have been described [1]. Typically, r- photoreceptors populate the visual systems of protostomes including insects, crustaceans, and annelids (reviewed in [2]). This wide phylogenetic distribution and the presence of both types of ph... |
10.1371/journal.pntd.0004211 | Socio-economic and Climate Factors Associated with Dengue Fever Spatial Heterogeneity: A Worked Example in New Caledonia | Understanding the factors underlying the spatio-temporal distribution of infectious diseases provides useful information regarding their prevention and control. Dengue fever spatio-temporal patterns result from complex interactions between the virus, the host, and the vector. These interactions can be influenced by env... | Dengue fever is the most important viral arthropod-borne disease worldwide and its geographical expansion during the past decades has been of growing concern for scientists and public health authorities because of its heavy sanitary burden and economic impacts. In the absence of an effective vaccine, control is current... | Dengue fever is the most important mosquito-borne viral disease, with an estimated 50 million people being infected each year and 2.5 billion people living in areas at risk of dengue worldwide [1]. The true burden of clinically apparent dengue could be twice as high, and the total burden of dengue fever infections coul... |
10.1371/journal.ppat.1007614 | Interleukin 21 collaborates with interferon-γ for the optimal expression of interferon-stimulated genes and enhances protection against enteric microbial infection | The mucosal surface of the intestinal tract represents a major entry route for many microbes. Despite recent progress in the understanding of the IL-21/IL-21R signaling axis in the generation of germinal center B cells, the roles played by this signaling pathway in the context of enteric microbial infections is not wel... | Diarrheal diseases still remain the second leading cause of mortality in children younger than 5 years old worldwide, leading to 1.3 million deaths per annum. The diarrheagenic Escherichia coli (DEC) pathotypes are considered NIAID Biodefense Category B agents. Human infections with enteropathogenic and enterohemorrhag... | Several microbial pathogens elicit the type I (e.g. IFN-α, IFN-β), type II (IFN-γ) or type III (e.g. IFN-λ) interferons, leading to the transcription of several hundred interferon-stimulated genes (ISGs) [1, 2]. The activation of each of these interferon systems induces a distinct but partially overlapping set of signa... |
10.1371/journal.pgen.1000263 | Aging Predisposes Oocytes to Meiotic Nondisjunction When the Cohesin Subunit SMC1 Is Reduced | In humans, meiotic chromosome segregation errors increase dramatically as women age, but the molecular defects responsible are largely unknown. Cohesion along the arms of meiotic sister chromatids provides an evolutionarily conserved mechanism to keep recombinant chromosomes associated until anaphase I. One attractive ... | In humans, chromosome segregation errors during meiosis are the leading cause of birth defects and miscarriages. Moreover, as women age, these errors increase dramatically. For accurate segregation during the first meiotic division, homologous chromosomes must remain physically associated until anaphase I. Normally, at... | In humans, meiotic chromosome segregation errors that give rise to aneuploid gametes are the leading cause of fetal loss and birth defects [1]. Approximately 30% of miscarriages result from aneuploidy and at least 5% of all clinically recognized pregnancies and 0.3% of live-borns are aneuploid [1]. Female meiosis in hu... |
10.1371/journal.pgen.1003476 | The Hourglass and the Early Conservation Models—Co-Existing Patterns of Developmental Constraints in Vertebrates | Developmental constraints have been postulated to limit the space of feasible phenotypes and thus shape animal evolution. These constraints have been suggested to be the strongest during either early or mid-embryogenesis, which corresponds to the early conservation model or the hourglass model, respectively. Conflictin... | During development, vertebrate embryos pass through a “phylotypic” stage, during which their morphology is most similar between different species. This gave rise to the hourglass model, which predicts the highest developmental constraints during mid-embryogenesis. In the last decade, a large effort has been made to unc... | Developmental constraints have been suggested to play an important role in shaping the evolution of embryonic development in animals. Briefly, the concept of developmental constraints assumes that the scope of developmental mechanisms limits the set of phenotypes that may evolve. Thus, morphological similarities betwee... |
10.1371/journal.pntd.0004799 | Inhibition of the Hantavirus Fusion Process by Predicted Domain III and Stem Peptides from Glycoprotein Gc | Hantaviruses can cause hantavirus pulmonary syndrome or hemorrhagic fever with renal syndrome in humans. To enter cells, hantaviruses fuse their envelope membrane with host cell membranes. Previously, we have shown that the Gc envelope glycoprotein is the viral fusion protein sharing characteristics with class II fusio... | The infection of cells by enveloped viruses involves the fusion of membranes between viruses and cells. This process is mediated by viral fusion proteins that have been grouped into at least three structural classes. Membrane-enveloped hantaviruses are worldwide spread pathogens that can cause human disease with mortal... | The genus Hantavirus of the family Bunyaviridae comprises diverse viruses that are highly pathogenic to humans. In Asia and Europe the Hantaan, Seoul and PUUV viruses cause hemorrhagic fever with renal syndrome, while in America ANDV and Sin Nombre virus can lead to hantavirus pulmonary syndrome with mortality rates ab... |
10.1371/journal.pgen.1002805 | A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone–Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation | Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cance... | Sex hormone-binding globulin (SHBG) is the key protein responsible for binding and transporting the sex steroid hormones, testosterone and estradiol, in the circulatory system. SHBG regulates their bioavailability and therefore their effects in the body. SHBG has been linked to chronic diseases including type 2 diabete... | Sex hormone-binding globulin (SHBG) is a protein secreted mainly by the liver that binds to the sex steroids, testosterone, dihydrotestosterone, and estradiol, transports them in the circulation, and influences their action in target tissues by regulating their bioavailability. SHBG thereby influences the expression of... |
10.1371/journal.pcbi.1000917 | Differences in Nutrient Requirements Imply a Non-Linear Emergence of Leaders in Animal Groups | Collective decision making and especially leadership in groups are among the most studied topics in natural, social, and political sciences. Previous studies have shown that some individuals are more likely to be leaders because of their social power or the pertinent information they possess. One challenge for all grou... | Making decisions together to reach a consensus is one of the most important challenges of any society. In some communities, however, some leaders have more weight in the decisions than the other individuals. Similar rules exist in animal societies. Studies on animal groups have shown that some individuals are more like... | Social animals have to coordinate their activities in order to maintain the advantages of group living [1]–[3]. This coordination constitutes one of the major challenges of any animal society, including human beings, and arouses the interest of scientists, sociologists, and politicians [4]–[9]. Whatever the group size ... |
10.1371/journal.pntd.0001035 | Triatoma dimidiata Infestation in Chagas Disease Endemic Regions of Guatemala: Comparison of Random and Targeted Cross-Sectional Surveys | Guatemala is presently engaged in the Central America Initiative to interrupt Chagas disease transmission by reducing intradomiciliary prevalence of Triatoma dimidiata, using targeted cross-sectional surveys to direct control measures to villages exceeding the 5% control threshold. The use of targeted surveys to guide ... | Chagas disease is a vector-borne parasitic zoonosis endemic throughout South and Central America and Mexico. Guatemala is engaged in the Central America Initiative to interrupt Chagas disease transmission. A major strategy is the reduction of Triatoma dimidiata domiciliary infestations through indoor application of res... | In Guatemala, nearly 4 million individuals are projected to be at risk for infection with Trypanosoma cruzi, the causative agent of Chagas disease, with approximately 30,000 new cases a year and a prevalence of 730,000 [1], [2]. The estimated prevalence and annual incidence is more than double any other country in Cent... |
10.1371/journal.pntd.0000192 | Infections with Immunogenic Trypanosomes Reduce Tsetse Reproductive Fitness: Potential Impact of Different Parasite Strains on Vector Population Structure | The parasite Trypanosoma brucei rhodesiense and its insect vector Glossina morsitans morsitans were used to evaluate the effect of parasite clearance (resistance) as well as the cost of midgut infections on tsetse host fitness. Tsetse flies are viviparous and have a low reproductive capacity, giving birth to only 6–8 p... | In many cases, parasites adapt to their hosts' biology over time and the extent of their harmful effects gradually diminishes. Insect-transmitted parasites such as African trypanosomes, however, are unusually pathogenic for their mammalian hosts because they rely on their invertebrate hosts for transmission to the next... | Insect vectors are essential for the transmission of malaria and African sleeping sickness, among many other diseases. Despite the high disease incidence in mammalian hosts, infection prevalence in insect vectors is typically low. For example, with the tsetse vectors of trypanosomes that cause African sleeping sickness... |
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