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10.1371/journal.pgen.1005781 | Extensive Recombination of a Yeast Diploid Hybrid through Meiotic Reversion | In somatic cells, recombination between the homologous chromosomes followed by equational segregation leads to loss of heterozygosity events (LOH), allowing the expression of recessive alleles and the production of novel allele combinations that are potentially beneficial upon Darwinian selection. However, inter-homolo... | The genetic diversity of eukaryotes relies on the diversification of the parental information, mostly occurring by recombination during gamete formation. Homologous chromosomes also recombine in somatic cells, though much less frequently. Here, we sequenced the genome of S. cerevisiae hybrid diploid cells that enter th... | Genetic diversity relies on diversification of the parental genome information. Besides spontaneous and environmentally induced de novo mutations, sexual reproduction is the prominent source of genetic diversity: it reshuffles the genetic information among individuals from a given species, creating the new combinations... |
10.1371/journal.pntd.0006058 | Mycolactone displays anti-inflammatory effects on the nervous system | Mycolactone is a macrolide produced by the skin pathogen Mycobacterium ulcerans, with cytotoxic, analgesic and immunomodulatory properties. The latter were recently shown to result from mycolactone blocking the Sec61-dependent production of pro-inflammatory mediators by immune cells. Here we investigated whether mycola... | Mycolactone is a complex macrolidic polyketide produced by the skin pathogen Mycobacterium ulcerans, with cytotoxic, analgesic and anti-inflammatory properties. Peripheral nerve destruction and activation of type 2 angiotensin II receptors on sensory neurons have been proposed to mediate bacteria-induced hypoesthesia i... | Mycolactone is a polyketide-derived macrolide produced by the skin pathogen Mycobacterium ulcerans, the causative agent of Buruli ulcer disease (BU) [1–3]. In addition to inducing local skin ulceration and analgesia, mycolactone diffuses in infected hosts to affect systemic inflammatory immune responses [4]. Why the ma... |
10.1371/journal.pntd.0000758 | Asymmetric Wolbachia Segregation during Early Brugia malayi Embryogenesis Determines Its Distribution in Adult Host Tissues | Wolbachia are required for filarial nematode survival and fertility and contribute to the immune responses associated with human filarial diseases. Here we developed whole-mount immunofluorescence techniques to characterize Wolbachia somatic and germline transmission patterns and tissue distribution in Brugia malayi, a... | Filarial diseases affect over 150 million people in tropical countries. They are caused by parasitic nematodes like Brugia malayi that rely on their endosymbiont Wolbachia for their survival and fertility. These bacteria are a recognized drug target in the search for treatments killing adult worms. To understand the tr... | Filarial nematodes are the causative agents of human filariasis, affecting over 150 million individuals. The most pathogenic diseases, lymphatic filariasis and onchocerciasis, (river blindness) comprise a major cause of global morbidity in the tropics, with over 1 billion people at risk of these arthropod-transmitted i... |
10.1371/journal.pcbi.1005805 | General principles of binding between cell surface receptors and multi-specific ligands: A computational study | The interactions between membrane receptors and extracellular ligands control cell-cell and cell-substrate adhesion, and environmental responsiveness by representing the initial steps of cell signaling pathways. These interactions can be spatial-temporally regulated when different extracellular ligands are tethered. Th... | In order to adapt to surrounding environments, multiple signaling pathways have been evolved in cells. The first step of these pathways is to detect external stimuli, which is conducted by the dynamic interactions between cell surface receptors and extracellular ligands. As a result, recognition of extracellular ligand... | Integral membrane proteins are the sensors of extracellular signals, including cell-cell and cell-substrate interactions, as well as environmental queues. Their interactions with extracellular ligands initiate most of the intracellular signaling pathways [1, 2], while the dysregulation of these receptor-initiated signa... |
10.1371/journal.pntd.0007022 | Widespread circulation of West Nile virus, but not Zika virus in southern Iran | West Nile virus (WNV) and Zika virus (ZIKV) are mosquito-borne viral infections. Over the past few decades, WNV has been associated with several outbreaks involving high numbers of neuroinvasive diseases among humans. The recent re-emergence of ZIKV has been associated with congenital malformation and also with Guillai... | In recent decades mosquito-borne viruses have reached and adapted to new habitats, and now they can be found in nearly all continents. Facilitated goods transportation, live stock exchange, people travelling more easily, and most importantly world climate alterations, might be some of the reasons for this mosquito habi... | West Nile virus (WNV) and Zika virus (ZIKV) are mosquito-transmitted viruses from the genus Flavivirus. The geosgraphic range of many arthropod-borne viruses (arboviruses) has increased in recent decades, due in part to changing global climatic conditions, as well as increasing global travel of both humans and domestic... |
10.1371/journal.pntd.0007669 | A novel MALDI-TOF MS-based method for blood meal identification in insect vectors: A proof of concept study on phlebotomine sand flies | Identification of blood sources of hematophagous arthropods is crucial for understanding the transmission cycles of vector-borne diseases. Many different approaches towards host determination were proposed, including precipitin test, ELISA, DNA- and mass spectrometry-based methods; yet all face certain complications an... | Leishmaniases belong among the most important and yet neglected vector-borne diseases, transmitted mostly by bite of female phlebotomine sand flies. To understand role of different reservoir hosts in the transmission cycles, it is important to determine blood meal sources of bloodfeeding females. Most of currently used... | Phlebotomine sand flies (Diptera, Phlebotominae) are tiny nocturnal dipterans of high medical and veterinary importance as they are involved in transmission of several arboviruses, bacteria and protozoans that affect human and animal health. Among these, parasitic protozoans of the genus Leishmania are of paramount imp... |
10.1371/journal.pcbi.1000367 | A Structural Model of the Pore-Forming Region of the Skeletal Muscle Ryanodine Receptor (RyR1) | Ryanodine receptors (RyRs) are ion channels that regulate muscle contraction by releasing calcium ions from intracellular stores into the cytoplasm. Mutations in skeletal muscle RyR (RyR1) give rise to congenital diseases such as central core disease. The absence of high-resolution structures of RyR1 has limited our un... | Ryanodine receptors (RyRs) are ion channels present in the membranes of an intracellular calcium storage organelle, the sarcoplasmic reticulum. Nerve impulse triggers the opening of RyR channels, thus increasing the cytoplasmic calcium levels, which subsequently leads to muscle contraction. Congenital mutations in a sp... | Muscle contraction upon excitation by nerve impulse is initiated by a rapid rise in cytoplasmic Ca2+. In skeletal muscle, the rise in cytoplasmic Ca2+ is brought about by the opening of the ryanodine receptor (RyR1), which releases Ca2+ from intracellular stores [1],[2]. RyRs are large tetrameric ion channels (molecula... |
10.1371/journal.pntd.0000272 | Conservation and Variability of Dengue Virus Proteins: Implications for Vaccine Design | Genetic variation and rapid evolution are hallmarks of RNA viruses, the result of high mutation rates in RNA replication and selection of mutants that enhance viral adaptation, including the escape from host immune responses. Variability is uneven across the genome because mutations resulting in a deleterious effect on... | Dengue viruses (DENVs) circulate in nature as a population of 4 distinct types, each with multiple genotypes and variants, and represent an increasing global public health issue with no prophylactic and therapeutic formulations currently available. Viral genomes contain sites that are evolutionarily stable and therefor... | Dengue viruses (DENVs) are mosquito-borne pathogens of the family Flaviviridae, genus Flavivirus, which are phylogenetically related to other important human pathogens, such as Yellow fever (YFV), Japanese encephalitis (JEV), and West Nile (WNV) viruses, among others. DENVs are enveloped, single-stranded RNA (+) viruse... |
10.1371/journal.pcbi.0040002 | Genes and (Common) Pathways Underlying Drug Addiction | Drug addiction is a serious worldwide problem with strong genetic and environmental influences. Different technologies have revealed a variety of genes and pathways underlying addiction; however, each individual technology can be biased and incomplete. We integrated 2,343 items of evidence from peer-reviewed publicatio... | Drug addiction has become one of the most serious problems in the world. It has been estimated that genetic factors contribute to 40%–60% of the vulnerability to drug addiction, and environmental factors provide the remainder. What are the genes and pathways underlying addiction? Is there a common molecular network und... | Drug addiction, defined as “the loss of control over drug use, or the compulsive seeking and taking of drugs despite adverse consequences,” has become one of the most serious problems in the world [1]. It has been estimated that genetic factors contribute to 40%–60% of the vulnerability to drug addiction, and environme... |
10.1371/journal.pntd.0002229 | Phylogenetic Findings Suggest Possible New Habitat and Routes of Infection of Human Eumyctoma | Eumycetoma is a traumatic fungal infection in tropical and subtropical areas that may lead to severe disability. Madurella mycetomatis is one of the prevalent etiologic agents in arid Northeastern Africa. The source of infection has not been clarified. Subcutaneous inoculation from plant thorns has been hypothesized, b... | Eumycetoma caused by Madurella mycetomatis is a common subcutaneous, mutilating fungal infection endemic in arid climate zones. Still there are many controversies on the route of infection, but traumatic inoculation of the subcutaneous tissue with the thorn or soil causative organism through minor skin trauma is a popu... | Eumycetoma is a subcutaneous disease with a high morbidity. It is prevalent in tropical and subtropical arid climate zones, with a focus in Northeastern Africa and particularly the Sudan [1]. Patients who develop advanced mycetoma of the extremities frequently become invalids due to the immobilizing nature of the disea... |
10.1371/journal.pgen.1004494 | Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population | Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantage... | We explored the coding regions of 3,000 Finnish individuals with 3,000 non-Finnish Europeans (NFEs) using whole-exome sequence data, in order to understand how an individual from a bottlenecked population might differ from an individual from an out-bred population. We provide empirical evidence that there are more rare... | After widespread success with genome-wide association studies (GWAS) of common variants, several studies have recently begun to identify rare (with <0.5% allele frequency) and low-frequency (0.5–5%) variants in complex diseases and traits such as triglycerides [1], insulin processing [2], bone mineral density [3], Alzh... |
10.1371/journal.pntd.0001174 | Tissue and Stage-Specific Distribution of Wolbachia in Brugia malayi | Most filarial parasite species contain Wolbachia, obligatory bacterial endosymbionts that are crucial for filarial development and reproduction. They are targets for alternative chemotherapy, but their role in the biology of filarial nematodes is not well understood. Light microscopy provides important information on m... | Most filarial nematodes contain Wolbachia endobacteria that are essential for development and reproduction. An antibody against a Wolbachia surface protein was used to monitor the distribution of endobacteria during the B. malayi life cycle. In situ hybridization with probes binding to Wolbachia 16S rRNA were used to c... | Filarial parasites infect more than 150 million people in tropical and subtropical countries and are responsible for important tropical diseases such as lymphatic filariasis (elephantiasis) and onchocerciasis (river blindness). Other filarial species are important veterinary pathogens (e.g. Dirofilaria immitis, the dog... |
10.1371/journal.ppat.1002258 | Development of a Transformation System for Chlamydia trachomatis: Restoration of Glycogen Biosynthesis by Acquisition of a Plasmid Shuttle Vector | Chlamydia trachomatis remains one of the few major human pathogens for which there is no transformation system. C. trachomatis has a unique obligate intracellular developmental cycle. The extracellular infectious elementary body (EB) is an infectious, electron-dense structure that, following host cell infection, differ... | C. trachomatis is a major human pathogen for which there is no means of genetically manipulating its DNA. It is an obligate intracellular bacterium which has a complex developmental cycle that takes place in a specialized host cell cytoplasmic vacuole known as an inclusion. We have constructed a shuttle vector based on... | C. trachomatis is a major human pathogen with a unique intracellular developmental cycle [1], [2]. This cycle begins when the extracellular, infectious form of the microorganism, the EB, binds to susceptible host cells [3], [4]. EBs are taken up into a phagocytic vesicle which is modified to become a chlamydial inclusi... |
10.1371/journal.pntd.0005768 | Cross-recognition of a pit viper (Crotalinae) polyspecific antivenom explored through high-density peptide microarray epitope mapping | Snakebite antivenom is a 120 years old invention based on polyclonal mixtures of antibodies purified from the blood of hyper-immunized animals. Knowledge on antibody recognition sites (epitopes) on snake venom proteins is limited, but may be used to provide molecular level explanations for antivenom cross-reactivity. I... | Although snakebite antivenom is a 120-year-old invention, saving lives and limbs of thousands of snakebite victims every year, little is known about the mechanisms and molecular interactions of how antivenoms neutralize snake toxins. Antivenoms are produced by immunizing large animals with cocktails of snake venoms res... | Snakebite envenoming constitutes a serious public health problem on a global basis [1–3]. It primarily affects impoverished populations living in rural settings of Africa, Asia, and Latin America [4]. It is estimated that about 70,000 snakebite cases occur in Latin America every year, although it is likely that the act... |
10.1371/journal.pgen.1004091 | Arabidopsis AL PHD-PRC1 Complexes Promote Seed Germination through H3K4me3-to-H3K27me3 Chromatin State Switch in Repression of Seed Developmental Genes | Seed germination and subsequent seedling growth define crucial steps for entry into the plant life cycle. For those events to take place properly, seed developmental genes need to be silenced whereas vegetative growth genes are activated. Chromatin structure is generally known to play crucial roles in gene transcriptio... | Seed germination is a key developmental transition during the plant life cycle. During this process, seed developmental genes are progressively turned off to allow proper seedling growth and development. Molecular mechanisms involved in establishing the repression state of seed developmental genes, however, are still p... | Timely transition from a growth-arrested seed to a growing seedling is a key process during the plant life cycle, which has great importance in plant adaptation to environmental conditions [1]. Seed germination, a developmental process spanning from initial seed hydration to embryonic root emergence, and subsequent see... |
10.1371/journal.ppat.1000403 | trans-Complementation of an NS2 Defect in a Late Step in Hepatitis C Virus (HCV) Particle Assembly and Maturation | Recent studies using cell culture infection systems that recapitulate the entire life cycle of hepatitis C virus (HCV) indicate that several nonstructural viral proteins, including NS2, NS3, and NS5A, are involved in the process of viral assembly and release. Other recent work suggests that Ser-168 of NS2 is a target o... | Worldwide, more than 200 million people are chronically infected with hepatitis C virus (HCV) and thus at risk for fatal liver disease. New, virus-specific therapies are under development by the pharmaceutical industry that target aspects of virus entry and genome replication. However, the process of viral assembly and... | Persistent infection with hepatitis C virus (HCV) is a common cause of chronic liver disease, and may lead to clinically severe cirrhosis and/or hepatocellular carcinoma [1],[2]. Over the two decades that have elapsed since its discovery [3], much has been learned about HCV, the proteins it encodes, and their roles in ... |
10.1371/journal.ppat.1000008 | Adenylyl Cyclase α and cAMP Signaling Mediate Plasmodium Sporozoite Apical Regulated Exocytosis and Hepatocyte Infection | Malaria starts with the infection of the liver of the host by Plasmodium sporozoites, the parasite form transmitted by infected mosquitoes. Sporozoites migrate through several hepatocytes by breaching their plasma membranes before finally infecting one with the formation of an internalization vacuole. Migration through... | Malaria is transmitted through the bite of an infected mosquito that deposits Plasmodium sporozoites under the skin. These sporozoites migrate from the skin into the circulation and then enter the liver to start a new infection inside hepatocytes. Sporozoites have the capacity to traverse mammalian cells. They breach t... | Plasmodium, the causative agent of malaria, is transmitted by the bite of infected mosquitoes that inoculate the sporozoite form of the parasite in the host. Sporozoites rapidly migrate to the liver, where they infect hepatocytes, replicate and develop into merozoites, the blood-stage form of the parasite. Plasmodium b... |
10.1371/journal.pgen.1002120 | Independent Chromatin Binding of ARGONAUTE4 and SPT5L/KTF1 Mediates Transcriptional Gene Silencing | Eukaryotic genomes contain significant amounts of transposons and repetitive DNA elements, which, if transcribed, can be detrimental to the organism. Expression of these elements is suppressed by establishment of repressive chromatin modifications. In Arabidopsis thaliana, they are silenced by the siRNA–mediated transc... | Transposons and other repetitive elements occupy vast areas of the eukaryotic genomes. They pose a threat to genome integrity but at the same time regulate expression of many genes and have been proposed to be a major factor contributing to genome evolution. One of the processes responsible for controlling activity of ... | Eukaryotic genomes contain significant amounts of transposons and other repetitive DNA elements, which usually remain transcriptionally inactive. Efficient silencing of transposon transcription is essential for preventing their mobility and for maintaining genome integrity [1]. Transposon silencing has also been hypoth... |
10.1371/journal.pcbi.1005352 | Activated Oncogenic Pathway Modifies Iron Network in Breast Epithelial Cells: A Dynamic Modeling Perspective | Dysregulation of iron metabolism in cancer is well documented and it has been suggested that there is interdependence between excess iron and increased cancer incidence and progression. In an effort to better understand the linkages between iron metabolism and breast cancer, a predictive mathematical model of an expand... | Iron is required for cellular metabolism and growth, but can be toxic due to its ability to cause high oxidative stress and consequently DNA damage. To prevent damage, all organisms that require iron have developed mechanisms to tightly control iron levels. Dysregulation of iron metabolism is detrimental and can contri... | Every aerobic organism requires iron for energy production, DNA synthesis, oxygen transport, and cellular respiration. However, this essential element has the potential to exist in various oxidation states and can enable the formation of reactive oxygen species. To avoid iron toxicity, all organisms requiring iron have... |
10.1371/journal.pgen.1003309 | Complex Patterns of Genomic Admixture within Southern Africa | Within-population genetic diversity is greatest within Africa, while between-population genetic diversity is directly proportional to geographic distance. The most divergent contemporary human populations include the click-speaking forager peoples of southern Africa, broadly defined as Khoesan. Both intra- (Bantu expan... | The Khoesan have received recent attention, as they are the most genetically diverse contemporary human populations. However, Khoesan populations are poorly defined, while archeological evidence suggests a once broader dispersal of click-speaking southern African foragers. Migrations into the regions populated by conte... | Southern Africa is home to populations carrying significant human genomic variation. The analysis of patterns of DNA variation, have placed modern human origins within Africa [1], with the most divergent contemporary lineages found in the indigenous Khoesan inhabitants of southern Africa [2]–[6]. Defined by their use o... |
10.1371/journal.ppat.1004690 | Rational Development of an Attenuated Recombinant Cyprinid Herpesvirus 3 Vaccine Using Prokaryotic Mutagenesis and In Vivo Bioluminescent Imaging | Cyprinid herpesvirus 3 (CyHV-3) is causing severe economic losses worldwide in common and koi carp industries, and a safe and efficacious attenuated vaccine compatible with mass vaccination is needed. We produced single deleted recombinants using prokaryotic mutagenesis. When producing a recombinant lacking open readin... | Common carp, and its colorful ornamental variety koi, is one of the most economically valuable species in aquaculture. Since the late 1990s, the common and koi carp culture industries have suffered devastating worldwide losses due to cyprinid herpesvirus 3 (CyHV-3). In the present study, we report the development of an... | Aquaculture is currently one of the world’s fastest growing food production sectors, with an annual growth rate of 6.2% between 2000 and 2012 [1]. Global aquaculture currently provides half of the fish consumed worldwide. However, aquaculture is suffering important economic losses due to outbreaks of infectious and par... |
10.1371/journal.pntd.0001807 | Secondary Mapping of Lymphatic Filariasis in Haiti-Definition of Transmission Foci in Low-Prevalence Settings | To eliminate Lymphatic filariasis (LF) as a public health problem, the World Health Organization (WHO) recommends that any area with infection prevalence greater than or equal to 1% (denoted by presence of microfilaremia or antigenemia) should receive mass drug administration (MDA) of antifilarial drugs for at least fi... | Lymphatic filariasis (LF) is among the leading causes of disability among tropical diseases and is caused by a mosquito-transmitted parasite but can be prevented using mass drug therapy and vector-control. In recent years, an international effort has been mounted to eliminate LF. In order to focus limited resources on ... | Lymphatic filariasis (LF) is one of 13 neglected tropical diseases (NTDs) known to chronically infect some of the worlds' poorest individuals [1]. While LF has been shown to be endemic in over 80 countries world-wide, it is one of six diseases that were deemed to be eradicable in 1993 by the International Task Force fo... |
10.1371/journal.pbio.2006812 | Attention promotes the neural encoding of prediction errors | The encoding of sensory information in the human brain is thought to be optimised by two principal processes: ‘prediction’ uses stored information to guide the interpretation of forthcoming sensory events, and ‘attention’ prioritizes these events according to their behavioural relevance. Despite the ubiquitous contribu... | The human brain is theorised to operate like a sophisticated hypothesis tester, using past experience to generate a model of the external world, testing predictions of this model against incoming sensory evidence, and generating a ‘prediction error’ signal that updates the model when predictions and sensory evidence do... | Perception is believed to arise from a process of active inference [1], during which the brain retrieves information from past experiences to build predictive models of likely future occurrences and compares these predictions with incoming sensory evidence [2,3]. In support of the idea that prediction increases the eff... |
10.1371/journal.ppat.1000643 | Mycobacteria Exploit Host Hyaluronan for Efficient Extracellular Replication | In spite of the importance of hyaluronan in host protection against infectious organisms in the alveolar spaces, its role in mycobacterial infection is unknown. In a previous study, we found that mycobacteria interact with hyaluronan on lung epithelial cells. Here, we have analyzed the role of hyaluronan after mycobact... | Mycobacterium tuberculosis and Mycobacterium bovis are major bacterial pathogens that kill approximately 2 million people annually by causing tuberculosis. The M. tuberculosis complex has several strategies to parasitize the host. After infection is established, these pathogens are rarely eliminated from the host, and ... | Infectious diseases caused by mycobacteria are serious threats to human health. Tuberculosis is caused by infection with mycobacteria, most frequently with Mycobacterium tuberculosis but also with Mycobacterium bovis, Mycobacterium africanum, Mycobacterium microti, and Mycobacterium canetii and kills around 2 million p... |
10.1371/journal.pcbi.1003069 | The Impact of a Ligand Binding on Strand Migration in the SAM-I Riboswitch | Riboswitches sense cellular concentrations of small molecules and use this information to adjust synthesis rates of related metabolites. Riboswitches include an aptamer domain to detect the ligand and an expression platform to control gene expression. Previous structural studies of riboswitches largely focused on aptam... | Folding dynamics is crucial for RNA function. Riboswitches are a classic example. A typical riboswitch senses the cellular concentration of a small molecule. By refolding itself into a new structure, the riboswitch converts that information into changes in rates for synthesis of related metabolites. Understanding how t... | Riboswitches reveal the versatility of Ribonucleic Acid (RNA) folding, and its remarkable biological impact. They are folded mRNAs that sense cellular metabolite levels and control expression of downstream genes [1]–[4]. Design of altered or novel riboswitches has been suggested for bioengineering applications [5]–[9].... |
10.1371/journal.pcbi.1000120 | Using Expression Profiles of Caenorhabditis elegans
Neurons To Identify Genes That Mediate Synaptic Connectivity | Synaptic wiring of neurons in Caenorhabditis elegans is largely
invariable between animals. It has been suggested that this feature stems from
genetically encoded molecular markers that guide the neurons in the final stage
of synaptic formation. Identifying th... | Synaptic wiring in the nematode Caenorhabditis elegans is
largely invariant between individuals, suggesting that this wiring is
genetically encoded. This is in essence the chemoaffinity hypothesis suggested
by Roger Sperry. However, proving this hypothesis in ... | The nervous system of Caenorhabditis elegans has exactly 302 neurons
with a simple gross morphology, often having only a single, unbranched process.
Processes run together in parallel bundles, forming synapses to adjacent processes.
The neuronal bodies and their processes... |
10.1371/journal.pntd.0005522 | Detecting and enumerating soil-transmitted helminth eggs in soil: New method development and results from field testing in Kenya and Bangladesh | Globally, about 1.5 billion people are infected with at least one species of soil-transmitted helminth (STH). Soil is a critical environmental reservoir of STH, yet there is no standard method for detecting STH eggs in soil. We developed a field method for enumerating STH eggs in soil and tested the method in Banglades... | Intestinal worm infections are common in populations living in tropical, low-income countries. People primarily become infected when they consume intestinal worm eggs from contaminated water, hands, and food. Intestinal worm eggs are transmitted from infected people and spread through the environment, particularly via ... | Almost one quarter of the world’s population is infected with at least one species of soil-transmitted helminth (STH) [1]. South Asia, Southeast Asia, and Sub-Saharan Africa are the regions with the highest prevalence [1]. Ascaris and Trichuris infection is spread via an environmentally-mediated fecal-oral transmission... |
10.1371/journal.pgen.1007163 | Identification of an elaborate NK-specific system regulating HLA-C expression | The HLA-C gene appears to have evolved in higher primates to serve as a dominant source of ligands for the KIR2D family of inhibitory MHC class I receptors. The expression of NK cell-intrinsic MHC class I has been shown to regulate the murine Ly49 family of MHC class I receptors due to the interaction of these receptor... | It has been proposed that the human HLA-C gene evolved in higher primates to serve as a ligand for the KIR family of inhibitory receptors for MHC class I that are expressed by natural killer (NK) cells and regulate their activity. NK cell potential is determined by the level of MHC class I on surrounding cells and on t... | Natural Killer (NK) cells use two major receptor systems to detect alterations in the expression of MHC class I on potential target cells: the CD94:NKG2A receptor recognizing non-classical HLA-E, and the MHC class I receptors represented by Ly49 in the mouse and KIR in humans [1]. The recognition of HLA-E by NKG2A is d... |
10.1371/journal.pgen.1005973 | FgPrp4 Kinase Is Important for Spliceosome B-Complex Activation and Splicing Efficiency in Fusarium graminearum | PRP4 encodes the only kinase among the spliceosome components. Although it is an essential gene in the fission yeast and other eukaryotic organisms, the Fgprp4 mutant was viable in the wheat scab fungus Fusarium graminearum. Deletion of FgPRP4 did not block intron splicing but affected intron splicing efficiency in ove... | In eukaryotic organisms, many genes containing introns that need to be spliced by the spliceosome after transcription. Among all the spliceosome components, Prp4 is the only protein kinase. Unlike other organisms, deletion of the FgPRP4 kinase gene was not lethal in the wheat scab fungus Fusarium graminearum. In this s... | Pre-mRNA splicing is mediated by the spliceosome that is formed by ordered interaction of the U1, U2, U4/U6, U5 snRNPs, and non-snRNP proteins [1]. U1 and U2 first interact with the 5’-splice site (5’-ss) and the branch point (BP) of the introns in pre-mRNA to generate the A complex. The A complex is then converted to ... |
10.1371/journal.pcbi.1004091 | Protein Sectors: Statistical Coupling Analysis versus Conservation | Statistical coupling analysis (SCA) is a method for analyzing multiple sequence alignments that was used to identify groups of coevolving residues termed “sectors”. The method applies spectral analysis to a matrix obtained by combining correlation information with sequence conservation. It has been asserted that the pr... | Statistical analyses of alignments of evolutionarily related protein sequences have been proposed as a method for obtaining information about protein structure and function. One such method, called statistical coupling analysis, identifies patterns of correlated mutations and uses them to find groups of coevolving resi... | A fundamental question in biology is the relation between the amino acid sequence of a protein and its function and three-dimensional structure. Given the rapid growth in the sequence data available from many organisms, it has become possible to use statistical sequence analysis to approach this question. Based on sequ... |
10.1371/journal.pmed.1002717 | Small for gestational age and risk of childhood mortality: A Swedish population study | Small for gestational age (SGA) has been associated with increased risks of stillbirth and neonatal mortality, but data on long-term childhood mortality are scarce. Maternal antenatal care, including globally reducing the risk of SGA birth, may be key to achieving the Millennium Development Goal of reducing under-5 mor... | Small for gestational age (SGA) occurs in more than 30 million infants every year.
SGA has been associated with increased risks of stillbirth and neonatal mortality, but data on long-term childhood mortality are scarce.
We evaluated the association between SGA and mortality from 28 days after birth to 18 years of age, ... | The Barker hypothesis proposes that intrauterine growth restriction may cause cardiovascular disease in middle and old age [1–3]. Some data indicate that fetal growth may also influence other diseases in adulthood [4,5], although confounding remains an issue [6].
Small for gestational age (SGA) refers to newborns with... |
10.1371/journal.pcbi.1004841 | Modeling the Excess Cell Surface Stored in a Complex Morphology of Bleb-Like Protrusions | Cells transition from spread to rounded morphologies in diverse physiological contexts including mitosis and mesenchymal-to-amoeboid transitions. When these drastic shape changes occur rapidly, cell volume and surface area are approximately conserved. Consequently, the rounded cells are suddenly presented with a severa... | Individual cells must have the capability for rapid morphological transformations under various physiological conditions. One of the most drastic shape transformations occurs during the transition from spread to rounded morphologies. When this transition occurs rapidly, there is insufficient time for significant change... | Cells maintain their structural integrity while being flexible enough to adopt a variety of shapes. In general, it is the cytoskeleton of eukaryotic cells that drives shape transformation leading to cell movement and provides the structural support to the cytoplasm and the means to resist external forces. The periphery... |
10.1371/journal.ppat.1002677 | Reversing the Resistance Phenotype of the Biomphalaria glabrata Snail Host Schistosoma mansoni Infection by Temperature Modulation | Biomphalaria glabrata snails that display either resistant or susceptible phenotypes to the parasitic trematode, Schistosoma mansoni provide an invaluable resource towards elucidating the molecular basis of the snail-host/schistosome relationship. Previously, we showed that induction of stress genes either after heat-s... | Biomphalaria glabrata snails that are either resistant or susceptible to the parasite, Schistosoma mansoni, have been an invaluable resource in studies aimed at understanding the molecular basis of the snail/schistosome interaction. Schistosomes cause the chronic debilitating disease schistosomiasis. Thus, it is hoped ... | Schistosomes are parasitic trematodes that cause the chronic debilitating disease schistosomiasis, a neglected tropical disease that persists in over 70 countries of the developing world. It is estimated that at least 200 million people are chronically infected with the parasite with another 800 million remaining at ri... |
10.1371/journal.pntd.0007203 | Efficacy of novel indoor residual spraying methods targeting pyrethroid-resistant Aedes aegypti within experimental houses | Challenges in maintaining high effectiveness of classic vector control in urban areas has renewed the interest in indoor residual spraying (IRS) as a promising approach for Aedes-borne disease prevention. While IRS has many benefits, application time and intrusive indoor applications make its scalability in urban areas... | Vector control is the primary strategy for managing Aedes aegypti and reducing transmission of Aedes-borne diseases; however, the indoor resting behavior of Ae. aegypti and the evolution of insecticide resistance reduces the effectiveness of many vector control tactics. Indoor residual spraying (IRS) is effective again... | Vector control is the principal approach for managing Aedes aegypti and reducing transmission of Aedes-borne diseases (ABD; e.g., dengue, chikungunya, Zika). Implementation of vector control targeting ABDs has primarily been in response to reports of virus transmission, using methods such as truck-mounted ultra-low vol... |
10.1371/journal.pgen.1002284 | A Barcode Screen for Epigenetic Regulators Reveals a Role for the NuB4/HAT-B Histone Acetyltransferase Complex in Histone Turnover | Dynamic modification of histone proteins plays a key role in regulating gene expression. However, histones themselves can also be dynamic, which potentially affects the stability of histone modifications. To determine the molecular mechanisms of histone turnover, we developed a parallel screening method for epigenetic ... | Packaging of eukaryotic genomes by the histone proteins influences many processes that use the DNA, such as transcription, repair, and replication. One well-known mechanism of regulation of histone function is the covalent modification of histone proteins. Replacement of modified histones by new histones has recently e... | The epigenetic landscape in the cell is dynamic and shaped by histone modifying and demodifying enzymes. In addition, histones themselves can also be dynamic; they can be moved along the DNA through the action of ATP-dependent nucleosome remodeling enzymes or can be evicted and replaced by new histones. Many histone mo... |
10.1371/journal.pbio.2001104 | Climate-Related Local Extinctions Are Already Widespread among Plant and Animal Species | Current climate change may be a major threat to global biodiversity, but the extent of species loss will depend on the details of how species respond to changing climates. For example, if most species can undergo rapid change in their climatic niches, then extinctions may be limited. Numerous studies have now documente... | Climate change is an important threat to the world’s plant and animal species, including species on which humans depend. However, predicting how species will respond to future climate change is very difficult. In this study, I analyze the extinctions caused by the climate change that has already occurred. Numerous stud... | Anthropogenic climate change may be a major driver of biodiversity loss in the next 100 years, but the possible impacts of climate change on species survival remain highly uncertain [1–3]. Global mean annual temperatures increased by ~0.85°C between 1880 and 2012 and are likely to rise by an additional 1°C to 4°C by 21... |
10.1371/journal.pbio.1002582 | A Low-Correlation Resting State of the Striatum during Cortical Avalanches and Its Role in Movement Suppression | During quiet resting behavior, involuntary movements are suppressed. Such movement control is attributed to cortico-basal ganglia loops, yet population dynamics within these loops during resting and their relation to involuntary movements are not well characterized. Here, we show by recording cortical and striatal ongo... | Even in the absence of apparent motor output, the brain produces a rich repertoire of neuronal activity patterns known as “resting state” activity. In the outer layer of the cortex, resting state patterns emerge as neuronal avalanches, precisely scale-invariant spatiotemporal bursts that often engage large populations ... | In the absence of specific sensory input or motor output, the brain nevertheless is highly active. In the cortex, such resting activity exhibits long-range spatial and temporal correlations [1–3], with intermittent neuronal bursts described by power laws and defined as neuronal avalanches [4]. Neuronal avalanches have ... |
10.1371/journal.pcbi.1006315 | Irrelevance by inhibition: Learning, computation, and implications for schizophrenia | Symptoms of schizophrenia may arise from a failure of cortical circuits to filter-out irrelevant inputs. Schizophrenia has also been linked to disruptions in cortical inhibitory interneurons, consistent with the possibility that in the normally functioning brain, these cells are in some part responsible for determining... | Individuals with schizophrenia have difficulty ignoring ideas and experiences that most people would treat as unimportant. There is evidence that this may be due to changes in neuronal inhibition, suggesting that inhibitory neurons may be involved in learning to ignore irrelevant inputs. By developing a computational m... | Many symptoms of schizophrenia can be understood as an inability of the brain to appropriately assign relevance to environmental stimuli and internal representations. Schizophrenic patients exhibit difficulties filtering-out, or gating, irrelevant external stimuli [1, 2, 3, 4, 5, 6, 7], and delusions may also be the pr... |
10.1371/journal.pgen.1002851 | F-Box Protein Specificity for G1 Cyclins Is Dictated by Subcellular Localization | Levels of G1 cyclins fluctuate in response to environmental cues and couple mitotic signaling to cell cycle entry. The G1 cyclin Cln3 is a key regulator of cell size and cell cycle entry in budding yeast. Cln3 degradation is essential for proper cell cycle control; however, the mechanisms that control Cln3 degradation ... | Most cells only divide when they receive the proper cues. When a cell receives a signal to divide, levels of G1 cyclin proteins increase and drive entry into the cell division cycle. Overexpression of G1 cyclins can drive cells into the cell cycle inappropriately and thus may contribute to the hyperproliferation of can... | The ubiquitin-proteasome system plays an essential role in controlling passage through the eukaryotic cell cycle [1]. A significant fraction of cell cycle-regulated ubiquitination is carried out by SCF (Skp1-Cullin-F-box protein) family ubiquitin ligases, which target numerous cell cycle regulators for proteasomal degr... |
10.1371/journal.pgen.1005943 | Swi1Timeless Prevents Repeat Instability at Fission Yeast Telomeres | Genomic instability associated with DNA replication stress is linked to cancer and genetic pathologies in humans. If not properly regulated, replication stress, such as fork stalling and collapse, can be induced at natural replication impediments present throughout the genome. The fork protection complex (FPC) is thoug... | In every round of the cell cycle, cells must accurately replicate their full genetic information. This process is highly regulated, as defects during DNA replication cause genomic instability, leading to various genetic disorders including cancers. To thwart these problems, cells carry an array of complex mechanisms to... | Eukaryotic cells must accurately replicate their genetic information every cell cycle. However, this process is challenged by the presence of natural impediments throughout the genome that can halt replisome progression, potentially causing genomic instability, a hallmark of cancer and other hereditary disorders [1–4].... |
10.1371/journal.pntd.0001374 | Comparison of Two Multilocus Sequence Based Genotyping Schemes for Leptospira Species | Several sequence based genotyping schemes have been developed for Leptospira spp. The objective of this study was to genotype a collection of clinical and reference isolates using the two most commonly used schemes and compare and contrast the results.
A total of 48 isolates consisting of L. interrogans (n = 40) and L.... | Two independent multilocus sequence based genotyping schemes (denoted here as 7L and 6L for schemes with 7 and 6 loci, respectively) are in use for Leptospira spp., which has led to uncertainty as to which should be adopted by the scientific community. The purpose of this study was to apply the two schemes to a single ... | Leptospirosis is a common zoonotic disease worldwide, with a particularly high prevalence in warm humid countries [1]–[4]. About 350,000 severe cases of leptospirosis are estimated to occur annually, with case fatality reports up to 50% [5]–[7]. Reported cases are likely to be a gross under-estimate of global incidence... |
10.1371/journal.ppat.1003156 | Dual Short Upstream Open Reading Frames Control Translation of a Herpesviral Polycistronic mRNA | The Kaposi's sarcoma-associated herpesvirus (KSHV) protein kinase, encoded by ORF36, functions to phosphorylate cellular and viral targets important in the KSHV lifecycle and to activate the anti-viral prodrug ganciclovir. Unlike the vast majority of mapped KSHV genes, no viral transcript has been identified with ORF36... | Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of multicentric Castleman's disease, primary effusion lymphoma and Kaposi's sarcoma. KSHV expresses a number of transcripts with the potential to generate multiple proteins, yet relies on the cellular translation machinery that is primed to synthesiz... | Translation initiation of eukaryotic mRNAs is dependent on the 5′ mRNA cap and proceeds by ribosomal scanning until recognition of an AUG codon in a favorable context [1], [2]. As a consequence of the translation machinery not engaging start codons at internal positions within the mRNA, eukaryotic transcripts generally... |
10.1371/journal.pgen.1005121 | The Zinc-Finger Antiviral Protein ZAP Inhibits LINE and Alu Retrotransposition | Long INterspersed Element-1 (LINE-1 or L1) is the only active autonomous retrotransposon in the human genome. To investigate the interplay between the L1 retrotransposition machinery and the host cell, we used co-immunoprecipitation in conjunction with liquid chromatography and tandem mass spectrometry to identify cell... | Long INterspersed Element-1 (LINE-1 or L1) is the only active autonomous retrotransposon in the human genome. L1s comprise ~17% of human DNA and it is estimated that an average human genome has ~80–100 active L1s. L1 moves throughout the genome via a “copy-and-paste” mechanism known as retrotransposition. L1 retrotrans... | Long INterspersed Element-1 (LINE-1, also known as L1) sequences comprise ~17% of human DNA and represent the only class of autonomously active retrotransposons in the genome [1]. L1s mobilize (i.e., retrotranspose) throughout the genome via an RNA intermediate by a copy-and-paste mechanism known as retrotransposition ... |
10.1371/journal.pbio.1001183 | Regulation of Nucleotide Excision Repair by UV-DDB: Prioritization of Damage Recognition to Internucleosomal DNA | How tightly packed chromatin is thoroughly inspected for DNA damage is one of the fundamental unanswered questions in biology. In particular, the effective excision of carcinogenic lesions caused by the ultraviolet (UV) radiation of sunlight depends on UV-damaged DNA-binding protein (UV-DDB), but the mechanism by which... | Like all molecules in living organisms, DNA undergoes spontaneous decay and is constantly under attack by endogenous and environmental agents. Unlike other molecules, however, DNA—the blueprint of heredity—cannot be re-created de novo; it can only be copied. The original blueprint must therefore remain pristine. All ki... | Ultraviolet (UV) light generates mutagenic DNA lesions in the skin, primarily 6-4 pyrimidine-pyrimidone photoproducts (6-4PPs) and cyclobutane pyrimidine dimers (CPDs) [1] whose cytotoxic, inflammatory, and carcinogenic effects are mitigated by nucleotide excision repair (NER). Defects in this DNA repair system cause x... |
10.1371/journal.pcbi.1000378 | Differential Affinity and Catalytic Activity of CheZ in E.
coli Chemotaxis | Push–pull networks, in which two antagonistic enzymes control the
activity of a messenger protein, are ubiquitous in signal transduction pathways.
A classical example is the chemotaxis system of the bacterium
Escherichia coli, in which the kinase CheA and ... | In both prokaryotes and eukaryotes, extra- and intracellular signals are often
processed by biochemical networks in which two enzymes together control the
activity of a messenger protein via opposite modification reactions. A
well-known example is the chemotax... | The protein network that controls chemotaxis of Escherichia coli is
arguably the most-studied and best-characterized signal transduction pathway. Its
relative simplicity makes it an ideal model system for studying signal
amplification, integration, transduction, and adapt... |
10.1371/journal.pntd.0004484 | A Heterologous Multiepitope DNA Prime/Recombinant Protein Boost Immunisation Strategy for the Development of an Antiserum against Micrurus corallinus (Coral Snake) Venom | Envenoming by coral snakes (Elapidae: Micrurus), although not abundant, represent a serious health threat in the Americas, especially because antivenoms are scarce. The development of adequate amounts of antielapidic serum for the treatment of accidents caused by snakes like Micrurus corallinus is a challenging task du... | Coral snakes are a group of deadly venomous snakes that exhibit a characteristic red, yellow/white, and black coloured banding pattern. Accidents involving these snakes tend to be very severe or even lethal, causing peripheral nervous system depression with muscle paralysis and vasomotor instability. The only acceptabl... | Envenomation by snakebite is a common and generally harmful, environmental and occupational neglected tropical disease that constitutes a highly relevant public health problem with worldwide mortality estimated to be around 50,000 deaths annually [1]. In the Americas, although most of the registered cases of snake enve... |
10.1371/journal.ppat.1000660 | The Bacterial Defensin Resistance Protein MprF Consists of Separable Domains for Lipid Lysinylation and Antimicrobial Peptide Repulsion | Many bacterial pathogens achieve resistance to defensin-like cationic antimicrobial peptides (CAMPs) by the multiple peptide resistance factor (MprF) protein. MprF plays a crucial role in Staphylococcus aureus virulence and it is involved in resistance to the CAMP-like antibiotic daptomycin. MprF is a large membrane pr... | Certain bacterial immune-evasion factors such as the MprF protein are highly conserved in many bacterial pathogens and represent attractive targets for new ‘anti-virulence’ drugs. MprF, initially discovered in the major human pathogen Staphylococcus aureus, protects bacteria against ‘innate human antibiotics’ such as t... | In order to combat increasingly antibiotic-resistant bacteria such as Staphylococcus aureus, Mycobacterium tuberculosis, Pseudomonas aeruginosa, and enterococci new antimicrobial strategies based on compounds with anti-virulence or anti-fitness properties are increasingly in the focus of research efforts [1],[2]. Bacte... |
10.1371/journal.pbio.1001156 | ESRRA-C11orf20 Is a Recurrent Gene Fusion in Serous Ovarian Carcinoma | Every year, ovarian cancer kills approximately 14,000 women in the United States and more than 140,000 women worldwide. Most of these deaths are caused by tumors of the serous histological type, which is rarely diagnosed before it has disseminated. By deep paired-end sequencing of mRNA from serous ovarian cancers, foll... | Serous ovarian cancer, the most common form of ovarian cancer, is especially lethal because it is usually only detected at a late stage in its progression, after the cancer has spread to other tissues. We searched for molecular markers of this cancer that might provide a better way to detect tumors at a curable stage a... | Ovarian cancer is estimated to kill more than 140,000 women every year [1]. Like most cancers, ovarian cancer has a dismal prognosis once the disease has spread beyond the site of origin [2]. The histological subtypes of ovarian cancer differ substantially in their molecular features and natural history and can be cons... |
10.1371/journal.pbio.1001460 | The Cell Cycle Timing of Centromeric Chromatin Assembly in Drosophila Meiosis Is Distinct from Mitosis Yet Requires CAL1 and CENP-C | CENP-A (CID in flies) is the histone H3 variant essential for centromere specification, kinetochore formation, and chromosome segregation during cell division. Recent studies have elucidated major cell cycle mechanisms and factors critical for CENP-A incorporation in mitosis, predominantly in cultured cells. However, w... | Centromeres are regions of eukaryotic chromosomes that recruit the kinetochores and are essential for faithful segregation of DNA during all cell divisions. The centromere-specific histone H3 variant CENP-A accumulates at the centromere, defining this region, and is maintained throughout cellular generations by epigene... | Centromeres are key regions of eukaryotic chromosomes that ensure proper chromosome segregation during cell divisions. In most eukaryotes, centromere identity is defined epigenetically by the presence of a centromere-specific histone H3 variant CENP-A (CID in flies, CENH3 in some organisms) [1]. Improper regulation of ... |
10.1371/journal.ppat.1004694 | Interaction between the Type III Effector VopO and GEF-H1 Activates the RhoA-ROCK Pathway | Vibrio parahaemolyticus is an important pathogen that causes food-borne gastroenteritis in humans. The type III secretion system encoded on chromosome 2 (T3SS2) plays a critical role in the enterotoxic activity of V. parahaemolyticus. Previous studies have demonstrated that T3SS2 induces actin stress fibers in various ... | Many bacterial pathogens manipulate the actin cytoskeleton of mammalian cells to establish pathogenesis via invasion, to evade killing by phagocytes, to disrupt a barrier function, and to induce inflammation caused by translocation type III secretion (T3S) effector proteins. We demonstrated that the T3S effector protei... | Vibrio parahaemolyticus is a Gram-negative halophilic bacterium that causes acute gastroenteritis in humans after the consumption of contaminated raw or undercooked seafood. The emergence of pandemic strains poses a worldwide health threat [1]. V. parahaemolyticus possesses two type III secretion systems (T3SSs): T3SS1... |
10.1371/journal.ppat.1003242 | HIV Restriction by APOBEC3 in Humanized Mice | Innate immune restriction factors represent important specialized barriers to zoonotic transmission of viruses. Significant consideration has been given to their possible use for therapeutic benefit. The apolipoprotein B mRNA editing enzyme catalytic polypeptide 3 (APOBEC3) family of cytidine deaminases are potent immu... | The APOBEC3 family of proteins is a potent cellular defense mechanism capable of restricting a broad range of viruses including HIV. HIV requires a critical accessory protein, Vif, which targets APOBEC3 for degradation thereby shielding its genome from lethal mutagenesis. Previous in vitro studies have shown that in th... | Innate immune restriction factors embody specialized barriers to zoonotic transmission of viruses. Substantial consideration has been given to their potential use for therapeutic benefit [1], [2]. The apolipoprotein B mRNA editing enzyme catalytic polypeptide 3 (APOBEC3) family of cytidine deaminases are potent innate ... |
10.1371/journal.pgen.1003854 | Xbp1 Directs Global Repression of Budding Yeast Transcription during the Transition to Quiescence and Is Important for the Longevity and Reversibility of the Quiescent State | Pure populations of quiescent yeast can be obtained from stationary phase cultures that have ceased proliferation after exhausting glucose and other carbon sources from their environment. They are uniformly arrested in the G1 phase of the cell cycle, and display very high thermo-tolerance and longevity. We find that G1... | Complex organisms depend on populations of non-dividing quiescent cells for their controlled growth, development and tissue renewal. These quiescent cells are maintained in a resting state, and divide only when stimulated to do so. Unscheduled exit or failure to enter this quiescent state results in uncontrolled prolif... | Budding yeast that are grown in rich glucose-containing media and are allowed to naturally exhaust their carbon source undergo a series of changes that enable a significant fraction of the cells, primarily daughter cells, to enter a protective quiescent (Q) state [1]. As yeast cells transition to quiescence, they shift... |
10.1371/journal.pgen.1006407 | Ancient Out-of-Africa Mitochondrial DNA Variants Associate with Distinct Mitochondrial Gene Expression Patterns | Mitochondrial DNA (mtDNA) variants have been traditionally used as markers to trace ancient population migrations. Although experiments relying on model organisms and cytoplasmic hybrids, as well as disease association studies, have served to underline the functionality of certain mtDNA SNPs, only little is known of th... | The mitochondrion is an organelle found in all cells of our body and plays a significant role in the energy and heat production. This is the only organelle in animal cells harboring its own genome outside of the nucleus. Mitochondrial DNA (mtDNA) variants have been traditionally used as neutral markers to trace ancient... | Genetic variants in the nuclear and mitochondrial genomes have been traditionally used to trace the ancient global migration paths of different human populations [1, 2]. Such studies assumed most variants to be neutral and hence merely reflective of the age of the populations studied. However, accumulating evidence sug... |
10.1371/journal.pgen.1003571 | Computational Identification of Diverse Mechanisms Underlying Transcription Factor-DNA Occupancy | ChIP-based genome-wide assays of transcription factor (TF) occupancy have emerged as a powerful, high-throughput method to understand transcriptional regulation, especially on a global scale. This has led to great interest in the underlying biochemical mechanisms that direct TF-DNA binding, with the ultimate goal of co... | Chromatin Immunoprecipitation (ChIP)-based genome-wide assays of transcription factor (TF) occupancy have emerged as a powerful, high throughput method to understand transcriptional regulation, especially on a global scale. Here, we utilize 45 ChIP-chip and ChIP-SEQ data sets from Drosophila to explore the underlying m... | A major challenge in the analysis of genomic sequences is the annotation of cis-regulatory elements. Significant progress has been made towards this goal through high throughput methods such as ChIP-chip and ChIP-SEQ that describe the locations where specific transcription factors (TFs) bind to the genome in vivo [1]–[... |
10.1371/journal.pgen.1002517 | The Dynamics and Prognostic Potential of DNA Methylation Changes at Stem Cell Gene Loci in Women's Cancer | Aberrant DNA methylation is an important cancer hallmark, yet the dynamics of DNA methylation changes in human carcinogenesis remain largely unexplored. Moreover, the role of DNA methylation for prediction of clinical outcome is still uncertain and confined to specific cancers. Here we perform the most comprehensive st... | DNA methylation is an important chemical modification of DNA that can affect and regulate the activity of genes in human tissue. Abnormal DNA methylation and its subsequent effects on gene activity are a hallmark of cancer, yet when precisely these DNA methylation changes occur and how they contribute to the developmen... | Aberrant DNA methylation is one of the most important cancer hallmarks [1], yet its precise role in carcinogenesis and clinical prognosis remains ill-defined [2]. Indeed, the dynamical changes in DNA methylation that happen during carcinogenesis, in particular those prior to morphological changes, have not yet been exp... |
10.1371/journal.pgen.1006054 | Ubr3, a Novel Modulator of Hh Signaling Affects the Degradation of Costal-2 and Kif7 through Poly-ubiquitination | Hedgehog (Hh) signaling regulates multiple aspects of metazoan development and tissue homeostasis, and is constitutively active in numerous cancers. We identified Ubr3, an E3 ubiquitin ligase, as a novel, positive regulator of Hh signaling in Drosophila and vertebrates. Hh signaling regulates the Ubr3-mediated poly-ubi... | Hedgehog signaling regulates many important biological processes and has been linked to developmental disorders, wound healing, and cancer. Although the major components in the pathway have been well studied in Drosophila and vertebrates, how the signaling is regulated by different modulators is not well understood. He... | Hedgehog (Hh) signaling regulates numerous developmental processes and is implicated in multiple cancers, wound healing and pain sensation in adults [1–3]. The Hh ligand acts as a morphogen to induce differential cell responses based on distinct activity thresholds of its signaling transduction cascade [4–6]. Mis-regul... |
10.1371/journal.ppat.1002820 | Germline Transgenesis and Insertional Mutagenesis in Schistosoma mansoni Mediated by Murine Leukemia Virus | Functional studies will facilitate characterization of role and essentiality of newly available genome sequences of the human schistosomes, Schistosoma mansoni, S. japonicum and S. haematobium. To develop transgenesis as a functional approach for these pathogens, we previously demonstrated that pseudotyped murine leuke... | Schistosomes, or blood flukes, are responsible for the major neglected tropical disease called schistosomiasis, which afflicts over 200 million people in impoverished regions of the developing world. The genome sequence of these parasites has been decoded. Integration sites of retroviral transgenes into the chromosomes... | The schistosomes are considered the most important helminth pathogens in terms of human morbidity and mortality. More than 200 million people are infected and a further 800 million at risk of schistosomiasis in tropical and sub-tropical latitudes. Treatment and control of schistosomiasis rely on the anthelmintic drug p... |
10.1371/journal.pcbi.1004454 | Modeling and Classification of Kinetic Patterns of Dynamic Metabolic Biomarkers in Physical Activity | The objectives of this work were the classification of dynamic metabolic biomarker candidates and the modeling and characterization of kinetic regulatory mechanisms in human metabolism with response to external perturbations by physical activity. Longitudinal metabolic concentration data of 47 individuals from 4 differ... | Human metabolism is controlled through basic kinetic regulatory mechanisms, where the overall system aims to maintain a state of homeostasis. In response to external perturbations, such as environmental influences, nutrition or physical exercise, circulating metabolites show specific kinetic response patterns, which ca... | Basic principles in reaction kinetics of biomolecules were described by the work of Guldberg & Waage [1–3] more than 150 years ago and recently resumed by Voit et al., 2015 [4] in their perspective article "150 years of mass action". The underlying concept is the law of mass action, describing the quantitative aspects ... |
10.1371/journal.ppat.1002919 | Structural Organization of Pregenomic RNA and the Carboxy-Terminal Domain of the Capsid Protein of Hepatitis B Virus | The Hepatitis B Virus (HBV) double-stranded DNA genome is reverse transcribed from its RNA pregenome (pgRNA) within the virus core (or capsid). Phosphorylation of the arginine-rich carboxy-terminal domain (CTD) of the HBV capsid protein (Cp183) is essential for pgRNA encapsidation and reverse transcription. However, th... | Many single stranded RNA virus encapsidate their genome through positively-charged domains of their capsid proteins. Hepatitis B virus (HBV) is a double stranded DNA virus which packages a single-stranded RNA pregenome (pgRNA) that is reverse transcribed within the capsid. RNA packaging requires a phosphorylated form o... | Chronic infection with hepatitis B virus (HBV) can lead to liver failure and cirrhosis; it is also the leading cause of hepatocellular carcinoma. Approximately 350 million individuals suffer from chronic HBV worldwide, and HBV contributes to 600,000 deaths per year [1]. It is a major public health issue and also a grea... |
10.1371/journal.ppat.1000933 | Effect of Neuraminidase Inhibitor–Resistant Mutations on Pathogenicity of Clade 2.2 A/Turkey/15/06 (H5N1) Influenza Virus in Ferrets | The acquisition of neuraminidase (NA) inhibitor resistance by H5N1 influenza viruses has serious clinical implications, as this class of drugs can be an essential component of pandemic control measures. The continuous evolution of the highly pathogenic H5N1 influenza viruses results in the emergence of natural NA gene ... | Highly pathogenic avian H5N1 influenza viruses remain a potential pandemic threat. If vaccination is not available in the event of a pandemic, antiviral drugs such as neuraminidase (NA) inhibitors (oseltamivir and zanamivir) will be crucial for disease control. However, the emergence of NA inhibitor–resistant virus mut... | The highly pathogenic avian H5N1 influenza viruses remain of concern as a pandemic threat. Of the 486 cases of human H5N1 infection confirmed between March 2003 and March 2010, ∼60% were lethal [1]. The H5N1 influenza viruses have continuously evolved and increased in genetic diversity: to date, 10 H5 hemagglutinin (HA... |
10.1371/journal.pgen.1005154 | Genome-Wide Negative Feedback Drives Transgenerational DNA Methylation Dynamics in Arabidopsis | Epigenetic variations of phenotypes, especially those associated with DNA methylation, are often inherited over multiple generations in plants. The active and inactive chromatin states are heritable and can be maintained or even be amplified by positive feedback in a transgenerational manner. However, mechanisms contro... | DNA methylation is important for controlling activity of transposable elements and genes. An intriguing feature of DNA methylation in plants is that its pattern can be inherited over multiple generations at high fidelity in a Mendelian manner. However, mechanisms controlling the trans-generational DNA methylation dynam... | Epigenetic variation of gene expression is mediated by chromatin marks, such as modifications of histones and DNA. Importantly, these marks and associated gene expression patterns can be inherited over multiple generations in both animals and plants [1,2]. Transgenerational epigenetic inheritance, especially the one as... |
10.1371/journal.pntd.0005566 | A pilot study to delimit tsetse target populations in Zimbabwe | Tsetse (Glossina sensu stricto) are cyclical vectors of human and animal trypanosomoses, that are presently targeted by the Pan African Tsetse and Trypanosomiasis Eradication Campaign (PATTEC) coordinated by the African Union. In order to achieve effective control of tsetse, there is need to produce elaborate plans to ... | Tse-tse flies are vectors of human and animal trypanosomoses, that are presently targeted by the Pan African Tsetse and Trypanosomiasis Eradication Campaign (PATTEC) coordinated by the African Union. In Zimbabwe, the government has devoted a full section of the veterinary services to tsetse and trypanosomosis control b... | Trypanosomosis is one of the major constraints to rural development in sub-Saharan Africa [1]. Tsetse (Glossina spp.), the primary vectors of animal and human trypanosomosis, are found in the semi-arid, sub-humid and humid lowlands of 37 countries across the continent with a potential distribution range of some 8.7 mil... |
10.1371/journal.pbio.1001915 | Intense Sperm-Mediated Sexual Conflict Promotes Reproductive Isolation in Caenorhabditis Nematodes | Conflict between the sexes over reproductive interests can drive rapid evolution of reproductive traits and promote speciation. Here we show that inter-species mating between Caenorhabditis nematodes sterilizes maternal individuals. The principal effectors of male-induced harm are sperm cells, which induce sterility an... | The sexes have divergent reproductive interests, and conflict arising from this disparity can drive the rapid evolution of reproductive traits and promote speciation. Here we describe a unique reproductive barrier in Caenorhabditis nematodes that is induced by sperm. We found that mating between species can sterilize m... | Rarely do reproductive interests of males and females perfectly align. Sexual selection can accelerate the evolution of the traits and molecules mediating reproductive encounters, and this can lead to sexual conflict [1],[2]. Components of the reproductive system that mediate male-female interactions, such as reproduct... |
10.1371/journal.pntd.0002404 | Molecular Assays for Determining Mycobacterium leprae Viability in Tissues of Experimentally Infected Mice | The inability of Mycobacterium leprae to grow on axenic media has necessitated specialized techniques in order to determine viability of this organism. The purpose of this study was to develop a simple and sensitive molecular assay for determining M. leprae viability directly from infected tissues.
Two M. leprae-specif... | M. leprae, the causative agent of leprosy, cannot be grown on laboratory culture media. This characteristic, along with its extremely long generation time of 12–14 days, makes the study of the pathogenicity of this organism and the experimental testing of new drugs for the treatment of leprosy extremely difficult. We d... | Mycobacterium leprae, an obligate intracellular pathogen and the etiologic agent of leprosy, cannot be grown in axenic medium. This characteristic, in conjunction with its extremely slow generation time of 12–14 days, hinders experimentation addressing even the most fundamental questions regarding its genetics, metabol... |
10.1371/journal.pntd.0003174 | Serological Diagnosis of Paracoccidioidomycosis: High Rate of Inter-laboratorial Variability among Medical Mycology Reference Centers | Serological tests have long been established as rapid, simple and inexpensive tools for the diagnosis and follow-up of PCM. However, different protocols and antigen preparations are used and the few attempts to standardize the routine serological methods have not succeeded.
We compared the performance of six Brazilian ... | Paracoccidioidomycosis (PCM) is a neglected systemic fungal infection prevalent mostly in South America. Serological tests have long been established as rapid, simple and inexpensive tools for the diagnosis and follow-up of PCM. However, different protocols and reagents are used. We compared here the performance of six... | Paracoccidioidomycosis (PCM) is a neglected systemic fungal infection prevalent mostly in South America. Despite the significant progress in several areas of knowledge since it was described by Adolpho Lutz, in 1908, it still shows high rates of morbidity and mortality and low visibility [1]. In rural areas of Brazil t... |
10.1371/journal.ppat.1005235 | Depletion of M. tuberculosis GlmU from Infected Murine Lungs Effects the Clearance of the Pathogen | M. tuberculosis N-acetyl-glucosamine-1-phosphate uridyltransferase (GlmUMtb) is a bi-functional enzyme engaged in the synthesis of two metabolic intermediates N-acetylglucosamine-1-phosphate (GlcNAc-1-P) and UDP-GlcNAc, catalyzed by the C- and N-terminal domains respectively. UDP-GlcNAc is a key metabolite essential fo... | The synthesis of the Mtb cell wall involves a cascade of reactions catalyzed by cytosolic and cell membrane-bound enzymes. The reaction catalyzed by GlmUMtb (an enzyme with acetyltransferase and uridyltransferase activities) generates UDP-GlcNAc, a central nucleotide-sugar building block of the cell wall. Apart from ce... | The cell wall, which contains a number of virulence determinants, is the first line of defence for survival of the pathogen in the hostile host environment [1]. The mycobacterial cell envelope includes three layers of cell membrane and a cell wall made up of peptidoglycan, mycolic acid, arabinogalactan and lipoarabinom... |
10.1371/journal.pbio.2005046 | The human lymph node microenvironment unilaterally regulates T-cell activation and differentiation | The microenvironment of lymphoid organs can aid healthy immune function through provision of both structural and molecular support. In mice, fibroblastic reticular cells (FRCs) create an essential T-cell support structure within lymph nodes, while human FRCs are largely unstudied. Here, we show that FRCs create a regul... | The lymph node microenvironment contains an abundance of immune cells that interact with and within an intricate structural framework created by fibroblastic reticular cells. In mice, fibroblastic reticular cells are known to regulate T-cell activation, proliferation, and function, but in humans, they are poorly unders... | Stromal cells create specialised lymphoid support compartments within secondary lymphoid organs. The signals they feed leukocytes have profound effects in many aspects of activation, proliferation, and differentiation [1].
Fibroblastic reticular cells (FRCs) construct the internal segregated structure of secondary lym... |
10.1371/journal.ppat.1004897 | Natural Killer Cell Sensing of Infected Cells Compensates for MyD88 Deficiency but Not IFN-I Activity in Resistance to Mouse Cytomegalovirus | In mice, plasmacytoid dendritic cells (pDC) and natural killer (NK) cells both contribute to resistance to systemic infections with herpes viruses including mouse Cytomegalovirus (MCMV). pDCs are the major source of type I IFN (IFN-I) during MCMV infection. This response requires pDC-intrinsic MyD88-dependent signaling... | Type I interferons (IFN-I) are innate cytokines crucial for vertebrate antiviral defenses. IFN-I exert antiviral effector functions and orchestrate antiviral immunity. IFN-I are induced early after infection, upon sensing of viral particles or infected cells by immune receptors. Intracellular Toll-like receptors (TLR) ... | Type I interferons (IFN-I) orchestrate vertebrate antiviral defenses through two complementary mechanisms [1]. These cytokines induce multiple Interferon Stimulated Genes (ISG) coding for effector molecules of cell-intrinsic antiviral immunity. IFN-I instruct antiviral innate and adaptive immunity, in part by promoting... |
10.1371/journal.ppat.1006819 | Infection and depletion of CD4+ group-1 innate lymphoid cells by HIV-1 via type-I interferon pathway | Innate lymphoid cells (ILCs) are severely depleted during chronic HIV-1 infection by unclear mechanisms. We report here that human ILC1s comprising of CD4+ and CD4- subpopulations were present in various human lymphoid organs but with different transcription programs and functions. Importantly, CD4+ ILC1s expressed HIV... | Innate lymphoid cells (ILCs), including ILC1, ILC2 and ILC3 populations, represent a novel cellular family of the immune system and have potentials to produce large amounts of T cell-associated cytokines in response to innate stimulation in the absence of specific antigen stimulation. ILCs have emerged as central playe... | Innate lymphoid cells (ILCs) represent a novel family of cellular subsets that produce large amounts of T cell-associated cytokines in response to innate stimulation in the absence of antigens [1, 2]. Based on the expression of specific transcription factors, cell surface markers and signature cytokines [1, 3, 4], ILCs... |
10.1371/journal.pntd.0003596 | Evaluation of the Diagnostic Accuracy of a New Dengue IgA Capture Assay (Platelia Dengue IgA Capture, Bio-Rad) for Dengue Infection Detection | Considering the short lifetime of IgA antibodies in serum and the key advantages of antibody detection ELISAs in terms of sensitivity and specificity, Bio-Rad has just developed a new ELISA test based on the detection of specific anti-dengue IgA. This study has been carried out to assess the performance of this Plateli... | Dengue disease has become a major global public health concern, but an ideal diagnostic test that permits early and rapid diagnosis is not yet available. Improving diagnostic performance in this area is a major challenge and necessitates the development and evaluation of new efficient, accurate methods. According to th... | Caused by any of four dengue virus serotypes (i.e. DENV-1 to DENV-4), dengue infection is currently the most significant arthropod-borne viral disease [1]. Whereas the World Health Organization (WHO) estimated in 2009 that 50–100 million infections occur each year [1], a recent study estimated that 390 million dengue i... |
10.1371/journal.pgen.1002511 | Ultrafast Evolution and Loss of CRISPRs Following a Host Shift in a Novel Wildlife Pathogen, Mycoplasma gallisepticum | Measureable rates of genome evolution are well documented in human pathogens but are less well understood in bacterial pathogens in the wild, particularly during and after host switches. Mycoplasma gallisepticum (MG) is a pathogenic bacterium that has evolved predominantly in poultry and recently jumped to wild house f... | Documenting the evolutionary changes occurring in pathogens when they switch hosts is important for understanding mechanisms of adaptation and rates of evolution. We took advantage of a novel host–pathogen system involving a bacterial pathogen (Mycoplasma gallisepticum, or MG) and a songbird host, the House Finch, to s... | Populations of animals are under constant threat from bacterial pathogens, which can be particularly destructive following a switch to a new host or the evolution of novel virulence mechanisms. Understanding the rate and process of evolutionary change in pathogens is thus important to assessing the risks of pandemics a... |
10.1371/journal.pgen.1004242 | FRA2A Is a CGG Repeat Expansion Associated with Silencing of AFF3 | Folate-sensitive fragile sites (FSFS) are a rare cytogenetically visible subset of dynamic mutations. Of the eight molecularly characterized FSFS, four are associated with intellectual disability (ID). Cytogenetic expression results from CGG tri-nucleotide-repeat expansion mutation associated with local CpG hypermethyl... | Some human genetic diseases are caused by dynamic mutations, or expansions of a short repeated sequence in the genome that can be unstably passed on from generation to generation. A subset of these dynamic mutations known as fragile sites can be seen as a break or gap on the chromosome when cells are cultured under spe... | Dynamic mutations are heritable unstable expansions of short, genomic repeat sequences. Various pathogenic mechanisms have been associated with dynamic mutations [1], [2] and at least 40 neurological, neurodegenerative and neuromuscular disorders are known to be caused by these types of mutations [3], [4]. Expansions o... |
10.1371/journal.ppat.1007041 | HCMV triggers frequent and persistent UL40-specific unconventional HLA-E-restricted CD8 T-cell responses with potential autologous and allogeneic peptide recognition | Immune response against human cytomegalovirus (HCMV) includes a set of persistent cytotoxic NK and CD8 T cells devoted to eliminate infected cells and to prevent reactivation. CD8 T cells against HCMV antigens (pp65, IE1) presented by HLA class-I molecules are well characterized and they associate with efficient virus ... | Understanding the mechanisms of immune control of viral infection is crucial to improve diagnosis and to design efficient immunotherapies. CD8 T lymphocytes are key components of the cellular immunity against human cytomegalovirus (HCMV), a widespread pathogen that cause severe illness and poor outcome in immunocomprom... | Human cytomegalovirus (HCMV; human herpesvirus 5) is the prototype member of β-herpesvirus and a widespread opportunistic pathogen. In healthy individuals, primary infection is asymptomatic and is followed by a life-long, persistent, infection that is controlled by host immune system [1]. Nevertheless, HCMV is a major ... |
10.1371/journal.ppat.1004822 | The EBNA3 Family of Epstein-Barr Virus Nuclear Proteins Associates with the USP46/USP12 Deubiquitination Complexes to Regulate Lymphoblastoid Cell Line Growth | The Epstein-Barr virus (EBV) nuclear proteins EBNA3A, EBNA3B, and EBNA3C interact with the cell DNA binding protein RBPJ and regulate cell and viral genes. Repression of the CDKN2A tumor suppressor gene products p16INK4A and p14ARF by EBNA3A and EBNA3C is critical for EBV mediated transformation of resting B lymphocyte... | Epstein-Barr virus (EBV) is a gammaherpesvirus implicated in the pathogenesis of multiple malignancies, including Burkitt lymphoma, Hodgkin lymphoma, post-transplant lymphoproliferative disease (PTLD), nasopharyngeal carcinoma, and gastric carcinoma. EBV infection of resting B-lymphocytes drives them to proliferate as ... | Epstein-Barr Virus (EBV) is a herpesvirus that establishes lifelong asymptomatic infection in up to 95% of the human population [1]. In vitro, EBV infection of resting B lymphocytes drives them to proliferate as lymphoblastoid cell lines (LCLs) [2,3]. The EBV genome resides in LCLs as a non-integrated episome and expre... |
10.1371/journal.pgen.1000672 | Genetic Determinants of Circulating Sphingolipid Concentrations in European Populations | Sphingolipids have essential roles as structural components of cell membranes and in cell signalling, and disruption of their metabolism causes several diseases, with diverse neurological, psychiatric, and metabolic consequences. Increasingly, variants within a few of the genes that encode enzymes involved in sphingoli... | Although several rare monogenic diseases are caused by defects in enzymes involved in sphingolipid biosynthesis and metabolism, little is known about the major variants that control the circulating levels of these important bioactive molecules. As well as being essential components of plasma membranes and endosomes, sp... | Sphingolipids are essential components of plasma membranes and endosomes and are believed to play critical roles in cell surface protection, protein and lipid transport and sorting, and cellular signalling cascades. They are known to have roles in both health and disease [1],[2]. Several rare monogenic diseases associa... |
10.1371/journal.pntd.0006345 | Seroepidemiology of helminths and the association with severe malaria among infants and young children in Tanzania | The disease burden of Wuchereria bancrofti and Plasmodium falciparum malaria is high, particularly in Africa, and co-infection is common. However, the effects of filarial infection on the risk of severe malaria are unknown. We used the remaining serum samples from a large cohort study in Muheza, Tanzania to describe ve... | In this paper, we used a multiplexed, serologic assessment to identify children with previous or current exposure to or infection with filarial parasites or S. stercoralis (a soil transmitted helminth), enhancing our understanding of co-infections in early childhood. We identified an increasing prevalence of filarial a... | Parasitic helminths and malaria are both highly prevalent globally and overlap extensively in tropical areas [1–3]. In 2016, more than 216 million cases of malaria were estimated to occur with 89 percent of cases occurring in Sub-Saharan Africa [4]. Nearly all cases of severe malaria are due to infection from Plasmodiu... |
10.1371/journal.ppat.1003505 | Discovery of Anthelmintic Drug Targets and Drugs Using Chokepoints in Nematode Metabolic Pathways | Parasitic roundworm infections plague more than 2 billion people (1/3 of humanity) and cause drastic losses in crops and livestock. New anthelmintic drugs are urgently needed as new drug resistance and environmental concerns arise. A “chokepoint reaction” is defined as a reaction that either consumes a unique substrate... | The World Health Organization estimates that 2.9 million people are infected with parasitic roundworms, causing high-morbidity and mortality rates, developmental delays in children, and low productivity of affected individuals. The agricultural industry experiences drastic losses in crop and livestock due to parasitic ... | Parasitic nematode (roundworm) infections impose an enormous burden of morbidity on humanity [1], [2]. Only a few drugs are commonly used to treat nematode infections, creating a dangerous environment for the emergence of drug resistance. Currently, administering anthelmintic drugs on a yearly basis is necessary to bre... |
10.1371/journal.pntd.0005507 | Unraveling Chagas disease transmission through the oral route: Gateways to Trypanosoma cruzi infection and target tissues | Oral transmission of Trypanosoma cruzi, the causative agent of Chagas disease, is the most important route of infection in Brazilian Amazon and Venezuela. Other South American countries have also reported outbreaks associated with food consumption. A recent study showed the importance of parasite contact with oral cavi... | Oral transmission of Trypanosoma cruzi associated with food/beverage consumption is presently an important route of infection in Brazil and Venezuela. Colombia, Bolivia, Argentina and Ecuador have also reported to have acute cases of Chagas disease transmission through the oral route. Significant studies about this for... | Human Chagas disease (American trypanosomiasis) is a neglected tropical illness caused by the protozoan Trypanosoma cruzi. Infection affects 6–8 million people worldwide and is considered a global health problem. Chagas disease is endemic in Mexico, Central America and South America and is also spreading in non-endemic... |
10.1371/journal.pntd.0001739 | Detection of Antibiotic Resistance in Leprosy Using GenoType LepraeDR, a Novel Ready-To-Use Molecular Test | Although leprosy is efficiently treated by multidrug therapy, resistance to first-line (dapsone, rifampin) and to second-line drugs (fluoroquinolones) was described worldwide. Since Mycobacterium leprae is not growing in vitro, phenotypic susceptibility testing requires a one year experiment in the mouse model and this... | Although leprosy is a curable disease using a combination of antibiotics for one year, the transmission is still active with 230,000 new cases in 2010. Drug resistance has been described and may prevent eradication of the disease. The infectious agent causing leprosy, Mycobacterium leprae, is not growing in vitro and a... | Leprosy, the second communicable disease due to mycobacteria after tuberculosis, is still a preoccupying disease as 230 000 new cases have been reported in 2010 (www.who.int/lep/). This disease remains difficult to diagnose and treat in low- and mid-developed countries, especially in rural areas. Global child rate has ... |
10.1371/journal.ppat.1000275 | Viral Mimicry of Cdc2/Cyclin-Dependent Kinase 1 Mediates Disruption of Nuclear Lamina during Human Cytomegalovirus Nuclear Egress | The nuclear lamina is a major obstacle encountered by herpesvirus nucleocapsids in their passage from the nucleus to the cytoplasm (nuclear egress). We found that the human cytomegalovirus (HCMV)-encoded protein kinase UL97, which is required for efficient nuclear egress, phosphorylates the nuclear lamina component lam... | Human cytomegalovirus (HCMV) causes life-threatening disease in transplant patients and people with AIDS, and is also an important cause of birth defects. Like all viruses, HCMV must have a way to leave the host cell, so that it can infect new cells. Moreover, as a member of the herpesvirus family, HCMV replicates its ... | Human cytomegalovirus (HCMV) is a pathogen that is especially dangerous in immunocompromised individuals [1]. As is true for all viruses, HCMV replication depends on the interplay between viral and host cell functions. An important example of this interplay is nuclear egress, a stage during which herpesviral DNA-contai... |
10.1371/journal.pcbi.1005332 | Computational investigation of sphingosine kinase 1 (SphK1) and calcium dependent ERK1/2 activation downstream of VEGFR2 in endothelial cells | Vascular endothelial growth factor (VEGF) is a powerful regulator of neovascularization. VEGF binding to its cognate receptor, VEGFR2, activates a number of signaling pathways including ERK1/2. Activation of ERK1/2 is experimentally shown to involve sphingosine kinase 1 (SphK1) activation and its calcium-dependent tran... | Vascular endothelial growth factor (VEGF) signaling is a potent regulator of angiogenesis, the growth and development of new vessels out of a preexisting vascular network. Angiogenesis requires enhanced survival, proliferation, and motility of the vascular endothelial cells. Crucial signaling endpoints in VEGF-mediated... | Angiogenesis is the growth of new capillaries from the pre-existing vasculature. The process of angiogenesis involves increased proliferation, survival, and migration of the endothelial cells that form the foundation of a developing vascular bed [1]. This process is critically involved in both health and disease [2]. P... |
10.1371/journal.ppat.1006126 | Toxoplasma gondii GRA7-Targeted ASC and PLD1 Promote Antibacterial Host Defense via PKCα | Tuberculosis is a global health problem and at least one-third of the world’s population is infected with Mycobacterium tuberculosis (MTB). MTB is a successful pathogen that enhances its own intracellular survival by inhibiting inflammation and arresting phago-lysosomal fusion. We previously demonstrated that Toxoplasm... | We previously demonstrated that Toxoplasma gondii (T. gondii) dense granule antigen (GRA) 7 interacts with TRAF6 via MyD88, enabling innate immune responses in macrophages and effective protection against T. gondii infection in vivo. However, its exact role and how it regulates host innate immune responses have not bee... | Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (MTB) [1]. The World Health Organization reported that in 2014, 9.6 million cases and 1.5 million deaths were globally [2]. Recent developments in TB drug-development strategies (including new and repurposed antimicrobials and host-directed... |
10.1371/journal.ppat.1005834 | Latency Entry of Herpes Simplex Virus 1 Is Determined by the Interaction of Its Genome with the Nuclear Environment | Herpes simplex virus 1 (HSV-1) establishes latency in trigeminal ganglia (TG) sensory neurons of infected individuals. The commitment of infected neurons toward the viral lytic or latent transcriptional program is likely to depend on both viral and cellular factors, and to differ among individual neurons. In this study... | Establishment of latency of herpes simplex virus 1 (HSV-1) at the cellular level results from the combination of a series of complex molecular events involving cellular and viral-associated features. HSV-1 establishes latency in trigeminal ganglia (TG) sensory neurons. HSV-1 genomes remain as extrachromosomal DNA; thei... | Herpes simplex virus 1 (HSV-1) is a neurotropic virus that establishes a life-long latent infection in the trigeminal ganglia (TG) (or Gasserian ganglia) of the infected human host. From time to time the virus asymptomatically or symptomatically reactivates from the latency stage producing epithelial lesions, most of t... |
10.1371/journal.pbio.1002464 | Structure, Regulation, and Inhibition of the Quorum-Sensing Signal Integrator LuxO | In a process called quorum sensing, bacteria communicate with chemical signal molecules called autoinducers to control collective behaviors. In pathogenic vibrios, including Vibrio cholerae, the accumulation of autoinducers triggers repression of genes responsible for virulence factor production and biofilm formation. ... | Bacteria communicate with one another and orchestrate group behaviors using a process called quorum sensing. The types of behaviors controlled by quorum sensing are typically unproductive when performed by a single bacterium acting alone but become effective when undertaken in unison by the group. Importantly, quorum s... | Quorum sensing is a widespread process of bacterial cell–cell communication that allows bacteria to monitor and respond to fluctuations in cell number and the species composition of bacterial consortia. Quorum sensing relies on the production, release, and subsequent group-wide detection of extracellular signal molecul... |
10.1371/journal.pbio.1002474 | Membrane Tension Acts Through PLD2 and mTORC2 to Limit Actin Network Assembly During Neutrophil Migration | For efficient polarity and migration, cells need to regulate the magnitude and spatial distribution of actin assembly. This process is coordinated by reciprocal interactions between the actin cytoskeleton and mechanical forces. Actin polymerization-based protrusion increases tension in the plasma membrane, which in tur... | How cells regulate the size and number of their protrusions for efficient polarity and motility is a fundamental question in cell biology. We recently found that immune cells known as neutrophils use physical forces to regulate this process. Actin polymerization-based protrusion stretches the plasma membrane, and this ... | Cells use multiple mechanisms of spatial signal propagation to orchestrate behaviors like polarity and motility. Well-characterized modes of information propagation include post-translational modifications, nucleotide binding and hydrolysis, and diffusion of signals from one subcellular location to another. More recent... |
10.1371/journal.pcbi.1004610 | From Sensory Signals to Modality-Independent Conceptual Representations: A Probabilistic Language of Thought Approach | People learn modality-independent, conceptual representations from modality-specific sensory signals. Here, we hypothesize that any system that accomplishes this feat will include three components: a representational language for characterizing modality-independent representations, a set of sensory-specific forward mod... | When viewing an object, people perceive the object’s shape. Similarly, when grasping the same object, they also perceive its shape. In general, the perceived shape is identical in these two scenarios, illustrating modality invariance, an important type of perceptual constancy. Modality invariance suggests that people i... | While eating breakfast, you might see your coffee mug, grasp your coffee mug, or both. When viewing your mug, your visual system extracts and represents the shape of your mug. Similarly, when grasping your mug, your haptic system also extracts and represents the shape of your mug. Are the representations acquired when ... |
10.1371/journal.pbio.1001234 | The Discovery of New Deep-Sea Hydrothermal Vent Communities in the Southern Ocean and Implications for Biogeography | Since the first discovery of deep-sea hydrothermal vents along the Galápagos Rift in 1977, numerous vent sites and endemic faunal assemblages have been found along mid-ocean ridges and back-arc basins at low to mid latitudes. These discoveries have suggested the existence of separate biogeographic provinces in the Atla... | Deep-sea hydrothermal vents are mainly associated with seafloor spreading at mid-ocean ridges and in basins near volcanic island arcs. They host animals found nowhere else that derive their energy not from the sun but from bacterial oxidation of chemicals in the vent fluids, particularly hydrogen sulphide. Hydrothermal... | The discovery of hydrothermal vents along the Galápagos Ridge in 1977 [1] led to the identification of chemoautotrophic symbiosis [2] and forced marine biologists to reassess the contribution chemosynthesis makes to marine primary production, particularly in the deep sea, where it supports a high biomass in an otherwis... |
10.1371/journal.pgen.1000938 | Myeloid Cell-Restricted Insulin Receptor Deficiency Protects Against Obesity-Induced Inflammation and Systemic Insulin Resistance | A major component of obesity-related insulin resistance is the establishment of a chronic inflammatory state with invasion of white adipose tissue by mononuclear cells. This results in the release of pro-inflammatory cytokines, which in turn leads to insulin resistance in target tissues such as skeletal muscle and live... | Obesity represents a major health burden with steadily increasing incidence. While it is associated with numerous co-morbidities, type 2 diabetes mellitus represents one of the major life-threatening, obesity-related conditions. Over the last years, it has become clear that during the course of obesity development not ... | Obesity in humans and rodents is associated with increased expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF) α, in white adipose tissue (WAT) [1]–[4]. This results from increased cytokine expression in WAT and more importantly from infiltration of WAT by macrophages [5]–[7]. Elevated concent... |
10.1371/journal.pntd.0003156 | Evaluation of a Rapid Diagnostic Test for Yaws Infection in a Community Surveillance Setting | Yaws is a non-venereal treponemal infection caused by Treponema pallidum ssp. pertenue. The WHO has launched a worldwide control programme, which aims to eradicate yaws by 2020. The development of a rapid diagnostic test (RDT) for serological diagnosis in the isolated communities affected by yaws is a key requirement f... | Yaws is a bacterial infection closely related to syphilis. The WHO has launched a worldwide campaign to eradicate yaws by 2020. If this goal is to be achieved, programme managers and clinical staff will need access to a rapid diagnostic test (RDT) for yaws that can be used in the remote communities where the disease is... | Yaws is a non-venereal treponemal infection caused by Treponema pallidum ssp. pertenue (T. pertenue) [1] which is currently thought to be endemic in fourteen countries [2]. The emergence of azithromycin as an effective oral agent in the treatment of yaws [3] has prompted renewed calls for a coordinated worldwide progra... |
10.1371/journal.ppat.1004924 | Evidence for a Novel Mechanism of Influenza Virus-Induced Type I Interferon Expression by a Defective RNA-Encoded Protein | Influenza A virus (IAV) defective RNAs are generated as byproducts of error-prone viral RNA replication. They are commonly derived from the larger segments of the viral genome and harbor deletions of various sizes resulting in the generation of replication incompatible viral particles. Furthermore, small subgenomic RNA... | Error-prone polymerase function of RNA viruses can result in expression of defective RNAs harboring internal deletions of various sizes. Small subgenomic RNAs are strong inducers of the antiviral response by serving as pathogen-associated patterns that are predominantly detected by cellular sensors. Recently, it has be... | Influenza A viruses (IAV) belong to the family of Orthomyxoviridae and are characterized by a segmented single-stranded RNA genome with negative orientation. These eight segments encode nine structural and up to seven nonstructural proteins [1–5]. For the production of infectious virus particles at least one copy of ea... |
10.1371/journal.pgen.1006790 | Specification and spatial arrangement of cells in the germline stem cell niche of the Drosophila ovary depend on the Maf transcription factor Traffic jam | Germline stem cells in the Drosophila ovary are maintained by a somatic niche. The niche is structurally and functionally complex and contains four cell types, the escort, cap, and terminal filament cells and the newly identified transition cell. We find that the large Maf transcription factor Traffic jam (Tj) is essen... | Establishment and maintenance of stem cells often depends on associated niche cells. The germline stem cell niche of the Drosophila ovary has been a long-standing model for the analysis of the interactions between stem cells and niche cells. Surprisingly little is known, however, about the mechanisms that pattern this ... | Stem cells retain the capacity for development in differentiated organisms, which is important for tissue growth, homeostasis and regeneration, and for long-term reproductive capability. Stem cells are often associated with a specialized microenvironment, a niche that is essential for the formation, maintenance, and se... |
10.1371/journal.pntd.0006933 | CYP-mediated permethrin resistance in Aedes aegypti and evidence for trans-regulation | Aedes aegypti poses a serious risk to human health due to its wide global distribution, high vector competence for several arboviruses, frequent human biting, and ability to thrive in urban environments. Pyrethroid insecticides remain the primary means of controlling adult A. aegypti populations during disease outbreak... | Cytochrome P450 monooxygenases (CYPs) are one of the most important mechanism of insecticide resistance in mosquitoes. These CYP enzymes break down insecticides into non-toxic forms that can be readily excreted. An increase of CYP-mediated detoxification is commonly found in pyrethroid resistant Aedes aegypti, however ... | Aedes aegypti is an important pest capable of transmitting four important human disease viruses: dengue, yellow fever, chikungunya, and Zika. Dengue, for example, causes morbidity and mortality in 141 countries across the tropical and subtropical regions of the world and is estimated to be a risk to over 50% of the wor... |
10.1371/journal.pntd.0002978 | Transmission and Control of Plasmodium knowlesi: A Mathematical Modelling Study | Plasmodium knowlesi is now recognised as a leading cause of malaria in Malaysia. As humans come into increasing contact with the reservoir host (long-tailed macaques) as a consequence of deforestation, assessing the potential for a shift from zoonotic to sustained P. knowlesi transmission between humans is critical.
A ... | Plasmodium knowlesi is a malaria of macaques which is now recognised as a leading cause of human malaria in Malaysia. Although current human infections are a result of human-macaque contact, there is a potential for P. knowlesi to be transmitted solely among humans. The authors developed a multi-host, multi-site transm... | Despite advances in the control and treatment of malaria more than half the world's population remain at risk of infection and disease. Of the estimated 216 million episodes of disease occurring worldwide in 2010, 13% were estimated to occur in South-East Asia [1]. In 2004, large numbers of malaria cases previously dia... |
10.1371/journal.ppat.1006753 | Long-term persistence and function of hematopoietic stem cell-derived chimeric antigen receptor T cells in a nonhuman primate model of HIV/AIDS | Chimeric Antigen Receptor (CAR) T-cells have emerged as a powerful immunotherapy for various forms of cancer and show promise in treating HIV-1 infection. However, significant limitations are persistence and whether peripheral T cell-based products can respond to malignant or infected cells that may reappear months or ... | Hematopoietic Stem/Progenitor Cell (HSPC) based gene therapy can be used to treat many infectious and genetic diseases. Here, we used an HSPC-based approach to redirect and enhance host immunity against HIV-1. We engineered HSPCs to carry chimeric antigen receptor (CAR) genes that detect and destroy HIV-infected cells.... | HIV-1 specific cytotoxic T lymphocytes mount a key immune response to HIV and are crucial for the control of viremia and the elimination of HIV infected cells. Previous studies have shown that a chimeric antigen receptor containing the CD4 molecule linked to the signaling domain of the T cell receptor ζ chain (CD4CAR) ... |
10.1371/journal.pgen.1005102 | Zinc Finger Independent Genome-Wide Binding of Sp2 Potentiates Recruitment of Histone-Fold Protein Nf-y Distinguishing It from Sp1 and Sp3 | Transcription factors are grouped into families based on sequence similarity within functional domains, particularly DNA-binding domains. The Specificity proteins Sp1, Sp2 and Sp3 are paradigmatic of closely related transcription factors. They share amino-terminal glutamine-rich regions and a conserved carboxy-terminal... | A major question in eukaryotic gene regulation is how transcription factors with similar structural features elicit specific biological responses. We used the three transcription factors Sp1, Sp2 and Sp3 as a paradigm for investigating this question. All three proteins are ubiquitously expressed, and they share glutami... | Eukaryotic transcription factors are grouped into families based on their common structural features. Prototypical zinc finger-containing transcription factors are the evolutionary conserved Specificity proteins/Krüppel-like factors (Sps/Klfs) (reviewed in [1,2,3,4]) that share three consecutive C2H2-type zinc fingers ... |
10.1371/journal.pbio.1001482 | Reciprocal Regulation of Protein Synthesis and Carbon Metabolism for Thylakoid Membrane Biogenesis | Metabolic control of gene expression coordinates the levels of specific gene products to meet cellular demand for their activities. This control can be exerted by metabolites acting as regulatory signals and/or a class of metabolic enzymes with dual functions as regulators of gene expression. However, little is known a... | Metabolic control of gene expression coordinates the levels of specific gene products to meet cellular demand for their activities. This control can be exerted by metabolites acting as regulatory signals on a class of metabolic enzymes with dual functions as regulators of gene expression. However, little is known about... | Accumulating evidence suggests that metabolism and gene expression are tightly linked. For instance, changes in metabolite levels affect protein modification, for example by acetylation or N-glycosylation, which in turn influences signal transduction and gene expression [1]–[3]. In line with this, several metabolic enz... |
10.1371/journal.pntd.0005996 | Characterization of the catalytic center of the Ebola virus L polymerase | Ebola virus (EBOV) causes a severe hemorrhagic fever in humans and non-human primates. While no licensed therapeutics are available, recently there has been tremendous progress in developing antivirals. Targeting the ribonucleoprotein complex (RNP) proteins, which facilitate genome replication and transcription, and pa... | Ebola viruses cause severe hemorrhagic fevers, and were responsible for the devastating Ebola virus disease epidemic in West Africa from 2013 to 2016. While a number of experimental therapeutics against these viruses target the viral polymerase, there are still significant gaps in our knowledge regarding this essential... | Ebola virus (EBOV) is a member of the genus Ebolavirus in the family of Filoviridae, and the causative agent of a severe hemorrhagic fever called Ebola virus disease (EVD) with case fatality rates of up to 90% [1]. While outbreaks are usually of comparatively small scale, the recent EVD epidemic in West Africa involved... |
10.1371/journal.ppat.1005790 | Virus Infection of Plants Alters Pollinator Preference: A Payback for Susceptible Hosts? | Plant volatiles play important roles in attraction of certain pollinators and in host location by herbivorous insects. Virus infection induces changes in plant volatile emission profiles, and this can make plants more attractive to insect herbivores, such as aphids, that act as viral vectors. However, it is unknown if ... | Cucumber mosaic virus, an important pathogen of tomato, causes plants to emit volatile chemicals that attract bumblebees. Bumblebees are important tomato pollinators, but do not transmit this virus. We propose that under natural conditions, helping host reproduction by encouraging bee visitation might represent a ‘payb... | Insects pollinate many plant species, including several major crops [1]. Bees are the single most important insect pollinator group and can be a limiting factor for the success of plant reproduction [1–3]. Consequently, there is strong inter- and intra-specific competition among plants for the attention of pollinators ... |
10.1371/journal.pntd.0007251 | A little goes a long way: Weak vaccine transmission facilitates oral vaccination campaigns against zoonotic pathogens | Zoonotic pathogens such as Ebola and rabies pose a major health risk to humans. One proven approach to minimizing the impact of a pathogen relies on reducing its prevalence within animal reservoir populations using mass vaccination. However, two major challenges remain for vaccination programs that target free-ranging ... | Zoonotic pathogens pose a significant health risk to humans. Mass vaccination programs have shown promise for controlling zoonoses in reservoir populations and, in turn, lessening the health burden posed to neighboring human populations. Despite some significant successes, major logistical challenges remain for program... | Zoonotic pathogens represent a global threat to human welfare. Rabies circulating in domestic dogs in Asia and Africa, for example, results in 59,000 human deaths each year [1]. Ebola, a disease that circulates in non-human primates and bats, killed over 11,000 people during the 2014 outbreak [2]. In addition to the co... |
10.1371/journal.pntd.0001021 | Comparative Gene Expression Analysis throughout the Life Cycle of
Leishmania braziliensis: Diversity of Expression Profiles
among Clinical Isolates | Most of the Leishmania genome is reported to be
constitutively expressed during the life cycle of the parasite, with a few
regulated genes. Inter-species comparative transcriptomics evidenced a low
number of species-specific differences related to ... | Leishmania is a group of parasites (Protozoa, Trypanosomatidae)
responsible for a wide spectrum of clinical forms. Among the factors explaining
this phenotypic polymorphism, parasite features are important contributors. One
approach to identify them consists i... | Leishmania are digenic Protozoan parasites endemic worldwide and
causing a spectrum of diseases in humans collectively referred to as leishmaniasis.
As part of their life cycle, Leishmania alternate between the
alimentary tract of the sandfly vector (where they grow as ex... |
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