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10.1371/journal.ppat.1006888 | Distinct susceptibility of HIV vaccine vector-induced CD4 T cells to HIV infection | The concerns raised from adenovirus 5 (Ad5)-based HIV vaccine clinical trials, where excess HIV infections were observed in some vaccine recipients, have highlighted the importance of understanding host responses to vaccine vectors and the HIV susceptibility of vector-specific CD4 T cells in HIV vaccination. Our recent... | Development of a safe and efficacious HIV vaccine is a critical global health priority. Recombinant viral vectors are an important platform for HIV vaccine delivery. Recent clinical trials testing candidate HIV vaccines based on Ad5 vectors failed and reported excess HIV infections in some vaccine recipients, underscor... | Over 30 years after the discovery of HIV as the causative agent of acquired immunodeficiency syndrome (AIDS), HIV/AIDS continues to be a significant challenge for global public health. More than 36 million people are currently living with HIV, with over 2 million new infections and 1 million AIDS-related deaths per yea... |
10.1371/journal.pmed.1002835 | Biannual mass azithromycin distributions and malaria parasitemia in pre-school children in Niger: A cluster-randomized, placebo-controlled trial | Mass azithromycin distributions have been shown to reduce mortality in preschool children, although the factors mediating this mortality reduction are not clear. This study was performed to determine whether mass distribution of azithromycin, which has modest antimalarial activity, reduces the community burden of malar... | The Macrolides Oraux pour Réduire les Décés avec un Oeil sur la Resistance (MORDOR) trial found that distributing the antibiotic azithromycin to all preschool children in communities in Niger was effective for preventing childhood mortality.
It is unclear how azithromycin might prevent mortality, though this antibiotic... | Mass azithromycin distributions have lowered childhood mortality in Africa, although the mechanism explaining this effect is unknown. Macrolides Oraux pour Réduire les Décés avec un Oeil sur la Resistance (MORDOR) was a cluster-randomized placebo-controlled trial conducted in Malawi, Niger, and Tanzania that found a 14... |
10.1371/journal.pcbi.1002078 | Enzyme Kinetics of the Mitochondrial Deoxyribonucleoside Salvage Pathway Are Not Sufficient to Support Rapid mtDNA Replication | Using a computational model, we simulated mitochondrial deoxynucleotide metabolism and mitochondrial DNA replication. Our results indicate that the output from the mitochondrial salvage enzymes alone is inadequate to support a mitochondrial DNA replication duration of as long as 10 hours. We find that an external sourc... | The powerhouses of human cells, mitochondria, contain DNA that is distinct from the primary genome, the DNA in the nucleus of cells. The mitochondrial genome needs to be replicated often to ensure continued generation of ATP (adenosine triphosphate) which is the energy currency of the cell. Problems with maintenance of... | Mitochondrial DNA (mtDNA) replication [1], and the mitochondrial nucleoside salvage pathway that generates the precursor deoxyribonucleoside triphosphates (dNTPs) for mitochondrial DNA replication, have generally been believed to function independently of nuclear DNA (nDNA) replication and cytoplasmic nucleotide metabo... |
10.1371/journal.ppat.1002573 | E2F1 Mediated Apoptosis Induced by the DNA Damage Response Is Blocked by EBV Nuclear Antigen 3C in Lymphoblastoid Cells | EBV latent antigen EBNA3C is indispensible for in vitro B-cell immortalization resulting in continuously proliferating lymphoblastoid cell lines (LCLs). EBNA3C was previously shown to target pRb for ubiquitin-proteasome mediated degradation, which facilitates G1 to S transition controlled by the major transcriptional a... | Aberrant cellular proliferation due to deregulation of E2F1 transcriptional activity as a result of either genetic or functional alterations of its upstream components is a hallmark of human cancer. Interestingly, E2F1 can also promote cellular apoptosis regardless of p53 status by activating a number of pro-apoptotic ... | The role of the pRb-E2F pathway in the regulation of cell-cycle progression, particularly the G1-S transition, is well established [1]. Several lines of evidence have suggested different roles for individual members of the E2F family of proteins in regulating cell proliferation [2], [3]. There are eight different E2F g... |
10.1371/journal.pntd.0000724 | Isolation and Characterization of New Leptospira Genotypes from Patients in Mayotte (Indian Ocean) | Leptospirosis has been implicated as a severe and fatal form of disease in Mayotte, a French-administrated territory located in the Comoros archipelago (southwestern Indian Ocean). To date, Leptospira isolates have never been isolated in this endemic region.
Leptospires were isolated from blood samples from 22 patients... | Leptospirosis has been recognized as an increasing public health problem affecting poor people from developing countries and tropical regions. However, the epidemiology of leptospirosis remains poorly understood in remote parts of the world. In this study of patients from the island of Mayotte, we isolated 22 strains f... | Leptospirosis, a zoonotic disease with a worldwide distribution, is an important emerging infectious disease [1]. Rodents are a main reservoir of the pathogenic agents of this disease, spirochetes of the genus Leptospira, excreting the bacteria in their urine. Humans are usually infected through contaminated water. Thi... |
10.1371/journal.ppat.1004220 | Defining Immune Engagement Thresholds for In Vivo Control of Virus-Driven Lymphoproliferation | Persistent infections are subject to constant surveillance by CD8+ cytotoxic T cells (CTL). Their control should therefore depend on MHC class I-restricted epitope presentation. Many epitopes are described for γ-herpesviruses and form a basis for prospective immunotherapies and vaccines. However the quantitative requir... | Chronic viral infections cause huge morbidity and mortality worldwide. γ-herpesviruses provide an example relevant to all human demographics, causing, inter alia, Hodgkin's disease, Burkitt's lymphoma, Kaposi's Sarcoma, and nasopharyngeal carcinoma. The proliferation of latently infected B cells and their control by CD... | The gamma-herpesviruses (γHVs) infect >90% of humans and cause diseases including nasopharyngeal carcinoma, African Burkitt's lymphoma and Kaposi's Sarcoma. Their colonization of circulating memory B cells is crucial to persistence and hence to disease ontogeny. Viral latency gene expression in B cells provides an immu... |
10.1371/journal.pcbi.1001030 | Spatial Pattern Switching Enables Cyclic Evolution in Spatial Epidemics | Infectious diseases often spread as spatial epidemic outbreak waves. A number of model studies have shown that such spatial pattern formation can have important consequences for the evolution of pathogens. Here, we show that such spatial patterns can cause cyclic evolutionary dynamics in selection for the length of the... | Parasites are commonly believed to evolve to make as many infections as possible. In large scale simulations of disease spread, however, natural selection can instead act to maximize outbreak frequency. Here, pathogens that cause short infections can be rewarded for their prudence by a rapid subsequent outbreak. Very s... | Recent studies show that in spatial models, evolutionary dynamics of infectious diseases change with respect to predictions from non-spatial model, which implicitly assume complete mixing of individuals [1]–[5]. Spatial epidemic waves have been observed for several diseases [6]–[9]. Starting with Rand et al. [10], a nu... |
10.1371/journal.pgen.1004988 | Prodomain Removal Enables Neto to Stabilize Glutamate Receptors at the Drosophila Neuromuscular Junction | Stabilization of neurotransmitter receptors at postsynaptic specializations is a key step in the assembly of functional synapses. Drosophila Neto (Neuropillin and Tolloid-like protein) is an essential auxiliary subunit of ionotropic glutamate receptor (iGluR) complexes required for the iGluRs clustering at the neuromus... | Synapse development is initiated by genetic programs, but is coordinated by neuronal activity, by communication between the pre- and postsynaptic compartments, and by cellular signals that integrate the status of the whole organisms and its developmental progression. The molecular mechanisms underlining these processes... | Synapse development is a highly orchestrated process that enables proper establishment of neural circuits and development of the nervous system. Crucial to synapse assembly is the recruitment and stabilization of neurotransmitter receptor complexes at synaptic sites [1]. Receptor complexes can be inserted directly into... |
10.1371/journal.pgen.1002864 | The MicroRNA mir-71 Inhibits Calcium Signaling by Targeting the TIR-1/Sarm1 Adaptor Protein to Control Stochastic L/R Neuronal Asymmetry in C. elegans | The Caenorhabditis elegans left and right AWC olfactory neurons communicate to establish stochastic asymmetric identities, AWCON and AWCOFF, by inhibiting a calcium-mediated signaling pathway in the future AWCON cell. NSY-4/claudin-like protein and NSY-5/innexin gap junction protein are the two parallel signals that an... | Cell identity determination requires a competition between the induction of cell type–specific genes and the suppression of genes that promote an alternative cell type. In the nematode C. elegans, a specific sensory neuron pair communicates to establish stochastic asymmetric identities by inhibiting a calcium signaling... | Cell fate determination during development requires both the induction of cell type specific genes and the suppression of genes that promote an alternative cell fate [1]–[4]. For example, both inductive signaling, mediated by an EGFR-Ras-MAPK pathway, and lateral inhibition, mediated by LIN-12/Notch activity and microR... |
10.1371/journal.pgen.1003549 | The Gene Desert Mammary Carcinoma Susceptibility Locus Mcs1a Regulates Nr2f1 Modifying Mammary Epithelial Cell Differentiation and Proliferation | Genome-wide association studies have revealed that many low-penetrance breast cancer susceptibility loci are located in non-protein coding genomic regions; however, few have been characterized. In a comparative genetics approach to model such loci in a rat breast cancer model, we previously identified the mammary carci... | Most non-Mendelian disease variants identified through genome-wide association studies are low-penetrance, common in the population and located in non-protein coding genomic loci. It is currently unknown how these loci modulate disease risk. Insights in their mechanisms could lead to the development of novel prevention... | An important indicator for breast cancer risk is the family history, suggesting a strong genetic component in breast cancer susceptibility [1]. The heritable portion of a woman's risk to breast cancer consists of numerous risk-increasing and risk-decreasing alleles. Through familial linkage studies in the 1990s, delete... |
10.1371/journal.pgen.1003368 | Long Noncoding RNA MALAT1 Controls Cell Cycle Progression by Regulating the Expression of Oncogenic Transcription Factor B-MYB | The long noncoding MALAT1 RNA is upregulated in cancer tissues and its elevated expression is associated with hyper-proliferation, but the underlying mechanism is poorly understood. We demonstrate that MALAT1 levels are regulated during normal cell cycle progression. Genome-wide transcriptome analyses in normal human d... | The mammalian genome encodes large number of long non protein-coding RNAs (lncRNAs). These lncRNAs are suggested to regulate key biological processes (including cellular proliferation and differentiation), and aberrant expression of these is associated with cancer. However, only a few of these lncRNAs have been functio... | The eukaryotic genome harbors a large number of noncoding RNAs, which include small and long noncoding RNAs (lncRNAs) [1], [2], [3], [4]. Small ncRNAs such as microRNAs regulate the expression of target genes at the level of translation or mRNA stability, whereas piwi-interacting RNAs (piRNA) have been linked to transc... |
10.1371/journal.pgen.1000690 | A Pol V–Mediated Silencing, Independent of RNA–Directed DNA Methylation, Applies to 5S rDNA | The plant-specific RNA polymerases Pol IV and Pol V are essential to RNA–directed DNA methylation (RdDM), which also requires activities from RDR2 (RNA–Dependent RNA Polymerase 2), DCL3 (Dicer-Like 3), AGO4 (Argonaute), and DRM2 (Domains Rearranged Methyltransferase 2). RdDM is dedicated to the methylation of target se... | In plant genomes, the RNA–directed DNA methylation (RdDM) process induces de novo methylation of cytosines at repeated sequences. The RNA polymerases Pol IV and Pol V are two key components of the RdDM pathway. Pol IV acts with RDR2 (RNA–dependent RNA polymerase 2) and DCL3 (Dicer-Like protein 3) to generate short inte... | The plant-specific RNA polymerases firstly named Pol IVa and Pol IVb and now referred as Pol IV and Pol V [1], contribute to siRNA production and are essential to RNA-directed DNA methylation (RdDM) [2]–[6]. The revised nomenclature denotes the largest subunits of Pol IV and Pol V as NRPD1 and NRPE1. Both Pol IV and Po... |
10.1371/journal.pcbi.1004353 | Modeling Inhibitory Interneurons in Efficient Sensory Coding Models | There is still much unknown regarding the computational role of inhibitory cells in the sensory cortex. While modeling studies could potentially shed light on the critical role played by inhibition in cortical computation, there is a gap between the simplicity of many models of sensory coding and the biological complex... | Cortical function is a result of coordinated interactions between excitatory and inhibitory neural populations. In previous theoretical models of sensory systems, inhibitory neurons are often ignored or modeled too simplistically to contribute to understanding their role in cortical computation. In biophysical reality,... | The diverse inhibitory interneuron population in cortex has been increasingly recognized as an important component in shaping cortical activity [1]. However, it remains unclear in many settings how the inhibitory circuit specifically contributes to the neural code. While theoretical and simulation investigations of pro... |
10.1371/journal.pcbi.1004520 | Established Microbial Colonies Can Survive Type VI Secretion Assault | Type VI secretion (T6S) is a cell-to-cell injection system that can be used as a microbial weapon. T6S kills vulnerable cells, and is present in close to 25% of sequenced Gram-negative bacteria. To examine the ecological role of T6S among bacteria, we competed self-immune T6S+ cells and T6S-sensitive cells in simulated... | Type VI secretion (T6S) is a cell-to-cell injection system that can be used as a microbial weapon. T6S kills vulnerable cells, and is present in a significant fraction of bacteria. Given the tactical advantage conferred by T6S, the system’s lack of universality suggests limits to its effectiveness relative to its costs... | Microbes employ a staggering range of extracellular tools to engineer their immediate environment [1–6]. Very often, that environment is defined by the multitude of other cells in close proximity. These neighbors pose both a threat and an opportunity, and represent an important target for manipulation [7–10].
The Type... |
10.1371/journal.pgen.0030121 | Plasticity of Fission Yeast CENP-A Chromatin Driven by Relative Levels of Histone H3 and H4 | The histone H3 variant CENP-A assembles into chromatin exclusively at centromeres. The process of CENP-A chromatin assembly is epigenetically regulated. Fission yeast centromeres are composed of a central kinetochore domain on which CENP-A chromatin is assembled, and this is flanked by heterochromatin. Marker genes are... | The DNA of all genomes is organized into chromosomes that are packaged in chromatin in which DNA is wrapped around nucleosomes composed of the histones H2A, H2B, H3, and H4. Centromeres are the specialized regions on chromosomes that attach them to spindle microtubules, and this process is required to allow each daught... | In most eukaryotes, chromosomes contain a centromere that occupies a single locus. The centromere acts as the site for assembly of the kinetochore that mediates the attachment of chromosomes to spindle microtubules and orchestrates their equational segregation to daughter nuclei at mitosis. In many organisms, long tand... |
10.1371/journal.pcbi.1003755 | Identifying Selection in the Within-Host Evolution of Influenza Using Viral Sequence Data | The within-host evolution of influenza is a vital component of its epidemiology. A question of particular interest is the role that selection plays in shaping the viral population over the course of a single infection. We here describe a method to measure selection acting upon the influenza virus within an individual h... | The evolution of the influenza virus is of great importance for human health. Through evolution, current influenza viruses develop the ability to infect people who have been vaccinated against earlier strains. New strains of influenza that infect birds and pigs could evolve to infect and spread between people, causing ... | The overall risk to human health posed by the novel H7N9 influenza virus [1], while potentially severe, is as yet unknown [2], [3]. Pandemic influenza is a zoonosis [4], and as such any new pandemic may be expected to arise through a two-step process [5], [6], the virus first gaining the ability to cause sporadic, loca... |
10.1371/journal.pgen.1005850 | Exome Sequencing of Uterine Leiomyosarcomas Identifies Frequent Mutations in TP53, ATRX, and MED12 | Uterine leiomyosarcomas (ULMSs) are aggressive smooth muscle tumors associated with poor clinical outcome. Despite previous cytogenetic and molecular studies, their molecular background has remained elusive. To examine somatic variation in ULMS, we performed exome sequencing on 19 tumors. Altogether, 43 genes were muta... | Uterine leiomyosarcomas are rare, malignant smooth muscle tumors with a poor 5-year survival and high recurrence rate. They account for 1–2% of all uterine malignancies with an estimated incidence of 0.4/100,000 women per year. The symptoms and signs of this tumor type widely overlap with those of common benign uterine... | Uterine leiomyosarcoma (ULMS) is a rare, highly malignant tumor that originates from the smooth muscle layer of the uterus, the myometrium. It is the most common subtype of uterine sarcoma and accounts for 1–2% of all uterine malignancies with an estimated incidence of 0.4/100,000 women per year [1,2]. The majority of ... |
10.1371/journal.pntd.0006773 | Molecular characterization and phylogenetic analysis of dengue viruses imported into Taiwan during 2011-2016 | A total of 1,596 laboratory-confirmed imported dengue cases were identified in Taiwan during 2011–2016. Most of the imported cases arrived from Southeast Asia as well as the Indian subcontinent, the Pacific region, Latin America, Australia and Africa. Phylogenetic analyses of the complete envelope protein gene sequence... | Dengue is the most prevalent mosquito-borne viral disease in the world. The expansion of dengue viruses to different parts of the world has been accelerated by the increase in worldwide travel and trade. In this study, we present the results of a laboratory-based dengue surveillance in Taiwan during 2011–2016. A total ... | Dengue is the most prevalent mosquito-borne viral infection of humans in tropical and subtropical regions of the world [1]. In recent decades, the incidence of dengue has grown dramatically; approximately half of the world’s population is now at risk [2]. An estimated 390 million dengue infections occur annually, of wh... |
10.1371/journal.pntd.0003411 | Regulation of Leishmania (L.) amazonensis Protein Expression by Host T Cell Dependent Responses: Differential Expression of Oligopeptidase B, Tryparedoxin Peroxidase and HSP70 Isoforms in Amastigotes Isolated from BALB/c and BALB/c Nude Mice | Leishmaniasis is an important disease that affects 12 million people in 88 countries, with 2 million new cases every year. Leishmania amazonensis is an important agent in Brazil, leading to clinical forms varying from localized (LCL) to diffuse cutaneous leishmaniasis (DCL). One interesting issue rarely analyzed is how... | Leishmaniasis is an important disease that affects 12 million people in 88 countries. Leishmania amazonensis is an important agent of leishmaniasis in Brazil, leading mainly to localized (LCL) and sometimes to diffuse cutaneous leishmaniasis (DCL), depending on the host immune response to infection. We believe that hos... | Leishmaniasis is an important disease that affects 12 million people in 88 different countries in Europe, Africa, Asia and America, and 2 million new cases are reported every year (WHO 2004; [1,2]. There are different forms of tegumentary and visceral leishmaniasis, that depend on the Leishmania species and on the gene... |
10.1371/journal.pntd.0003476 | Intrachromosomal Amplification, Locus Deletion and Point Mutation in the Aquaglyceroporin AQP1 Gene in Antimony Resistant Leishmania (Viannia) guyanensis | Antimony resistance complicates the treatment of infections caused by the parasite Leishmania.
Using next generation sequencing, we sequenced the genome of four independent Leishmania guyanensis antimony-resistant (SbR) mutants and found different chromosomal alterations including aneuploidy, intrachromosomal gene ampl... | Drug resistance remains a major concern in leishmaniasis chemotherapy, a neglected tropical disease that causes 60,000 deaths around the world annually. To better understand the molecular mechanisms behind drug resistance, we selected L. guyanensis parasites resistant to antimony, the first-line drug against this disea... | Leishmaniasis defines a spectrum of infectious diseases caused by protozoan parasites belonging to the genus Leishmania that are transmitted to mammals via the bite of sandflies. Leishmaniasis are neglected tropical diseases that could potentially affect ~ 350 million people in 98 countries [1]. Clinical manifestations... |
10.1371/journal.pntd.0006829 | Rodent control to fight Lassa fever: Evaluation and lessons learned from a 4-year study in Upper Guinea | Lassa fever is a viral haemorrhagic fever caused by an arenavirus. The disease is endemic in West African countries, including Guinea. The rodents Mastomys natalensis and Mastomys erythroleucus have been identified as Lassa virus reservoirs in Guinea. In the absence of a vaccine, rodent control and human behavioural ch... | In the absence of a Lassa fever vaccine, rodent control is the primary prevention option. An effective rodent control intervention must understand human behaviour towards the rodent such as: human–rodent interactions, cohabitation, and local rodent control measures. We conducted a rodent control intervention at communi... | Lassa fever is a viral haemorrhagic fever caused by an arenavirus, which was first discovered in Nigeria in 1969 [1, 2]. The disease is endemic in West African countries, including Sierra Leone, Liberia, Guinea, southern Mali, northern Cote d’Ivoire and Nigeria [3–6]. Lassa fever recently emerged in Benin and Togo [7–9... |
10.1371/journal.pgen.1007735 | Genotype to phenotype: Diet-by-mitochondrial DNA haplotype interactions drive metabolic flexibility and organismal fitness | Diet may be modified seasonally or by biogeographic, demographic or cultural shifts. It can differentially influence mitochondrial bioenergetics, retrograde signalling to the nuclear genome, and anterograde signalling to mitochondria. All these interactions have the potential to alter the frequencies of mtDNA haplotype... | The detection and quantitation of mtDNA polymorphisms in populations and across whole habitats continues to be used as a central investigatory tool in evolutionary genetics. But, the approach is laden with assumptions about selection that are rarely examined. We present a series of studies that traverse the genotype to... | Diet and an organism’s genes contribute towards its phenotype and impact a range of scientific disciplines that span from the more fundamental disciplines of evolutionary biology and quantitative genetics to the more medically applied fields of nutrigenomics and pharmacogenomics. In nature, the dietary macronutrient ba... |
10.1371/journal.pntd.0006993 | Vector competence of biting midges and mosquitoes for Shuni virus | Shuni virus (SHUV) is an orthobunyavirus that belongs to the Simbu serogroup. SHUV was isolated from diverse species of domesticated animals and wildlife, and is associated with neurological disease, abortions, and congenital malformations. Recently, SHUV caused outbreaks among ruminants in Israel, representing the fir... | Arthropod-borne (arbo)viruses are notorious for causing unpredictable and large-scale epidemics and epizootics. Apart from viruses such as West Nile virus and Rift Valley fever virus that are well known to have a significant impact on human and animal health, many arboviruses remain neglected. Shuni virus (SHUV) is a n... | Arthropod-borne (arbo)viruses continue to pose a threat to human and animal health [1, 2]. In particular the order Bunyavirales comprises emerging pathogens such as Crimean-Congo haemorrhagic fever virus (CCHFV) and Rift Valley fever virus (RVFV) [3, 4]. The World Health Organization (WHO) has included both CCHFV and R... |
10.1371/journal.pgen.1000528 | Comprehensive Linkage and Association Analyses Identify Haplotype, Near to the TNFSF15 Gene, Significantly Associated with Spondyloarthritis | Spondyloarthritis (SpA) is a chronic inflammatory disorder with a strong genetic predisposition dominated by the role of HLA-B27. However, the contribution of other genes to the disease susceptibility has been clearly demonstrated. We previously reported significant evidence of linkage of SpA to chromosome 9q31–34. The... | Spondyloarthritis (SpA) is a common variety of articular inflammatory disorder characterized by axial and/or peripheral arthritis, frequently associated with extra-articular manifestations such as psoriasis, uveitis, and inflammatory bowel diseases (ulcerative colitis or Crohn's disease (CD)). SpA is a complex disorder... | Spondyloarthritis (SpA) is one of the most frequent varieties of articular inflammatory disorders with an estimated prevalence of 0.3% in the western European adult population [1]. It is characterized by a predominant axial skeleton inflammation, by a frequent occurrence of enthesitis and peripheral arthritis, and also... |
10.1371/journal.ppat.1005840 | Progesterone-Based Therapy Protects Against Influenza by Promoting Lung Repair and Recovery in Females | Over 100 million women use progesterone therapies worldwide. Despite having immunomodulatory and repair properties, their effects on the outcome of viral diseases outside of the reproductive tract have not been evaluated. Administration of exogenous progesterone (at concentrations that mimic the luteal phase) to proges... | Worldwide, the use of hormonal contraceptives is on the rise as a primary intervention for improving women’s health outcomes through reduced maternal mortality and increased childhood survival. There are many hormone contraceptive formulations, all of which contain some form of progesterone. Although the effects of hor... | Hormonal contraceptives are listed as an essential medication by the World Health Organization (WHO)[1] because of the profound benefits these compounds can have on women’s health outcomes, including decreased rates of maternal mortality and improved perinatal outcomes and child survival, by widening the intervals betw... |
10.1371/journal.pcbi.1003419 | Combinatorial Modeling of Chromatin Features Quantitatively Predicts DNA Replication Timing in Drosophila | In metazoans, each cell type follows a characteristic, spatio-temporally regulated DNA replication program. Histone modifications (HMs) and chromatin binding proteins (CBPs) are fundamental for a faithful progression and completion of this process. However, no individual HM is strictly indispensable for origin function... | Before a cell divides, its genome must be faithfully duplicated to ensure that the daughter cell receives an exact copy of the parental genetic material. However, this process requires disruption of chromatin, the combination of DNA and histone proteins, whose structure and function have to be readily restored afterwar... | In eukaryotes, DNA replication is regulated both in time and space and initiates at multiple origins along the genome [1]. When averaged over a cell population, each genomic region shows reproducible replication timing in S-phase [2], [3]. The timing of replication is a mitotically stable cell-type specific feature of ... |
10.1371/journal.pntd.0002475 | Aquaporin 2 Mutations in Trypanosoma brucei gambiense Field Isolates Correlate with Decreased Susceptibility to Pentamidine and Melarsoprol | The predominant mechanism of drug resistance in African trypanosomes is decreased drug uptake due to loss-of-function mutations in the genes for the transporters that mediate drug import. The role of transporters as determinants of drug susceptibility is well documented from laboratory-selected Trypanosoma brucei mutan... | Human African Trypanosomiasis, or sleeping sickness, is a fatal disease restricted to sub-Saharan Africa, caused by Trypanosoma brucei gambiense and T. b. rhodesiense. The treatment relies on chemotherapy exclusively. Drug resistance in T. brucei was investigated mainly in laboratory-selected lines and found to be link... | The chemotherapy of human African trypanosomiasis (HAT, also known as sleeping sickness) currently relies on suramin or pentamidine for the first, haemolymphatic stage and on melarsoprol or eflornithine/nifurtimox combination therapy (NECT) for the second stage, when the trypanosomes have invaded the central nervous sy... |
10.1371/journal.ppat.1005833 | The RNA Binding Specificity of Human APOBEC3 Proteins Resembles That of HIV-1 Nucleocapsid | The APOBEC3 (A3) cytidine deaminases are antiretroviral proteins, whose targets include human immunodeficiency virus type-1 (HIV-1). Their incorporation into viral particles is critical for antiviral activity and is driven by interactions with the RNA molecules that are packaged into virions. However, it is unclear whe... | Cellular intrinsic immunity constitutes a key defense against infection by viruses. The APOBEC3 (A3) family of cytidine deaminases are intrinsic immune proteins that can hypermutate and destabilize retroviral genomes. For A3 proteins to exert their antiviral activity, they must be incorporated into nascent virions. Alt... | APOBEC3 (A3) proteins are a family of germline-encoded proteins that inhibit the replication of a broad range of viruses and retroelements (reviewed in [1, 2]). A3 proteins exert their antiretroviral activity largely through their deoxycytosine deaminase activity, i.e. modification of dC-to-dU in single-stranded DNA re... |
10.1371/journal.ppat.1007651 | The opportunistic pathogen Stenotrophomonas maltophilia utilizes a type IV secretion system for interbacterial killing | Bacterial type IV secretion systems (T4SS) are a highly diversified but evolutionarily related family of macromolecule transporters that can secrete proteins and DNA into the extracellular medium or into target cells. It was recently shown that a subtype of T4SS harboured by the plant pathogen Xanthomonas citri transfe... | Competition between microorganisms determines which species will dominate or be eradicated from a specific habitat. Bacteria use a series of mechanisms to kill or prevent multiplication of competitors. We show that an opportunistic pathogen, Stenotrophomonas maltophilia, harbours a type IV secretion system (T4SS) that ... | The ecological interactions between bacterial species range from cooperative to competitive and can be mediated by diffusible soluble factors secreted into the extracellular medium or by factors transferred directly into target cells in a contact-dependent manner [1]. Several types of contact-dependent antagonistic int... |
10.1371/journal.pgen.1007351 | Cytokinin stabilizes WUSCHEL by acting on the protein domains required for nuclear enrichment and transcription | Concentration-dependent transcriptional regulation and the spatial regulation of transcription factor levels are poorly studied in plant development. WUSCHEL, a stem cell-promoting homeodomain transcription factor, accumulates at a higher level in the rib meristem than in the overlying central zone, which harbors stem ... | Stem cell regulation is critical for the development of all organisms, and plants have particularly unique stem cell populations that are maintained throughout their lifespan at the tips of both the shoots and roots. Proper spatial and temporal regulation of gene expression by mobile proteins is essential for maintaini... | Plant meristem development depends largely on positional information. Determining how cells interpret positional cues to regulate gene expression is central to cell fate specification during pattern formation. The concentration of transcription factors (TFs) in developmental fields have been shown to provide positional... |
10.1371/journal.pntd.0000805 | Neurocysticercosis, a Persisting Health Problem in Mexico | The ongoing epidemiological transition in Mexico minimizes the relative impact of neurocysticercosis (NC) on public health. However, hard data on the disease frequency are not available.
All clinical records from patients admitted in the Instituto Nacional de Neurologia y Neurocirugia (INNN) at Mexico City in 1994 and ... | Human neurocysticercosis is a severe parasitic disease caused by the installation of Taenia solium larvae in the central nervous system. Neurocysticercosis is still deeply rooted in Latin-America, Africa and Asia, where it develops its complete life cycle promoted by poor sanitary conditions. It is also emerging in dev... | Neurocysticercosis (NC) is a life-threatening and costly parasitic disease, endemic in most non-developed countries and increasing in developed world [1]–[5]. NC real prevalence and incidence are difficult to assess, as symptoms are highly heterogeneous and its diagnosis requires neuroradiological studies, not availabl... |
10.1371/journal.pcbi.1004803 | Revealing the True Incidence of Pandemic A(H1N1)pdm09 Influenza in Finland during the First Two Seasons — An Analysis Based on a Dynamic Transmission Model | The threat of the new pandemic influenza A(H1N1)pdm09 imposed a heavy burden on the public health system in Finland in 2009-2010. An extensive vaccination campaign was set up in the middle of the first pandemic season. However, the true number of infected individuals remains uncertain as the surveillance missed a large... | In 2009, the threat of the new pandemic influenza A(H1N1)pdm09 (referenced in media as ‘swine flu’) created a heavy burden to the public health systems wordwide. In Finland, an extensive vaccination campaign was set up in the middle of the first pandemic season 2009/2010. However, the true number of infected individual... | The threat of the pandemic influenza A strain, A(H1N1)pdm09 (‘swine flu’), imposed a huge burden on the public health system in Finland in 2009 [1]. The first A(H1N1)pdm09 season was part of the global pandemic and occurred from September 2009 through January 2010 with a major outbreak in November 2009. To mitigate the... |
10.1371/journal.pgen.1003045 | Notch-Mediated Suppression of TSC2 Expression Regulates Cell Differentiation in the Drosophila Intestinal Stem Cell Lineage | Epithelial homeostasis in the posterior midgut of Drosophila is maintained by multipotent intestinal stem cells (ISCs). ISCs self-renew and produce enteroblasts (EBs) that differentiate into either enterocytes (ECs) or enteroendocrine cells (EEs) in response to differential Notch (N) activation. Various environmental a... | Stem cells maintain tissue homeostasis in metazoans. A productive model to study the regulation of stem cell function is the Drosophila posterior midgut. Notch (N) signaling controls intestinal stem cell (ISC) differentiation in this tissue, while ISC proliferation is regulated by growth factor signaling pathways, incl... | Regenerative processes in somatic tissues require coordinated regulation of stem cell proliferation and daughter cell differentiation to ensure long-term tissue homeostasis [1]–[3]. The Drosophila posterior midgut epithelium has emerged as an excellent model system to study this regulation [4]–[7]. It is maintained by ... |
10.1371/journal.pbio.1000622 | Clusters of Nucleotide Substitutions and Insertion/Deletion Mutations Are Associated with Repeat Sequences | The genome-sequencing gold rush has facilitated the use of comparative genomics to uncover patterns of genome evolution, although their causal mechanisms remain elusive. One such trend, ubiquitous to prokarya and eukarya, is the association of insertion/deletion mutations (indels) with increases in the nucleotide subst... | An intriguing observation made during the comparison of genomes is that insertion and deletion mutations (indels) cluster together with nucleotide substitutions. Two (not mutually exclusive) hypotheses have been proposed to explain this phenomenon. The first postulates that an indel mutation causes an increase in the l... | A major challenge of evolutionary genetics is to determine the mechanisms underlying cryptic patterns of mutation rate variation and how they influence evolutionary outcomes [1]. One of the most striking of these trends is the association between indel mutations and nucleotide substitutions [2]–[7]. Inter-species genom... |
10.1371/journal.pgen.1003173 | Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk | Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted... | Women who carry BRCA2 mutations have an increased risk of breast cancer that varies widely. To identify common genetic variants that modify the breast cancer risk associated with BRCA2 mutations, we have built upon our previous work in which we examined genetic variants across the genome in relation to breast cancer ri... | The lifetime risk of breast cancer associated with carrying a BRCA2 mutation varies from 40 to 84% [1]. To determine whether common genetic variants modify breast cancer risk for BRCA2 mutation carriers, we previously conducted a GWAS of BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1... |
10.1371/journal.pntd.0003281 | A Comprehensive Assessment of Lymphatic Filariasis in Sri Lanka Six Years after Cessation of Mass Drug Administration | The Sri Lankan Anti-Filariasis Campaign conducted 5 rounds of mass drug administration (MDA) with diethycarbamazine plus albendazole between 2002 and 2006. We now report results of a comprehensive surveillance program that assessed the lymphatic filariasis (LF) situation in Sri Lanka 6 years after cessation of MDA.
Tra... | Lymphatic Filariasis (LF, also known as “elephantiasis”) is a disabling and deforming disease that is caused by parasitic worms that are transmitted by mosquitoes. The Sri Lankan Anti-Filariasis Campaign provided five annual rounds of mass drug administration (MDA) with diethylcarbamazine and albendazole between 2002 a... | Lymphatic filariasis (LF, caused by the mosquito borne filarial nematodes Wuchereria bancrofti, Brugia malayi, and B. timori), is a major public-health problem in many tropical and subtropical countries. The latest summary from the World Health Organization (WHO) reported that 56 of 73 endemic countries have implemente... |
10.1371/journal.pntd.0005740 | Cardio-haemodynamic assessment and venous lactate in severe dengue: Relationship with recurrent shock and respiratory distress | Dengue can cause plasma leakage that may lead to dengue shock syndrome (DSS). In approximately 30% of DSS cases, recurrent episodes of shock occur. These patients have a higher risk of fluid overload, respiratory distress and poor outcomes. We investigated the association of echocardiographically-derived cardiac functi... | Dengue is a viral illness that can lead to severe and potentially fatal complications. The most common complication is fluid leakage from blood vessels, which can cause low blood pressure or dengue shock syndrome (DSS). The majority of patients recover with simple intravenous fluid replacement, however in approximately... | Dengue is a flaviviral infection that causes substantial morbidity in endemic areas, with 96 million clinically apparent cases each year [1]. Although the majority of infections result in a self-limiting febrile illness, 1–5% of cases can experience more severe manifestations, in the form of organ impairment, coagulopa... |
10.1371/journal.pgen.1000226 | Effects of Aneuploidy on Genome Structure, Expression, and Interphase
Organization in Arabidopsis thaliana | Aneuploidy refers to losses and/or gains of individual chromosomes from the
normal chromosome set. The resulting gene dosage imbalance has a noticeable
affect on the phenotype, as illustrated by aneuploid syndromes, including Down
syndrome in humans, and by hu... | Most plants and animals have two copies of each chromosome in the normal
chromosome set. Unbalanced numerical changes resulting from gains or losses of
individual chromosomes (aneuploidy) usually have deleterious consequences. For
example, Down syndrome in hum... | Changes in the number of chromosomes from the normal diploid set can be grouped into
two types: polyploidy and aneuploidy. Polyploidy refers to whole genome duplications
whereas aneuploidy refers to unbalanced losses and/or gains of individual
chromosomes, or parts of chr... |
10.1371/journal.pntd.0001574 | Implementing Preventive Chemotherapy through an Integrated National Neglected Tropical Disease Control Program in Mali | Mali is endemic for all five targeted major neglected tropical diseases (NTDs). As one of the five ‘fast-track’ countries supported with the United States Agency for International Development (USAID) funds, Mali started to integrate the activities of existing disease-specific national control programs on these diseases... | Neglected tropical diseases (NTDs) are a group of chronic infections that affect the poorest group of the populations in the world. There are currently five major NTDs targeted through mass drug treatment in the affected communities. The drug delivery can be integrated to deliver different drug packages as these NTDs o... | Neglected tropical diseases (NTDs) are a group of diseases that affect the most vulnerable and the poorest group of the populations in the world [1], [2]. The World Health Organization (WHO) recommends five public health strategies for the prevention and control of the NTDs: preventive chemotherapy (PCT); intensified c... |
10.1371/journal.pntd.0002751 | Enhanced Protective Efficacy of Nonpathogenic Recombinant Leishmania tarentolae Expressing Cysteine Proteinases Combined with a Sand Fly Salivary Antigen | Novel vaccination approaches are needed to prevent leishmaniasis. Live attenuated vaccines are the gold standard for protection against intracellular pathogens such as Leishmania and there have been new developments in this field. The nonpathogenic to humans lizard protozoan parasite, Leishmania (L) tarentolae, has bee... | More than 98 countries are reported as endemic for leishmaniasis, a vector-borne disease transmitted by sand flies. Drug-resistant forms have emerged and there is an increased need to develop advanced preventive strategies. Live attenuated vaccines are the gold standard for protection against intracellular pathogens su... | Leishmaniasis is one of the greatest health challenges in nearly 98 countries, contributing to 2 million new clinical cases per year in tropical and subtropical regions of the globe [1]. The disease is transmitted by sandflies and is manifested in several clinical forms, mainly cutaneous leishmaniasis (CL), mucocutaneo... |
10.1371/journal.pgen.1005940 | The Chromatin Remodelling Enzymes SNF2H and SNF2L Position Nucleosomes adjacent to CTCF and Other Transcription Factors | Within the genomes of metazoans, nucleosomes are highly organised adjacent to the binding sites for a subset of transcription factors. Here we have sought to investigate which chromatin remodelling enzymes are responsible for this. We find that the ATP-dependent chromatin remodelling enzyme SNF2H plays a major role org... | CTCF is a transcriptional regulator acting as an insulator element interfering with enhancer function and as a boundary between chromatin domains. CTCF has been shown to organise an exquisite array of phased nucleosomes flanking its binding sites. Here we identified SNF2H as the enzyme primarily responsible for organis... | The genomes of eukaryotes exist predominantly as chromatin. The fundamental subunit of chromatin is the nucleosome which consists of 147 bp of DNA wrapped around an octamer of histone proteins [1]. Typically nucleosomes are distributed along DNA with defined spacing at distinct loci in a given cell type [2]. In additio... |
10.1371/journal.pntd.0001732 | Dengue Infection in Children in Ratchaburi, Thailand: A Cohort Study. I. Epidemiology of Symptomatic Acute Dengue Infection in Children, 2006–2009 | There is an urgent need to field test dengue vaccines to determine their role in the control of the disease. Our aims were to study dengue epidemiology and prepare the site for a dengue vaccine efficacy trial.
We performed a prospective cohort study of children in primary schools in central Thailand from 2006 through 2... | There is an urgent need to field test dengue vaccine. Efficacy trials need to be conducted in study sites with
sufficiently high dengue incidence to make a robust estimate of vaccine efficacy and where all dengue virustypes
circulate frequently. In this paper, we report on dengue disease surveillance on approximately 3... | Dengue virus (DENV) infection with any one of the four virus serotypes (DENV-1 to -4), and 4) can produce a spectrum of outcomes, ranging from asymptomatic infection to mild undifferentiated fever (UF), classic dengue fever (DF) and the most severe form of illness, dengue hemorrhagic fever (DHF) [1]. Dengue is an impor... |
10.1371/journal.pcbi.1004145 | A Dynamical Phyllotaxis Model to Determine Floral Organ Number | How organisms determine particular organ numbers is a fundamental key to the development of precise body structures; however, the developmental mechanisms underlying organ-number determination are unclear. In many eudicot plants, the primordia of sepals and petals (the floral organs) first arise sequentially at the edg... | Why do most eudicot flowers have either four or five petals? This fundamental and attractive problem in botany has been little investigated. Here, we identify the properties responsible for organ-number determination in floral development using mathematical modeling. Earlier experimental and theoretical studies showed ... | How to determine the numbers of body parts is a fundamental problem for the development of complete body structures in multicellular organisms. Digit numbers in vertebrates are evolutionarily optimized for the specific demands of the organism [1]; the body-segment number in insects is constant despite the evolutionaril... |
10.1371/journal.ppat.1003289 | Low-Volume Toolbox for the Discovery of Immunosuppressive Fungal Secondary Metabolites | The secondary metabolome provides pathogenic fungi with a plethoric and versatile panel of molecules that can be deployed during host ingress. While powerful genetic and analytical chemistry methods have been developed to identify fungal secondary metabolites (SMs), discovering the biological activity of SMs remains an... | Several fungal pathogens produce bioactive small molecules, commonly known as secondary metabolites (SMs) that contribute towards disease development in susceptible hosts. Genome assessment of human pathogenic Aspergillus species indicates these fungi have the capabilities of producing hundreds of SMs, most of which ar... | The secondary metabolome provides filamentous fungi with a biologically active panel of molecules, deployed in the presence of competing/host organisms or specific microenvironmental factors, and increasingly found to afford both physical and competitive fitness to the producing fungus [1]. Although the study of fungal... |
10.1371/journal.pntd.0002835 | Enhanced Passive Bat Rabies Surveillance in Indigenous Bat Species from Germany - A Retrospective Study | In Germany, rabies in bats is a notifiable zoonotic disease, which is caused by European bat lyssaviruses type 1 and 2 (EBLV-1 and 2), and the recently discovered new lyssavirus species Bokeloh bat lyssavirus (BBLV). As the understanding of bat rabies in insectivorous bat species is limited, in addition to routine bat ... | According to the World Health Organization rabies is considered both a neglected zoonotic and a tropical disease. The causative agents are lyssaviruses which have their primary reservoir in bats. Although bat rabies is notifiable in Germany, the number of submitted bats during routine surveillance is rarely representat... | Lyssaviruses are non-segmented negative-strand RNA viruses of the order Mononegavirales, family Rhabdoviridae and causative agents of rabies in bats and other mammals as well as in humans [1]. While rabies in dogs and other carnivores has been known since antiquity, the first evidence of rabies in haematophagous and in... |
10.1371/journal.pcbi.1002363 | OptCom: A Multi-Level Optimization Framework for the Metabolic Modeling and Analysis of Microbial Communities | Microorganisms rarely live isolated in their natural environments but rather function in consolidated and socializing communities. Despite the growing availability of high-throughput sequencing and metagenomic data, we still know very little about the metabolic contributions of individual microbial players within an ec... | Microorganisms rarely live isolated in their natural environments but rather function in consolidated and socializing communities. Despite the growing availability of experimental data, we still know very little about the metabolic contributions of individual species within an ecological niche and the extent and direct... | Solitary species are rarely found in natural environments as most microorganisms tend to function in concert in integrative and interactive units, (i.e., communities). Natural microbial ecosystems drive global biogeochemical cycling of energy and carbon [1] and are involved in applications ranging from production of bi... |
10.1371/journal.pcbi.1002257 | Metabolic Regulation in Progression to Autoimmune Diabetes | Recent evidence from serum metabolomics indicates that specific metabolic disturbances precede β-cell autoimmunity in humans and can be used to identify those children who subsequently progress to type 1 diabetes. The mechanisms behind these disturbances are unknown. Here we show the specificity of the pre-autoimmune m... | We have recently found that distinct metabolic disturbances precede β-cell autoimmunity in children who later progress to type 1 diabetes (T1D). Here we performed a murine study using non-obese diabetic (NOD) mice that recapitulated the protocol used in human, followed up by independent studies where NOD mice were stud... | Type 1 diabetes (T1D) is an autoimmune disease that results from the selective destruction of insulin-producing β-cells in pancreatic islets. The diagnosis of T1D is commonly preceded by a long prodromal period which includes seroconversion to islet autoantibody positivity [1] and subtle metabolic disturbances [2]. The... |
10.1371/journal.pcbi.1007338 | MHC binding affects the dynamics of different T-cell receptors in different ways | T cells use their T-cell receptors (TCRs) to scan other cells for antigenic peptides presented by MHC molecules (pMHC). If a TCR encounters a pMHC, it can trigger a signalling pathway that could lead to the activation of the T cell and the initiation of an immune response. It is currently not clear how the binding of p... | The interaction between T-cells and other cells is one of the most important interactions in the human immune system. If T-cells are not triggered major parts of the immune system cannot be activated or are not working effectively. Despite many years of research the exact mechanism of how a T-cell is initially triggere... | The interaction between T-cell receptors (TCRs) on the surface of T-cells and peptides bound by Major Histocompatibility Complexes (MHCs) on the surface of antigen presenting cells is one of the most important processes of the adaptive immune system [1]. In the case of MHC class I molecules intracellular proteins are d... |
10.1371/journal.pcbi.1002523 | Conformational Spread in the Flagellar Motor Switch: A Model Study | The reliable response to weak biological signals requires that they be amplified with fidelity. In E. coli, the flagellar motors that control swimming can switch direction in response to very small changes in the concentration of the signaling protein CheY-P, but how this works is not well understood. A recently propos... | Bacteria swim to find nutrients or to avoid toxins. Their swimming is powered by the rotation of flagella (hair-like structures) that act as propellers. Each flagellum is driven by a rotary molecular engine (the bacterial flagellar motor) that can rotate in either a counterclockwise or clockwise direction and switches ... | Bacterial chemotaxis enables the cell to move towards favorable environments. This sensing ability relies closely on collective coordination of several operation modules in the signal transduction pathway (reviewed in [1][2]). The first component of this system is responsible for detecting environmental signals and con... |
10.1371/journal.pntd.0002422 | Patterns of Migration and Risks Associated with Leprosy among Migrants in Maranhão, Brazil | Leprosy remains a public health problem in Brazil with new case incidence exceeding World Health Organization (WHO) goals in endemic clusters throughout the country. Migration can facilitate movement of disease between endemic and non-endemic areas, and has been considered a possible factor in continued leprosy inciden... | In Brazil, leprosy remains a significant public health problem in endemic clusters of high transmission risk throughout the country. Migration is thought to be a factor associated with continued leprosy transmission, as migration has also been found to be associated with other Neglected Tropical Diseases (NTDs). We ana... | Leprosy continues to be an endemic disease in many parts of the world. Brazil has globally the second highest new case incidence [1]. National leprosy prevalence of 1.54/10,000 in 2010 [2] remains above the WHO goal of <1 per 10,000. Highly endemic areas of the disease continue to persist despite large-scale national e... |
10.1371/journal.ppat.1008022 | Exposure to opposing temperature extremes causes comparable effects on Cardinium density but contrasting effects on Cardinium-induced cytoplasmic incompatibility | Terrestrial arthropods, including insects, commonly harbor maternally inherited intracellular symbionts that confer benefits to the host or manipulate host reproduction to favor infected female progeny. These symbionts may be especially vulnerable to thermal stress, potentially leading to destabilization of the symbios... | Insects often harbor heritable symbiotic bacteria that infect their cells and/or bodily fluids. These heritable bacteria are passed from mother to offspring and can have substantial effects on host insect biology, and include bacteria like Cardinium that cause mating incompatibilities between symbiont-infected and unin... | Temperature has profound effects on the biology of ectothermic organisms as well as on the microbiota inhabiting these organisms [1–4]. The heritable symbionts of arthropods, which are primarily vertically transmitted from mother to offspring, are closely integrated with host biology [5], and may be particularly vulner... |
10.1371/journal.ppat.1002784 | The Rhoptry Proteins ROP18 and ROP5 Mediate Toxoplasma gondii Evasion of the Murine, But Not the Human, Interferon-Gamma Response | The obligate intracellular parasite Toxoplasma gondii secretes effector proteins into the host cell that manipulate the immune response allowing it to establish a chronic infection. Crosses between the types I, II and III strains, which are prevalent in North America and Europe, have identified several secreted effecto... | Toxoplasma gondii can infect any warm-blooded animal and is transmitted orally by consumption of tissue cysts. To facilitate transmission, the parasite must balance induction and evasion of host immune responses to allow parasite growth and persistence, while avoiding excessive parasite burden, which can kill the host ... | Toxoplasma gondii is a widespread intracellular parasite capable of infecting most warm-blooded animals and is an important opportunistic pathogen for immunocompromised individuals and unborn fetuses. Toxoplasma resides within a non-fusogenic parasitophorous vacuole and has three apical secretory organelles, the micron... |
10.1371/journal.pcbi.0030232 | CATHEDRAL: A Fast and Effective Algorithm to Predict Folds and Domain Boundaries from Multidomain Protein Structures | We present CATHEDRAL, an iterative protocol for determining the location of previously observed protein folds in novel multidomain protein structures. CATHEDRAL builds on the features of a fast secondary-structure–based method (using graph theory) to locate known folds within a multidomain context and a residue-based, ... | Proteins comprise individual folding units known as domains, with a significant proportion containing two or more (multidomain structures). Each domain is thought to represent a unit of evolution and adopts a specific fold. Detecting domains is often the first step in classifying proteins into evolutionary families for... | Proteins comprise individual folding units known as domains, with a significant proportion containing two or more units (multidomain structures) [1]. Each domain adopts a specific fold, and it is estimated that there are up to several thousand such folds in nature [2–4]. As the domain is thought to be an important evol... |
10.1371/journal.pgen.1000385 | Ploidy Reductions in Murine Fusion-Derived Hepatocytes | We previously showed that fusion between hepatocytes lacking a crucial liver enzyme, fumarylacetoacetate hydrolase (FAH), and wild-type blood cells resulted in hepatocyte reprogramming. FAH expression was restored in hybrid hepatocytes and, upon in vivo expansion, ameliorated the effects of FAH deficiency. Here, we sho... | The liver comprises many different types of cells, including hepatocytes. Hepatocytes perform numerous physiological functions, such as detoxification, metabolism, and protein synthesis. Hepatocytes have the ability to fuse with blood cells, generating hybrid hepatocytes that contain nuclei from both fusion partners. I... | Cell divisions in mitosis are thought to always produce daughter cells with the same chromosome content as the parental cell. Our recent studies with fusion-derived polyploid hepatocytes challenge that ideology. We propose that polyploid hepatocytes can undergo ploidy reductions, leading to the generation of geneticall... |
10.1371/journal.ppat.1004649 | Role of Pentraxin 3 in Shaping Arthritogenic Alphaviral Disease: From Enhanced Viral Replication to Immunomodulation | The rising prevalence of arthritogenic alphavirus infections, including chikungunya virus (CHIKV) and Ross River virus (RRV), and the lack of antiviral treatments highlight the potential threat of a global alphavirus pandemic. The immune responses underlying alphavirus virulence remain enigmatic. We found that pentraxi... | Chikungunya virus (CHIKV) and Ross River virus (RRV) are arthropod-borne viruses associated with massive epidemics affecting millions of people worldwide, causing widespread distribution of alphaviral-induced arthritis. The rising prevalence of alphavirus infections and, critically, the lack of therapeutic treatments w... | Arthritogenic alphaviruses including Ross River virus (RRV) and chikungunya virus (CHIKV) are the causative agents of the widespread arthropod-borne illnesses, Ross River virus disease (RRVD) and chikungunya fever (CHIKF) respectively [1]. RRV is endemic to Australia, Papua New Guinea and South Pacific islands. An aver... |
10.1371/journal.pgen.1003393 | A Gene Transfer Agent and a Dynamic Repertoire of Secretion Systems Hold the Keys to the Explosive Radiation of the Emerging Pathogen Bartonella | Gene transfer agents (GTAs) randomly transfer short fragments of a bacterial genome. A novel putative GTA was recently discovered in the mouse-infecting bacterium Bartonella grahamii. Although GTAs are widespread in phylogenetically diverse bacteria, their role in evolution is largely unknown. Here, we present a compar... | Viruses are selfish genetic elements that replicate and transfer their own DNA, often killing the host cell in the process. Unlike viruses, gene transfer agents (GTAs) transfer random pieces of the bacterial genome rather than their own DNA. GTAs are widespread in bacterial genomes, but it is not known whether they are... | Double-stranded DNA viruses are extremely abundant and evolve rapidly, yielding highly diverse viral populations. The transfer of bacteriophage DNA from one bacterial cell to another is regulated by the viral genome. Bacteriophage sequences may account for up to 20% of the bacterial chromosome, but most insertions are ... |
10.1371/journal.pbio.0050203 | Targeted Inhibition of miRNA Maturation with Morpholinos Reveals a Role for miR-375 in Pancreatic Islet Development | Several vertebrate microRNAs (miRNAs) have been implicated in cellular processes such as muscle differentiation, synapse function, and insulin secretion. In addition, analysis of Dicer null mutants has shown that miRNAs play a role in tissue morphogenesis. Nonetheless, only a few loss-of-function phenotypes for individ... | The striking tissue-specific expression patterns of microRNAs (miRNAs) suggest that they play a role in tissue development. These small RNA molecules (∼22 bases in length) are processed from long primary transcripts (pri-miRNA) and regulate gene expression at the posttranscriptional level. There are hundreds of differe... | MicroRNAs (miRNAs) have a profound impact on the development of multicellular organisms. Animals lacking the Dicer enzyme, which is responsible for the processing of the precursor miRNA into the mature form, cannot live [1–3]. MiRNA mutants have been described only for Caenorhabditis elegans and Drosophila, reviewed in... |
10.1371/journal.pbio.3000172 | Lateral hypothalamic neurotensin neurons promote arousal and hyperthermia | Sleep and wakefulness are greatly influenced by various physiological and psychological factors, but the neuronal elements responsible for organizing sleep-wake behavior in response to these factors are largely unknown. In this study, we report that a subset of neurons in the lateral hypothalamic area (LH) expressing t... | Adjusting sleep-wake behavior in response to environmental and physiological challenges may not only be of protective value, but can also be vital for the survival of the organism. For example, while it is crucial to increase wake to explore a novel environment to search for potential threats and food sources, it is al... | We first analyzed the distribution of Nts neurons in the LH by generating transgenic mice expressing green fluorescent protein (GFP) exclusively in Nts neurons (Nts-Cre::L10-GFP; henceforth “Nts-GFP” mice; see Methods section). We found that Nts neurons are densely packed in the perifornical LH, intermingled with orexi... |
10.1371/journal.pntd.0005459 | Cost-effectiveness of meglumine antimoniate versus miltefosine caregiver DOT for the treatment of pediatric cutaneous leishmaniasis | Oral miltefosine has been shown to be non-inferior to first-line, injectable meglumine antimoniate (MA) for the treatment of cutaneous leishmaniasis (CL) in children. Miltefosine may be administered via in-home caregiver Directly Observed Therapy (cDOT), while patients must travel to clinics to receive MA. We performed... | Cutaneous leishmaniasis (CL) is a tropical parasitic disease transmitted by sand flies that causes chronic skin and mucosal ulcers. Current standard of care therapy requires patients to travel to a clinic for twenty consecutive days for injections of meglumine antimoniate (MA). This may represent an economic burden, pa... | Cutaneous leishmaniasis (CL) is a neglected tropical disease primarily affecting poor, marginalized populations. Worldwide incidence of CL has been estimated at 1–5 million cases per year [1,2]. In Latin America, over 57,000 annual cases were reported on average between 2001 and 2013 [3]. In Colombia, 7,000–18,000 case... |
10.1371/journal.pcbi.1006978 | Synchronization dependent on spatial structures of a mesoscopic whole-brain network | Complex structural connectivity of the mammalian brain is believed to underlie the versatility of neural computations. Many previous studies have investigated properties of small subsystems or coarse connectivity among large brain regions that are often binarized and lack spatial information. Yet little is known about ... | In a previous study, a data-driven large-scale model of mouse brain connectivity was constructed. This mouse brain connectivity model is estimated by a simplified model which only takes in account anatomy and distance dependence of connection strength which is best fit by a power law. The distance dependence model capt... | Structural neural connectivity and its implications for brain function have been a long-sought subject in neuroscience. Many previous studies have been limited either to small networks of few cells or coarser connectivity among larger brain regions [1–9], often binarized and without spatial information. Recent developm... |
10.1371/journal.pntd.0003932 | Histamine 1 Receptor Blockade Enhances Eosinophil-Mediated Clearance of Adult Filarial Worms | Filariae are tissue-invasive nematodes that cause diseases such as elephantiasis and river blindness. The goal of this study was to characterize the role of histamine during Litomosoides sigmodontis infection of BALB/c mice, a murine model of filariasis. Time course studies demonstrated that while expression of histidi... | Filariae are tissue-invasive parasitic roundworms that infect over 100 million people worldwide and cause debilitating conditions such as river blindness and elephantiasis. One of the major factors limiting our ability to eliminate these infections is the lack of drugs that kill adult worms when given as a short course... | Filariae are vector-borne tissue-invasive nematodes that infect over 100 million people worldwide and cause the debilitating conditions of river blindness and elephantiasis [1]. A major obstacle to ongoing efforts to control and potentially eradicate these diseases is the limited ability of anti-filarial drugs to kill ... |
10.1371/journal.pgen.1002813 | Balancing Selection at the Tomato RCR3 Guardee Gene Family Maintains Variation in Strength of Pathogen Defense | Coevolution between hosts and pathogens is thought to occur between interacting molecules of both species. This results in the maintenance of genetic diversity at pathogen antigens (or so-called effectors) and host resistance genes such as the major histocompatibility complex (MHC) in mammals or resistance (R) genes in... | Pathogens have a negative impact on the fitness of their hosts and are responsible for drastic epidemics in humans, animals, and plants. In plants, it has been thought that natural selection acts predominantly on so-called “resistance genes,” which recognize pathogens following a key-lock interaction. In this study, we... | The coevolutionary arms race between hosts and pathogens is often described as a recurrent struggle for increased resistance in hosts and evasion of recognition by pathogens [1]–[3]. The coevolutionary dynamics can be driven by negative frequency-dependent selection, leading to the maintenance of allelic diversity at g... |
10.1371/journal.ppat.1005874 | Screen of Non-annotated Small Secreted Proteins of Pseudomonas syringae Reveals a Virulence Factor That Inhibits Tomato Immune Proteases | Pseudomonas syringae pv. tomato DC3000 (PtoDC3000) is an extracellular model plant pathogen, yet its potential to produce secreted effectors that manipulate the apoplast has been under investigated. Here we identified 131 candidate small, secreted, non-annotated proteins from the PtoDC3000 genome, most of which are com... | The extracellular space in the leaf (the apoplast) is colonized by a diversity of microbes that will have to deal with host-secreted hydrolytic enzymes, many of which accumulate during defence responses. We hypothesize that in addition to fungal and oomycete pathogens, the bacterial model plant pathogen Pseudomonas syr... | Pseudomonas syringae is an important model system for plant-pathogen interactions. Different pathovars of this Gram-negative bacterium can cause disease on a broad variety of plants. Most intensively studied is pathovar tomato DC3000 (PtoDC3000), which causes bacterial speck disease on tomato and Arabidopsis [1, 2]. Th... |
10.1371/journal.pgen.1003458 | Dialects of the DNA Uptake Sequence in Neisseriaceae | In all sexual organisms, adaptations exist that secure the safe reassortment of homologous alleles and prevent the intrusion of potentially hazardous alien DNA. Some bacteria engage in a simple form of sex known as transformation. In the human pathogen Neisseria meningitidis and in related bacterial species, transforma... | Through computational and biological methods, this work analyzes the function and evolution of short DNA sequences called DNA uptake sequences (DUS) that regulate genetic transformation of bacteria in the family Neisseriaceae. Previous studies show that DUS affects transformation favourably. Here, for the first time, w... | Transformation in bacteria is a complex process involving uptake of naked extracellular DNA followed by homologous recombination (HR). Different reproductive barriers have evolved in diverse transformation-competent bacteria, which distinguish in favour of acquisition and recombination of homologous DNA sequences and d... |
10.1371/journal.pcbi.1003902 | Relationships between Th1 or Th2 iNKT Cell Activity and Structures of CD1d-Antigen Complexes: Meta-analysis of CD1d-Glycolipids Dynamics Simulations | A number of potentially bioactive molecules can be found in nature. In particular, marine organisms are a valuable source of bioactive compounds. The activity of an α-galactosylceramide was first discovered in 1993 via screening of a Japanese marine sponge (Agelas mauritanius). Very rapidly, a synthetic glycololipid an... | To modulate the natural immune response toward aggressive (Th1) or protective (Th2) profiles remains a difficult challenge, but can also offer great therapeutic opportunities, particularly for the treatment of cancer or auto-immune diseases. It has been demonstrated that a particular type of cells, named invariant Natu... | Compound 1, [1], [2] also referred to as α-GalCer, is a synthetic glycolipid that has shown promising bioactivity against diverse pathologies (atherosclerosis, malaria, auto-immune diseases…). [3]–[7] This compound is presented to the iNKT cells via a MHC class 1-like protein, named CD1d, associated to β2-microglobulin... |
10.1371/journal.pntd.0006957 | Accuracy of the WHO praziquantel dose pole for large-scale community treatment of urogenital schistosomiasis in northern Mozambique: Is it time for an update? | A pioneering strategy developed by the World Health Organization (WHO) for the control of schistosomiasis was the concept of a height-based dose pole to determine praziquantel (PZQ) dosing in large-scale treatment campaigns. However, some recent studies have shown variable accuracy for the dose pole in terms of predict... | Schistosomiasis control is currently based on large-scale, preventive chemotherapy treatment with praziquantel (PZQ), and this has resulted in a significant reduction in its prevalence and associated morbidity worldwide. Recommended PZQ dosing is 40–60 mg/Kg body weight, but to facilitate large-scale drug administratio... | Human schistosomiasis is an acute and chronic neglected tropical disease (NTD) caused by six species of parasitic blood flukes of genus Schistosoma: S. guineensis, S. haematobium, S. intercalatum, S. japonicum, S. mansoni and S. mekongi. Together, they affect about 250 million people worldwide, with more than 779 milli... |
10.1371/journal.pcbi.0030007 | Large-Scale Discovery of Promoter Motifs in Drosophila melanogaster | A key step in understanding gene regulation is to identify the repertoire of transcription factor binding motifs (TFBMs) that form the building blocks of promoters and other regulatory elements. Identifying these experimentally is very laborious, and the number of TFBMs discovered remains relatively small, especially w... | In contrast to the genomic sequences that encode proteins, little is known about the regulatory elements that instruct the cell as to when and where a given gene should be active. Regulatory elements are thought to consist of clusters of short DNA words (motifs), each of which acts as a binding site for sequence-specif... | Essentially complete sequences of metazoan genomes have now been available for nearly ten years, and in that time considerable progress has been made towards annotation of their best-known features, the protein coding genes. Computational pipelines such as that run by Ensembl [1] provide automated annotation of most pr... |
10.1371/journal.ppat.1006547 | Different rates of spontaneous mutation of chloroplastic and nuclear viroids as determined by high-fidelity ultra-deep sequencing | Mutation rates vary by orders of magnitude across biological systems, being higher for simpler genomes. The simplest known genomes correspond to viroids, subviral plant replicons constituted by circular non-coding RNAs of few hundred bases. Previous work has revealed an extremely high mutation rate for chrysanthemum ch... | Spontaneous mutations are the ultimate source of genetic variation and their characterization provides fundamental information about evolutionary processes. The highest mutation rate so far described corresponds to a hammerhead viroid infecting plant chloroplasts. Viroids are plant-exclusive parasites constituted by 25... | Spontaneous mutations are pivotal to evolution as they constitute the ultimate source of genetic variation. The biochemical and genetic bases of replication fidelity have been extensively studied, and it is well-established that spontaneous mutation rates vary by orders of magnitude across biological systems [1, 2]. Wh... |
10.1371/journal.ppat.1006383 | Detection of a microbial metabolite by STING regulates inflammasome activation in response to Chlamydia trachomatis infection | The innate immune system is a critical component of host defence against microbial pathogens, but effective responses require an ability to distinguish between infectious and non-infectious insult to prevent inappropriate inflammation. Using the important obligate intracellular human pathogen Chlamydia trachomatis; an ... | Innate responses to bacterial infection such as Chlamydia trachomatis activate inflammasomes to enable the processing of IL-1β, IL-18 and the induction of an inflammatory form of cell death termed pyroptosis. Inflammasomes are crucial to host defence but require tight regulation in order to prevent inappropriate inflam... | The obligate intracellular pathogen Chlamydia trachomatis is a major cause of infectious disease world-wide and can initiate inflammatory pathology such as pelvic inflammatory disease, reactive arthritis and infectious blindness (trachoma). Significantly, murine models of Chlamydia infection demonstrate that host infla... |
10.1371/journal.pntd.0002086 | A Neglected Aspect of the Epidemiology of Sleeping Sickness: The Propensity of the Tsetse Fly Vector to Enter Houses | When taking a bloodmeal from humans, tsetse flies can transmit the trypanosomes responsible for sleeping sickness, or human African trypanosomiasis. While it is commonly assumed that humans must enter the normal woodland habitat of the tsetse in order to have much chance of contacting the flies, recent studies suggeste... | To explore the nature of houses as venues for the contact between humans and tsetse flies, and hence for the transmission of sleeping sickness, we studied the sex and species composition and physiological condition of samples of tsetse caught in various types of house throughout the day and at different seasons. These ... | Sleeping sickness, or human African trypanosomiasis, is caused by two species of trypanosome, i.e., Trypanosoma brucei gambiense and T. b. rhodesiense, that are transmitted by tsetse flies (Glossina spp.) when taking blood from hosts [1]. It seems to have been assumed that the risk of humans being bitten by tsetse is b... |
10.1371/journal.pntd.0006475 | The protein family TcTASV-C is a novel Trypanosoma cruzi virulence factor secreted in extracellular vesicles by trypomastigotes and highly expressed in bloodstream forms | TcTASV-C is a protein family of about 15 members that is expressed only in the trypomastigote stage of Trypanosoma cruzi. We have previously shown that TcTASV-C is located at the parasite surface and secreted to the medium. Here we report that the expression of different TcTASV-C genes occurs simultaneously at the tryp... | Trypanosoma cruzi is the kinetoplastid parasite that causes Chagas’ disease, a neglected infection endemic in Latin America and emerging worldwide. Being vaccines currently unavailable and treatments not completely effective, identification and characterization of parasite molecules that can be target for these interve... | Trypanosoma cruzi, is the kinetoplastid pathogen that causes Chagas’ disease. There are about 10 million people currently infected and more than 50–60 million people living in endemic areas, at risk of infection. Chagas’ disease is a chronic debilitating illness with symptoms generally appearing 10 or more years after ... |
10.1371/journal.pgen.1006047 | Enhancement of Transcription by a Splicing-Competent Intron Is Dependent on Promoter Directionality | Enhancement of transcription by a splicing-competent intron is an evolutionarily conserved feature among eukaryotes. The molecular mechanism underlying the phenomenon, however, is not entirely clear. Here we show that the intron is an important regulator of promoter directionality. Employing strand-specific transcripti... | Eukaryotic genes differ from their prokaryotic counterparts in having intervening non-coding sequences called introns. The precise biological role of introns in eukaryotic systems remains unclear even more than forty years after their initial discovery. One function of intron that has been remarkably conserved during e... | Although introns were discovered more than four decades ago, their precise physiological role in biological systems still remains an enigma [1, 2]. One of the evolutionarily conserved functions of introns in eukaryotes is in regulation of the mRNA output of a gene [2–6]. The promoter-proximal introns often stimulate tr... |
10.1371/journal.pgen.1000381 | Sporadic Infantile Epileptic Encephalopathy Caused by Mutations in PCDH19 Resembles Dravet Syndrome but Mainly Affects Females | Dravet syndrome (DS) is a genetically determined epileptic encephalopathy mainly caused by de novo mutations in the SCN1A gene. Since 2003, we have performed molecular analyses in a large series of patients with DS, 27% of whom were negative for mutations or rearrangements in SCN1A. In order to identify new genes respo... | Severe epilepsies associated with cognitive impairment in children are multifarious and most affected patients are sporadic cases. Thus, there is a challenge to identify which of these epilepsies are genetically determined, since their sporadic status excludes the use of classical genetic approaches. We have used micro... | Epileptic encephalopathies are a group of rare disorders in which impairment of cognitive, behavioural and other brain functions is caused by the same underlying disease process. This heterogeneous group of disorders has multiple aetiologies such as symptomatic brain lesions, metabolic causes and diverse genetic syndro... |
10.1371/journal.pgen.1001360 | The Toll-Like Receptor Gene Family Is Integrated into Human DNA Damage and p53 Networks | In recent years the functions that the p53 tumor suppressor plays in human biology have been greatly extended beyond “guardian of the genome.” Our studies of promoter response element sequences targeted by the p53 master regulatory transcription factor suggest a general role for this DNA damage and stress-responsive re... | Among the most prominently studied regulators of gene function is the p53 tumor suppressor, which has many roles in human biology. The transcriptional master regulator p53 directly targets expression of >200 genes. Previously, we sought to define the p53 network in terms of functionality, specifically the ability of ta... | The p53 master regulator is responsive to a variety of DNA metabolic stresses resulting in induction or repression of over 200 genes as well as several LINC- and micro-RNAs [1], [2]. In its role as tumor suppressor and “guardian of the genome” many of the target genes in humans influence cell cycle progression or apopt... |
10.1371/journal.pbio.1001569 | Rare Species Support Vulnerable Functions in High-Diversity Ecosystems | Around the world, the human-induced collapses of populations and species have triggered a sixth mass extinction crisis, with rare species often being the first to disappear. Although the role of species diversity in the maintenance of ecosystem processes has been widely investigated, the role of rare species remains co... | In ecological systems most species are rare—that is, represented by only a few individuals or restricted to particular habitats—and are vulnerable to being lost. Yet the ecological consequences of such biodiversity loss are often overlooked and remain controversial. In the best-case scenario, the functions that these r... | The vast majority of species are rare—that is, comprising few individuals—and often have restricted geographic distributions [1]. Although several forms of rarity have been defined with respect to the trajectories by which species become extinct [2],[3], rare species are all seen as highly vulnerable to overexploitatio... |
10.1371/journal.pgen.1002918 | Loss of Axonal Mitochondria Promotes Tau-Mediated Neurodegeneration and Alzheimer's Disease–Related Tau Phosphorylation Via PAR-1 | Abnormal phosphorylation and toxicity of a microtubule-associated protein tau are involved in the pathogenesis of Alzheimer's disease (AD); however, what pathological conditions trigger tau abnormality in AD is not fully understood. A reduction in the number of mitochondria in the axon has been implicated in AD. In thi... | Abnormal phosphorylation and toxicity of a microtubule-associated protein tau are involved in the pathogenesis of Alzheimer's disease (AD). Tau is phosphorylated at multiple sites, and phosphorylation of tau regulates its microtubule binding and physiological functions such as regulation of microtubule stability. Abnor... | Mitochondria are principal mediators of local ATP supply and Ca2+ buffering. In neuronal axons, these requirements need to be addressed locally, and the proper distribution of mitochondria is essential for neuronal functions and survival [1]. Defects in mitochondrial distribution have been observed in the brains of pat... |
10.1371/journal.ppat.1000449 | In Vivo Transcriptional Profiling of Listeria monocytogenes and Mutagenesis Identify New Virulence Factors Involved in Infection | Listeria monocytogenes is a human intracellular pathogen able to colonize host tissues after ingestion of contaminated food, causing severe invasive infections. In order to gain a better understanding of the nature of host–pathogen interactions, we studied the L. monocytogenes genome expression during mouse infection. ... | The facultative intracellular bacterial pathogen Listeria monocytogenes is the etiological agent of a severe foodborne disease. In humans it causes a variety of manifestations ranging from asymptomatic intestinal carriage and gastroenteritis to invasive and disseminated severe diseases. Septicemia, meningoencephalitis,... | Listeria monocytogenes is an intracellular food-borne pathogen that causes listeriosis, an infection characterized by gastroenteritis, meningitis, encephalitis, and maternofetal infections in humans. It has one of the highest fatality rate among food-borne infections (20%–30%) [1]. Our knowledge of the infectious proce... |
10.1371/journal.pcbi.1005630 | Optimal structure of metaplasticity for adaptive learning | Learning from reward feedback in a changing environment requires a high degree of adaptability, yet the precise estimation of reward information demands slow updates. In the framework of estimating reward probability, here we investigated how this tradeoff between adaptability and precision can be mitigated via metapla... | Successful learning from our experience and feedback from the environment requires that the reward value assigned to a given option or action to be updated by a precise amount after each feedback. In the standard model for reward-based learning known as reinforcement learning, the learning rates determine the strength ... | To successfully learn from reward feedback, the brain must adjust how it responds to and integrates reward outcomes, since reward contingencies can unpredictably change over time [1,2]. At the heart of this learning problem is a tradeoff between adaptability and precision. On the one hand, the brain must rapidly update... |
10.1371/journal.pbio.1001298 | Cytoneme-Mediated Delivery of Hedgehog Regulates the Expression of Bone Morphogenetic Proteins to Maintain Germline Stem Cells in Drosophila | Stem cells reside in specialised microenvironments, or niches, which often contain support cells that control stem cell maintenance and proliferation. Hedgehog (Hh) proteins mediate homeostasis in several adult niches, but a detailed understanding of Hh signalling in stem cell regulation is lacking. Studying the Drosop... | The Drosophila ovary contains a well-defined stem cell niche that hosts 2–3 germline stem cells (GSCs). The Hedgehog (Hh) family of signalling proteins mediates cellular homeostasis in several adult tissues, and here we decipher the detailed mechanism of action of Hh in the adult female GSC niche. We demonstrate that H... | Stem cells are responsible for the integrity of tissues during growth, ageing, and repair. They reside in specialised microenvironments, or niches, which frequently comprise support cells that control stem cell self-renewal, proliferation, and differentiation [1],[2]. Stem cell niche regulation often involves short-ran... |
10.1371/journal.ppat.1005976 | Evolution of Fitness Cost-Neutral Mutant PfCRT Conferring P. falciparum 4-Aminoquinoline Drug Resistance Is Accompanied by Altered Parasite Metabolism and Digestive Vacuole Physiology | Southeast Asia is an epicenter of multidrug-resistant Plasmodium falciparum strains. Selective pressures on the subcontinent have recurrently produced several allelic variants of parasite drug resistance genes, including the P. falciparum chloroquine resistance transporter (pfcrt). Despite significant reductions in the... | Point mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) earlier thwarted the clinical efficacy of chloroquine, the former gold standard, and constitute a major determinant of parasite susceptibility to antimalarial drugs. Recently, we reported that the highly mutated Cambodian PfCRT isof... | Human malaria remains a leading global health scourge in part due to multidrug resistance mechanisms evolved by Plasmodium falciparum, the protozoan species responsible for the most severe forms of disease [1]. Artemisinin-based combination therapies (ACTs) are the current first-line means of controlling pathogenic ase... |
10.1371/journal.pntd.0004590 | Assessing Lymphatic Filariasis Data Quality in Endemic Communities in Ghana, Using the Neglected Tropical Diseases Data Quality Assessment Tool for Preventive Chemotherapy | The activities of the Global Programme for the Elimination of Lymphatic Filariasis have been in operation since the year 2000, with Mass Drug Administration (MDA) undertaken yearly in disease endemic communities. Information collected during MDA–such as population demographics, age, sex, drugs used and remaining, and t... | The Global Programme for the Elimination of Lymphatic Filariasis has been conducting yearly treatment of entire communities in endemic countries since the year 2000. During the treatments various information is collected on the populations, number of medicine tablets distributed and remaining, the number of people trea... | The Global Programme to Eliminate Lymphatic Filariasis (GPELF) started its activities in the year 2000, with the aims of eliminating lymphatic filariasis (LF) as a public health problem by the year 2020, through mass drug administration (MDA) in endemic implementation units (IU) [1]. In many countries significant progr... |
10.1371/journal.pbio.2005712 | Within-host competition can delay evolution of drug resistance in malaria | In the malaria parasite P. falciparum, drug resistance generally evolves first in low-transmission settings, such as Southeast Asia and South America. Resistance takes noticeably longer to appear in the high-transmission settings of sub-Saharan Africa, although it may spread rapidly thereafter. Here, we test the hypoth... | The malaria parasite Plasmodium falciparum has evolved resistance to most antimalarial drugs, greatly complicating treatment and control of the disease. Curiously, although sub-Saharan Africa accounts for the majority of the global burden of malaria, the evolution of drug resistance in Africa has been markedly delayed ... | Drug resistance is a recurring threat to effective treatment and control of P. falciparum malaria. Chloroquine—a highly effective synthetic antimalarial—was used to combat malaria on a massive scale in the 1950s; by the 1960s, resistance to chloroquine had developed in Southeast Asia and South America, and over the nex... |
10.1371/journal.pmed.1002431 | Validity of a minimally invasive autopsy for cause of death determination in maternal deaths in Mozambique: An observational study | Despite global health efforts to reduce maternal mortality, rates continue to be unacceptably high in large parts of the world. Feasible, acceptable, and accurate postmortem sampling methods could provide the necessary evidence to improve the understanding of the real causes of maternal mortality, guiding the design of... | Since 1990, the maternal mortality ratio (MMR) has dropped by 43%, but despite this progress, hundreds of women still die every day in large parts of the world due to pregnancy or childbirth complications.
A reliable knowledge of the causes of maternal death is a necessary condition to reduce this burden through adequa... | As the Millennium Development Goals came to a close in 2015, the maternal mortality ratio (MMR) had dropped by 43% since 1990 [1]. Although this progress is certainly encouraging, it is lower than the 75% target initially planned, and hundreds of women still die every day due to complications of pregnancy or childbirth... |
10.1371/journal.ppat.1006187 | Multiple UBXN family members inhibit retrovirus and lentivirus production and canonical NFκΒ signaling by stabilizing IκBα | UBXN proteins likely participate in the global regulation of protein turnover, and we have shown that UBXN1 interferes with RIG-I-like receptor (RLR) signaling by interacting with MAVS and impeding its downstream effector functions. Here we demonstrate that over-expression of multiple UBXN family members decreased lent... | A family of human genes termed UBXN is thought to control many cellular processes, including protein destruction. While working with these proteins, we noticed several profoundly blocked the production of human immunodeficiency virus (HIV) and other, similar viruses. We delved into the how this occurs, and it appears t... | The UBX family member proteins are thought to regulate diverse cellular processes, including protein stability and degradation. Members of the gene family include UBXN2a (also termed UBXD4), UBXN2b (p37), UBXN2c (UBXD10, p47, or UBX1), UBXN3a (FAF1 or UBXD12), UBXN3b (FAF2 or UBXD8), UBXN4 (UBXD2 or UBXDC1), UBXN6 (UBX... |
10.1371/journal.pgen.1001220 | Systematic Dissection and Trajectory-Scanning Mutagenesis of the Molecular Interface That Ensures Specificity of Two-Component Signaling Pathways | Two-component signal transduction systems enable bacteria to sense and respond to a wide range of environmental stimuli. Sensor histidine kinases transmit signals to their cognate response regulators via phosphorylation. The faithful transmission of information through two-component pathways and the avoidance of unwant... | Maintaining the specificity of signal transduction pathways is critical to the ability of cells to process information, make decisions, and regulate their behavior. Preventing cross-talk often relies predominantly on molecular recognition and a set of specificity-determining residues in cognate proteins. Identifying th... | Protein-protein interactions are crucial to virtually every cellular process. Within the crowded confines of the cell, proteins must distinguish between their cognate partners and non-cognate partners, in order to avoid unproductive and potentially deleterious interactions. The problem of interaction specificity is par... |
10.1371/journal.ppat.1000764 | Six RNA Viruses and Forty-One Hosts: Viral Small RNAs and Modulation of Small RNA Repertoires in Vertebrate and Invertebrate Systems | We have used multiplexed high-throughput sequencing to characterize changes in small RNA populations that occur during viral infection in animal cells. Small RNA-based mechanisms such as RNA interference (RNAi) have been shown in plant and invertebrate systems to play a key role in host responses to viral infection. Al... | Short RNAs derived from invading viruses with RNA genomes are important components of antiviral immunity in plants, worms and flies. The regulated generation of these short RNAs, and their engagement by the immune apparatus, is essential for inhibiting viral growth in these organisms. Mammals have the necessary protein... | Biological systems are protected by innate immune mechanisms initiated by host sensors called pattern recognition receptors (‘PRRs’) that recognize specific “foreign” features of invading pathogens to initiate multiple downstream anti-pathogen cascades. PRRs that detect nucleic acid structures characteristic of viral i... |
10.1371/journal.pgen.1002940 | Transcriptional Repression of Hox Genes by C. elegans HP1/HPL and H1/HIS-24 | Elucidation of the biological role of linker histone (H1) and heterochromatin protein 1 (HP1) in mammals has been difficult owing to the existence of a least 11 distinct H1 and three HP1 subtypes in mice. Caenorhabditis elegans possesses two HP1 homologues (HPL-1 and HPL-2) and eight H1 variants. Remarkably, one of eig... | Linker histone (H1) and heterochromatin protein 1 (HP1) play central roles in the formation of higher-order chromatin structure and gene expression. Recent studies have shown a physical interaction between H1 and HP1; however, the biological role of histone H1 and HP1 is not well understood. Additionally, the function ... | Linker histone H1 and heterochromatin protein HP1 are involved in numerous processes ranging from stabilizing heterochromatin condensation to the regulation of gene expression [1]–[5]. As has been reported, a methylation mark on vertebrate histone H1 is specifically recognized by the chromodomain of HP1. However, the e... |
10.1371/journal.ppat.0030155 | RNAi Screen in Drosophila Cells Reveals the Involvement of the Tom Complex in Chlamydia Infection | Chlamydia spp. are intracellular obligate bacterial pathogens that infect a wide range of host cells. Here, we show that C. caviae enters, replicates, and performs a complete developmental cycle in Drosophila SL2 cells. Using this model system, we have performed a genome-wide RNA interference screen and identified 54 f... | Chlamydia spp. are intracellular bacterial pathogens that infect a wide range of hosts and cause various diseases, including preventable blindness in developing countries, sexually transmitted disease, and pneumonia. Chlamydia spp. are able to establish their replication niche inside the host cell, residing in a membra... | Chlamydia spp. are Gram-negative, obligate, intracellular bacterial pathogens that infect a wide range of hosts and cause various diseases. Three species infect humans. C. trachomatis is the leading cause of preventable blindness in developing countries [1] and the most common cause of bacterial sexually transmitted di... |
10.1371/journal.ppat.1000699 | T Cell Detection of a B-Cell Tropic Virus Infection: Newly-Synthesised versus Mature Viral Proteins as Antigen Sources for CD4 and CD8 Epitope Display | Viruses that naturally infect cells expressing both MHC I and MHC II molecules render themselves potentially visible to both CD8+ and CD4+ T cells through the de novo expression of viral antigens. Here we use one such pathogen, the B-lymphotropic Epstein-Barr virus (EBV), to examine the kinetics of these processes in t... | Many viruses infect cells in which both the MHC I and MHC II pathways of antigen presentation are active, and so viral proteins expressed in those cells may be presented as MHC I-peptide complexes to CD8+ T cells and as MHC II-peptide complexes to CD4+ T cells. Here we study these processes in a model system involving ... | Many intracellular pathogens, particularly viruses, naturally infect cells of the haemopoietic system that express both MHC I and MHC II molecules. Such infected cells may be rendered visible to the host T cell response through the intracellular processing of virally-encoded proteins, leading to cell surface display of... |
10.1371/journal.pntd.0000535 | The Production of Antibody by Invading B Cells Is Required for the Clearance of Rabies Virus from the Central Nervous System | The pathogenesis of rabies is associated with the inability to deliver immune effectors across the blood-brain barrier and to clear virulent rabies virus from CNS tissues. However, the mechanisms that facilitate immune effector entry into CNS tissues are induced by infection with attenuated rabies virus.
Infection of n... | Every year over 50,000 people die from rabies worldwide, primarily due to the poor availability of rabies vaccine in developing countries. However, even when vaccines are available, human deaths from rabies occur if exposure to the causative virus is not recognized and vaccination is not sought in time. This is because... | Rabies viruses spread from peripheral sites of entry to the central nervous system (CNS) tissues via axonal transport thereby bypassing the specialized features of the neurovasculature known as the blood-brain barrier (BBB). Once the virus reaches CNS tissues three alternative outcomes are likely: (1) the BBB remains i... |
10.1371/journal.ppat.1002754 | African Swine Fever Virus Uses Macropinocytosis to Enter Host Cells | African swine fever (ASF) is caused by a large and highly pathogenic DNA virus, African swine fever virus (ASFV), which provokes severe economic losses and expansion threats. Presently, no specific protection or vaccine against ASF is available, despite the high hazard that the continued occurrence of the disease in su... | ASFV is a highly pathogenic zoonotic virus, which can cause severe economic losses and bioterrorism threats. No vaccine against ASFV is available so far. A strong hazard of ASFV dissemination through EU countries from Caucasian areas has recently emerged, thus making urgent to acquire knowledge and tools for protection... | ASFV is a 200 nm large DNA virus that infects different species of swine, causing acute and often fatal disease [1]–[3]. Infection by ASFV is characterized by the absence of a neutralizing immune response, which has so far hampered the development of a conventional vaccine. A strong hazard of ASFV dissemination through... |
10.1371/journal.pcbi.1005713 | A conceptual and computational framework for modelling and understanding the non-equilibrium gene regulatory networks of mouse embryonic stem cells | The capacity of pluripotent embryonic stem cells to differentiate into any cell type in the body makes them invaluable in the field of regenerative medicine. However, because of the complexity of both the core pluripotency network and the process of cell fate computation it is not yet possible to control the fate of st... | Pluripotent stem cells possess the capacity both to renew themselves indefinitely and to differentiate to any cell type in the body. Thus the ability to direct stem cell differentiation would have immense potential in regenerative medicine. There is a massive amount of biological data relevant to stem cells; here we ex... | Stem cells present an important instance of the complexity of cellular function and gene regulation. Pluripotent stem cells possess the capacity both to renew themselves indefinitely and to differentiate to any cell type in the body. This second capacity means that the ability to direct stem cell differentiation would ... |
10.1371/journal.ppat.1000250 | The Staphylococcus aureus Protein Sbi Acts as a Complement Inhibitor and Forms a Tripartite Complex with Host Complement Factor H and C3b | The Gram-positive bacterium Staphylococcus aureus, similar to other pathogens, binds human complement regulators Factor H and Factor H related protein 1 (FHR-1) from human serum. Here we identify the secreted protein Sbi (Staphylococcus aureus binder of IgG) as a ligand that interacts with Factor H by a—to our knowledg... | Staphylococcus aureus is a Gram-positive bacterium that can live as a commensal but can also cause severe life threatening infections in humans. Upon infection the bacterium is attacked by the host immune system, and in particular by the complement system which forms the immediate, first defence line of innate immunity... | In order to establish an infection pathogens have developed multiple mechanisms to avoid immune recognition and to escape host immune attack [1],[2]. Complement, which mediates a powerful immediate innate immune defense of vertebrate hosts, is activated, within seconds upon entry of a foreign invader [1],[2]. Activatio... |
10.1371/journal.pcbi.1006601 | Determinants of drug-target interactions at the single cell level | The physiochemical determinants of drug-target interactions in the microenvironment of the cell are complex and generally not defined by simple diffusion and intrinsic chemical reactivity. Non-specific interactions of drugs and macromolecules in cells are rarely considered formally in assessing pharmacodynamics. Here, ... | Small-molecule drug design assumes target binding of high affinity. Most small molecules can interact with other macromolecules in the cell ‘nonspecifically,’ i.e., with significantly lower affinity. The extent to which these nonspecific interactions influence the availability and action of the drug for its specific ta... | Drug efficacy in vivo is notoriously difficult to predict owing, in part, to the complexity of the underlying biochemical processes that govern drug–target interactions in situ. Semi-empiric pharmacokinetic/pharmacodynamic (PK/PD) models typically describe accumulation of the drug in tissue(s) and, hence, do not addres... |
10.1371/journal.pgen.1006690 | Cis-eQTL-based trans-ethnic meta-analysis reveals novel genes associated with breast cancer risk | Breast cancer is the most common solid organ malignancy and the most frequent cause of cancer death among women worldwide. Previous research has yielded insights into its genetic etiology, but there remains a gap in the understanding of genetic factors that contribute to risk, and particularly in the biological mechani... | There is a clear genetic basis of breast cancer, and previous work has identified numerous genetic variants that increase risk of this common disease. However, much of the underlying genetic variation in breast cancer remains unexplained. To address this void, as part of the National Cancer Institute’s “Up for a Challe... | Breast cancer is the most common solid organ malignancy and the most frequent cause of cancer death among women worldwide [1]. Family history is among the strongest known risk factors for breast cancer. Individuals with a first-degree relative affected by the disease have a roughly two-fold increased risk of developing... |
10.1371/journal.ppat.1000235 | Structure of Reovirus σ1 in Complex with Its Receptor Junctional Adhesion Molecule-A | Viral attachment to specific host receptors is the first step in viral infection and serves an essential function in the selection of target cells. Mammalian reoviruses are highly useful experimental models for studies of viral pathogenesis and show promise as vectors for oncolytics and vaccines. Reoviruses engage cell... | Mammalian orthoreoviruses (reoviruses) are useful models for studies of virus–receptor interactions and viral pathogenesis. They are closely related in structure to adenoviruses and share similar mechanisms of cell attachment and entry. The receptor for reovirus, junctional adhesion molecule-A (JAM-A), is a component o... | Viruses have evolved a variety of strategies to engage cellular receptors, often taking advantage of the adhesive properties of these molecules. Immunoglobulin superfamily (IgSF) members mediate cellular adhesion functions including antigen recognition, stabilization of intercellular junctions, adhesion to extracellula... |
10.1371/journal.pcbi.1003976 | Structure, Dynamics and Implied Gating Mechanism of a Human Cyclic Nucleotide-Gated Channel | Cyclic nucleotide-gated (CNG) ion channels are nonselective cation channels, essential for visual and olfactory sensory transduction. Although the channels include voltage-sensor domains (VSDs), their conductance is thought to be independent of the membrane potential, and their gating regulated by cytosolic cyclic nucl... | Cyclic nucleotide-gated (CNG) channels mediate the passage of cations through the cytoplasmic membrane. They are involved in sensory transduction and cellular development in the rod and cone photoreceptors, as well as in brain, kidney, heart and other cells, and are linked to achromatopsia and other rare genetic diseas... | Cyclic nucleotide-gated (CNG) ion channels are nonselective cation channels, essential for visual and olfactory sensory transduction in vertebrates [1]–[4]. Like other members of the voltage-gated-like ion channel superfamily [2], the CNG channels are composed of four (identical or similar) monomers, each containing si... |
10.1371/journal.pbio.1000454 | Aging in a Long-Lived Clonal Tree | From bacteria to multicellular animals, most organisms exhibit declines in survivorship or reproductive performance with increasing age (“senescence”) [1],[2]. Evidence for senescence in clonal plants, however, is scant [3],[4]. During asexual growth, we expect that somatic mutations, which negatively impact sexual fit... | Aging has been demonstrated in many animals and even in bacteria, but there is little empirical work showing that clonal plants age. Evidence for aging in long-lived perennials is scarce because it typically requires survivorship or fecundity schedules from long-term demographic data. Given the extreme lifespan of many... | Many species of animals, and even bacteria, demonstrate a decline in survivorship or reproductive performance with increasing age (“senescence”) [1],[2]. Evidence for senescence in perennial plants, however, is scant [3],[4],[7]. One feature that distinguishes plants from many animals is indeterminate growth. Indetermi... |
10.1371/journal.pgen.1003367 | A Novel Role for the RNA–Binding Protein FXR1P in Myoblasts Cell-Cycle Progression by Modulating p21/Cdkn1a/Cip1/Waf1 mRNA Stability | The Fragile X-Related 1 gene (FXR1) is a paralog of the Fragile X Mental Retardation 1 gene (FMR1), whose absence causes the Fragile X syndrome, the most common form of inherited intellectual disability. FXR1P plays an important role in normal muscle development, and its absence causes muscular abnormalities in mice, f... | Muscle development is a complex process controlled by the timely expression of genes encoding crucial regulators of the muscle cell precursors called myoblasts. We know from previous studies that inactivation of the Fragile X related 1 (FXR1) gene in various animal models (mouse, frog, and zebrafish) causes muscular an... | The Fragile X-Related 1 (FXR1) gene belongs to a small gene family that includes the Fragile X Mental Retardation 1 (FMR1) and Fragile X-Related 2 (FXR2) genes (reviewed in [1]). Human FMR1 is located on chromosome Xq27.3 [2] and inactivation of FMR1 expression leads to the Fragile X syndrome in human, the first cause ... |
10.1371/journal.ppat.1006650 | Reduced accumulation of defective viral genomes contributes to severe outcome in influenza virus infected patients | Influenza A virus (IAV) infection can be severe or even lethal in toddlers, the elderly and patients with certain medical conditions. Infection of apparently healthy individuals nonetheless accounts for many severe disease cases and deaths, suggesting that viruses with increased pathogenicity co-circulate with pandemic... | Influenza A viruses are the causative agents of annual epidemics, sporadic zoonotic outbreaks and occasionally pandemics. Worldwide, acute respiratory infections caused by influenza A viruses continue to be one of the main causes of acute illness and death. The appearance in 2009 of a new H1N1 pandemic influenza strain... | Acute respiratory infections are a main cause of severe illness and death worldwide. Influenza A virus (IAV) causes annual epidemics and occasional pandemics with potentially fatal outcome [1]; the global burden of seasonal influenza is >600 million cases, with 5 million cases of severe illness and up to 500,000 deaths... |
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