doi stringlengths 28 28 | title stringlengths 19 311 | abstract stringlengths 217 5.08k | plain language summary stringlengths 115 4.83k | article stringlengths 3.87k 161k |
|---|---|---|---|---|
10.1371/journal.pgen.1007211 | Th-POK regulates mammary gland lactation through mTOR-SREBP pathway | The Th-inducing POK (Th-POK, also known as ZBTB7B or cKrox) transcription factor is a key regulator of lineage commitment of immature T cell precursors. It is yet unclear the physiological functions of Th-POK besides helper T cell differentiation. Here we show that Th-POK is restrictedly expressed in the luminal epithe... | Th-POK, aka cKrox or ZBTB7B, is a zinc finger transcription factor that specifies the cell fate of immature T cell precursors towards the CD4 lineage. It is yet largely unknown if Th-POK participates in the regulation of other biological processes. It is also not known if Th-POK functions beyond cell fate determination... | Transcription factor Th-POK (Th-inducing POK, also known as ZBTB7B or cKrox) is a key regulator of lineage commitment of immature T cell precursors [1–3]. Loss of Th-POK expression or impaired Th-POK function disrupts the development of CD4 T cells [4], whereas enforced expression of Th-POK results in lineage conversio... |
10.1371/journal.pcbi.1003439 | Consequences of Converting Graded to Action Potentials upon Neural Information Coding and Energy Efficiency | Information is encoded in neural circuits using both graded and action potentials, converting between them within single neurons and successive processing layers. This conversion is accompanied by information loss and a drop in energy efficiency. We investigate the biophysical causes of this loss of information and eff... | As in electronics, many of the brain's neural circuits convert continuous time signals into a discrete-time binary code. Although some neurons use only graded voltage signals, most convert these signals into discrete-time action potentials. Yet the costs and benefits associated with such a switch in signalling mechanis... | Information is encoded, processed and transmitted in neural circuits both as graded potentials (continuous, analogue) and action potentials (pulsatile, digital). Although sensory and chemical synaptic inputs to neurons are graded [1], in most neurons these are converted into a train of action potentials. This conversio... |
10.1371/journal.pntd.0003605 | Geographic Distribution and Mortality Risk Factors during the Cholera Outbreak in a Rural Region of Haiti, 2010-2011 | In 2010 and 2011, Haiti was heavily affected by a large cholera outbreak that spread throughout the country. Although national health structure-based cholera surveillance was rapidly initiated, a substantial number of community cases might have been missed, particularly in remote areas. We conducted a community-based s... | In October 2010, a large cholera outbreak was declared in Haiti and rapidly spread throughout the country, quickly overwhelming the existing health system. Specialized treatment structures were opened rapidly, generally in cities or large villages, and decentralized treatment units or rehydration points were gradually ... | The cholera epidemic in Haiti, which began in 2010 spread rapidly in both urban and rural areas. One month after confirmation of the first case in Mirebalais, in the department of Centre, the whole country had been affected [1,2]. During the first few days, the focus was on case management in hospitals, which were quic... |
10.1371/journal.pntd.0000293 | Impact of Long-Term Treatment with Ivermectin on the Prevalence and Intensity of Soil-Transmitted Helminth Infections | Control of soil-transmitted helminth (STH) infections relies on the periodic and long-term administration of anthelmintic drugs to high-risk groups, particularly school-age children living in endemic areas. There is limited data on the effectiveness of long-term periodic anthelmintic treatment on the prevalence of STHs... | Soil-transmitted helminth (intestinal worm) infections are very common in developing countries and are an important cause of illness. Mass de-worming treatments of school children are an important strategy to reduce illness caused by these infections in communities without access to clean water and sanitation. Few stud... | Soil-transmitted helminths (STHs, also known as geohelminths or intestinal helminths) are important infectious diseases of humans and are estimated to infect over 2 billion humans worldwide [1], being particularly prevalent in poor populations living in tropical and sub-tropical regions of developing countries [2]. Soi... |
10.1371/journal.ppat.1002558 | LEDGF/p75-Independent HIV-1 Replication Demonstrates a Role for HRP-2 and Remains Sensitive to Inhibition by LEDGINs | Lens epithelium–derived growth factor (LEDGF/p75) is a cellular cofactor of HIV-1 integrase (IN) that interacts with IN through its IN binding domain (IBD) and tethers the viral pre-integration complex to the host cell chromatin. Here we report the generation of a human somatic LEDGF/p75 knockout cell line that allows ... | Like other viruses, HIV has a limited genome and needs to exploit the machinery of the host cell to complete its replication cycle. The elucidation of virus-host interactions not only sheds light on pathogenesis but also provides opportunities in a limited number of cases to develop novel antiviral drugs. A prototypica... | Integration of viral DNA into the host cell genome is a critical step during HIV replication. A stably inserted provirus is essential for productive infection and archives the genetic information of HIV in the host cell. The presence of a permanent viral reservoir that evades the immune system and enables HIV to reboun... |
10.1371/journal.pbio.2003962 | Design of synthetic bacterial communities for predictable plant phenotypes | Specific members of complex microbiota can influence host phenotypes, depending on both the abiotic environment and the presence of other microorganisms. Therefore, it is challenging to define bacterial combinations that have predictable host phenotypic outputs. We demonstrate that plant–bacterium binary-association as... | Symbiotic microbes influence host development and health, but predicting which microbes or groups of microbes will have a helpful or harmful effect is a major challenge in microbiome research. In this article, we describe a new method to design and predict bacterial communities that alter the plant host response to pho... | The composition of plant-associated microbial communities influences plant health and development [1][2]. This has raised interest in the use of microbes for biotechnology and agriculture [3][4]. However, it is challenging to measure the contribution of individual microbes from a complex microbiota to host health. Thus... |
10.1371/journal.pgen.1006513 | Protein Phosphatase 6 Protects Prophase I-Arrested Oocytes by Safeguarding Genomic Integrity | Mammalian oocytes are arrested at prophase of the first meiotic division in the primordial follicle pool for months, even years, after birth depending on species, and only a limited number of oocytes resume meiosis, complete maturation, and ovulate with each reproductive cycle. We recently reported that protein phospha... | Formation of haploid gametes from diploid germ cells requires a specialized reductive cell division known as meiosis. In contrast to male meiosis that takes place continuously, a unique feature of female meiosis in mammals is the long arrest in meiosis I, which lasts up to 50 years in humans. Because the size of the ge... | In mammals, females are born with a finite number of oocytes contained within primordial follicles that serve as the source of ova for the entire period of reproductive life. To produce mature eggs, dormant primordial follicles are recruited into the growing follicle pool, a process termed as initial follicular recruit... |
10.1371/journal.pcbi.1003501 | An Integrated Model of Multiple-Condition ChIP-Seq Data Reveals Predeterminants of Cdx2 Binding | Regulatory proteins can bind to different sets of genomic targets in various cell types or conditions. To reliably characterize such condition-specific regulatory binding we introduce MultiGPS, an integrated machine learning approach for the analysis of multiple related ChIP-seq experiments. MultiGPS is based on a gene... | Many proteins that regulate the activity of other genes do so by attaching to the genome at specific binding sites. The locations that a given regulatory protein will bind, and the strength or frequency of such binding at an individual location, can vary depending on the cell type. We can profile the locations that a p... | Profiling the activity of regulatory proteins in multiple cell types is important for understanding cellular function, as a single regulator can bind to distinct sets of genomic targets depending on the cellular context in which it is expressed. Characterizing the determinants of such binding specificity is key to unde... |
10.1371/journal.ppat.1008031 | A nanobody targeting the translocated intimin receptor inhibits the attachment of enterohemorrhagic E. coli to human colonic mucosa | Enterohemorrhagic E. coli (EHEC) is a human intestinal pathogen that causes hemorrhagic colitis and hemolytic uremic syndrome. No vaccines or specific therapies are currently available to prevent or treat these infections. EHEC tightly attaches to the intestinal epithelium by injecting the intimin receptor Tir into the... | Currently, there is no effective treatment or vaccine against enterohemorrhagic E. coli (EHEC), a bacterial pathogen that infects human colon after the ingestion of contaminated food. It thrives in the colon thanks to its ability to attach intimately to the intestinal epithelium. Here, we have identified and characteri... | Enterohemorrhagic E. coli (EHEC) is a major public health concern in industrial countries with most severe infections linked to serotype O157:H7. In addition to diarrhoea, EHEC can cause hemorrhagic colitis as well as life-threatening hemolytic uremic syndrome (HUS) damaging the kidneys and central nervous system [1–4]... |
10.1371/journal.pntd.0005124 | Oral Cholera Vaccination Delivery Cost in Low- and Middle-Income Countries: An Analysis Based on Systematic Review | Use of the oral cholera vaccine (OCV) is a vital short-term strategy to control cholera in endemic areas with poor water and sanitation infrastructure. Identifying, estimating, and categorizing the delivery costs of OCV campaigns are useful in analyzing cost-effectiveness, understanding vaccine affordability, and in pl... | We reviewed and re-estimated oral cholera vaccine delivery costs in low and middle income countries standardizing cost categories. The cost categorization proposed here can help in collation, analysis, comparison and economic analysis of OCV delivery costs across countries.
| Cholera is transmitted through the fecal-oral route, and humans are the natural host. It is caused by the ingestion of O1 and less commonly O139 serogroups of the Vibrio cholerae bacterium and characterized by severe, potentially life-threatening diarrhea [1]. The disease inflicts a significant health burden on many lo... |
10.1371/journal.pgen.1000426 | Independent S-Locus Mutations Caused Self-Fertility in Arabidopsis thaliana | A common yet poorly understood evolutionary transition among flowering plants is a switch from outbreeding to an inbreeding mode of mating. The model plant Arabidopsis thaliana evolved to an inbreeding state through the loss of self-incompatibility, a pollen-rejection system in which pollen recognition by the stigma is... | The mating system adopted by a species has a profound influence on extent of polymorphism, population structure, and evolutionary potential. In flowering plants, the switch from outbreeding to inbreeding has occurred repeatedly, yet little is known about the underlying genetic events. This is true even for the model sp... | Sexual reproduction may have evolved because it can combine different sequence variants through recombination [1] and because it can remove deleterious mutations linked to advantageous ones [2],[3]. However, approximately 20% of flowering plants are self-fertilizing and engage in sexual reproduction without obtaining e... |
10.1371/journal.pntd.0000175 | Increased Risk for Entamoeba histolytica Infection and Invasive Amebiasis in HIV Seropositive Men Who Have Sex with Men in Taiwan | Incidence of Entamoeba histolytica infection and clinical manifestations and treatment response of invasive amebiasis (IA) in HIV-infected patients have rarely been investigated before.
At the National Taiwan University Hospital, medical records of HIV-infected patients who received a diagnosis of IA between 1994 and 2... | Entamoeba histolytica, morphologically identical to but genetically different from E. dispar and E. moshkovskii, is the causative agent of amebiasis. Recently there have been reports of increased risk for amebiasis among men who have sex with men (MSM) due to oral-anal sexual contact in several developed countries. In ... | Invasive amebiasis (IA) is the second most common cause of mortality due to parasite infections worldwide, accounting for 40,000 to 100,000 deaths annually. High risk populations for developing IA include infants, pregnant women, and patients who are taking immunosuppressives [1],[2]. Interestingly, IA has not been con... |
10.1371/journal.pbio.1002355 | Interpreting the Dependence of Mutation Rates on Age and Time | Mutations can originate from the chance misincorporation of nucleotides during DNA replication or from DNA lesions that arise between replication cycles and are not repaired correctly. We introduce a model that relates the source of mutations to their accumulation with cell divisions, providing a framework for understa... | We relate how mutations arise to how they accumulate in different sexes, with age and with cell division. This model provides a single framework within which to interpret emerging results from evolutionary biology, human genetics, and cancer genetics. We show that the accrual of mutations should track cell divisions no... | Because mutations are the ultimate source of all genetic variation, deleterious and advantageous, mutagenesis has been of central interest even before the discovery of DNA as the genetic material (e.g., [1]), and developing a model of mutational heterogeneity along the genome is a major focus of current disease mapping... |
10.1371/journal.ppat.1003966 | Insights into the Initiation of JC Virus DNA Replication Derived from the Crystal Structure of the T-Antigen Origin Binding Domain | JC virus is a member of the Polyomavirus family of DNA tumor viruses and the causative agent of progressive multifocal leukoencephalopathy (PML). PML is a disease that occurs primarily in people who are immunocompromised and is usually fatal. As with other Polyomavirus family members, the replication of JC virus (JCV) ... | Polyomaviruses have been invaluable tools for biomedical research into basic cellular processes. It is becoming increasingly clear, however, that members of this family are also involved in human diseases, particularly among the immunocompromised and the elderly. The subject of this study, the JC virus (JCV), is a memb... | There are now twelve known human polyomavirus members (e.g., [1], [2]) and particularly for immuno-compromised individuals, there is an increasing association between these viruses and human diseases (reviewed in [3], [4], [5]). For example, JC virus (JCV) is the causative agent of Progressive Multifocal Leukoencephalo... |
10.1371/journal.pgen.1004850 | A Multi-Megabase Copy Number Gain Causes Maternal Transmission Ratio Distortion on Mouse Chromosome 2 | Significant departures from expected Mendelian inheritance ratios (transmission ratio distortion, TRD) are frequently observed in both experimental crosses and natural populations. TRD on mouse Chromosome (Chr) 2 has been reported in multiple experimental crosses, including the Collaborative Cross (CC). Among the eight... | One of the strongest expectations in genetics is that chromosomes segregate randomly during meiosis. However, genetic loci that exhibit transmission ratio distortion (TRD) are sometimes observed in offspring of F1 hybrids. Meiotic drive is a type of non-Mendelian inheritance in which a “selfish” genetic element exploit... | Mendel’s Laws provide the theoretical foundation of transmission genetics and explain many of the inheritance patterns of biological traits in sexually reproducing organisms. The Laws state that each gamete receives a random collection of alleles—exactly one per pair of homologous loci—and that gametes unite at random.... |
10.1371/journal.ppat.1001285 | Atypical/Nor98 Scrapie Infectivity in Sheep Peripheral Tissues | Atypical/Nor98 scrapie was first identified in 1998 in Norway. It is now considered as a worldwide disease of small ruminants and currently represents a significant part of the detected transmissible spongiform encephalopathies (TSE) cases in Europe. Atypical/Nor98 scrapie cases were reported in ARR/ARR sheep, which ar... | Following the bovine spongiform encephalopathy (BSE) crisis and the identification of its zoonotic properties, a sanitary policy has been implemented based on both eradication of transmissible spongiform encephalopathies (TSE) in food-producing animals and exclusion of known infectious materials from the food chain. At... | Transmissible spongiform encephalopathies (TSE), or prion diseases, are fatal neurodegenerative disorders occurring in sheep (scrapie), cattle (bovine spongiform encephalopathy - BSE), or humans (Creutzfeldt-Jakob disease - CJD). The key event in TSE is the conversion of a normal cellular protein (PrPc) into an abnorma... |
10.1371/journal.pcbi.1000910 | Gene Expression Variability within and between Human Populations and Implications toward Disease Susceptibility | Variations in gene expression level might lead to phenotypic diversity across individuals or populations. Although many human genes are found to have differential mRNA levels between populations, the extent of gene expression that could vary within and between populations largely remains elusive. To investigate the dyn... | Many human genes have population-specific expression levels, which are linked to population-specific polymorphisms and copy-number variations. However, it is unclear whether human genes show similar dynamic range of expression between populations. In this work we analyzed HapMap gene expression compendium, and quantifi... | In both prokaryotic and eukaryotic organisms, variations in gene expression exist widely within and between populations, which can be attributed to either genetic or non-genetic factors. Genetic factors are changes in DNA sequence that cause expression differences, such as single nucleotide polymorphisms (SNPs) and cop... |
10.1371/journal.pbio.3000065 | Contest models highlight inherent inefficiencies of scientific funding competitions | Scientific research funding is allocated largely through a system of soliciting and ranking competitive grant proposals. In these competitions, the proposals themselves are not the deliverables that the funder seeks, but instead are used by the funder to screen for the most promising research ideas. Consequently, some ... | The grant proposal system compels researchers to devote substantial time to writing proposals that could have instead been used to do science. Here, we use the economic theory of contests to show that as fewer grants are funded, the value of the science that researchers forgo while preparing proposals can approach or e... | Over the past 50 years, research funding in the United States has failed to keep pace with growth in scientific activity. Funding rates in grant competitions have plummeted (S1 Fig, [1–4]) and researchers spend far more time writing grant proposals than they did in the past [5]. A large survey of top US universities fo... |
10.1371/journal.pbio.1001658 | Dectin-1 Is Essential for Reverse Transcytosis of Glycosylated SIgA-Antigen Complexes by Intestinal M Cells | Intestinal microfold (M) cells possess a high transcytosis capacity and are able to transport a broad range of materials including particulate antigens, soluble macromolecules, and pathogens from the intestinal lumen to inductive sites of the mucosal immune system. M cells are also the primary pathway for delivery of s... | Secretory IgA (SIgA) antibodies are secreted into the gut lumen and are considered to be a first line of defense in protecting the intestinal epithelium from gut pathogens. SIgA patrol the mucus and are usually known to help immune tolerance via entrapping dietary antigens and microorganisms and other mechanisms. SIgA,... | The mucosal immune system comprises the largest part of the entire immune system, and the mucosal surface represents the primary site of entry for pathogenic agents. SIgA has long been recognized as a first line of defense in protecting the intestinal epithelium from enteric pathogens and toxins. It is generally assume... |
10.1371/journal.pgen.1007633 | Glycine promotes longevity in Caenorhabditis elegans in a methionine cycle-dependent fashion | The deregulation of metabolism is a hallmark of aging. As such, changes in the expression of metabolic genes and the profiles of amino acid levels are features associated with aging animals. We previously reported that the levels of most amino acids decline with age in Caenorhabditis elegans (C. elegans). Glycine, in c... | There is a growing number of studies showing that amino acids function as signal metabolites that influence aging and health. Although contemporary -OMICs studies have uncovered various associations between metabolite levels and aging, in many cases the directionality of the relationships is unclear. In a recent metabo... | Aging is characterized by a progressive deterioration of the functional capacity of tissues and organs. Pioneering studies in the nematode C. elegans have identified longevity-associated genes and provided us with great insights into the plasticity of aging [1–3]. In the last few decades, genetic and nutritional interv... |
10.1371/journal.pntd.0007311 | Molecular characterization of Brucella species from Zimbabwe | Brucella abortus and B. melitensis have been reported in several studies in animals in Zimbabwe but the extent of the disease remains poorly known. Thus, characterizing the circulating strains is a critical first step in understanding brucellosis in the country. In this study we used an array of molecular assays includ... | Brucellosis is endemic in Zimbabwe. This article describes the use of various assays such as AMOS, Bruce-ladder, MLVA, and whole genome sequencing to characterize Brucella species isolated from different animals in Zimbabwe. Choice of which assays to use in the laboratory is generally done considering reproducibility, ... | Brucellosis is a worldwide infectious disease affecting a wide range of domestic and wildlife animals and humans [1]. Brucellosis is caused by species in the genus Brucella, which consists of six classic species, Brucella abortus, B. melitensis, B. suis, B. ovis, B. canis, and B. neotomae [2]. Recently, the genus has e... |
10.1371/journal.pcbi.1000011 | Entropy Measures Quantify Global Splicing Disorders in Cancer | Most mammalian genes are able to express several splice variants in a phenomenon known as alternative splicing. Serious alterations of alternative splicing occur in cancer tissues, leading to expression of multiple aberrant splice forms. Most studies of alternative splicing defects have focused on the identification of... | RNA splicing is the process by which gene products are pieced together to form a mature messenger RNA (mRNA). In normal cells, RNA splicing is a tightly controlled process that leads to production of a well-defined set of mRNAs. Cancer cells, however, often produce aberrant, mis-spliced mRNAs. Such disorders have not b... | The majority of mammalian genes produce alternative transcripts as part of their normal expression program [1]–[4]. Alternative transcripts include splicing, polyadenylation and transcription initiation variants which can be expressed differentially in different tissues [4]–[7] providing the fine tuning of gene express... |
10.1371/journal.ppat.1002876 | A Unique Bivalent Binding and Inhibition Mechanism by the Yatapoxvirus Interleukin 18 Binding Protein | Interleukin 18 (IL18) is a cytokine that plays an important role in inflammation as well as host defense against microbes. Mammals encode a soluble inhibitor of IL18 termed IL18 binding protein (IL18BP) that modulates IL18 activity through a negative feedback mechanism. Many poxviruses encode homologous IL18BPs, which ... | Interleukin 18 (IL18) is an important cytokine in inflammation and immunity. Mammals and poxviruses encode homologous inhibitory proteins of IL18, named IL18BPs, which regulate IL18 activity and, in the case of the viral proteins, contribute to virulence. Previous structural and functional studies revealed residues at ... | Poxviruses are a family of large, complex DNA viruses, infecting a variety of organisms including insects, reptiles, birds and mammals [1]. The poxvirus family is further subdivided into genera based on shared characteristics such as host range, morphology, antigenicity, and sequence similarity [2]. Four genera of poxv... |
10.1371/journal.pcbi.1002454 | Quantifying Type-Specific Reproduction Numbers for Nosocomial Pathogens: Evidence for Heightened Transmission of an Asian Sequence Type 239 MRSA Clone | An important determinant of a pathogen's success is the rate at which it is transmitted from infected to susceptible hosts. Although there are anecdotal reports that methicillin-resistant Staphylococcus aureus (MRSA) clones vary in their transmissibility in hospital settings, attempts to quantify such variation are lac... | Different strains of hospital pathogens may differ in their ability to spread between patients and respond differently to control measures. Attempts to quantify such between-strain variation are lacking in high prevalence settings. We analysed data from concurrent outbreaks with different MRSA strains in two adult inte... | Methicillin-resistant Staphylococcus aureus (MRSA) is responsible for a high burden of morbidity and mortality worldwide [1]–[4]. While community-associated MRSA is becoming increasingly important globally [5], [6], in many countries, including the United Kingdom, MRSA remains predominantly a nosocomial pathogen [7], [... |
10.1371/journal.pntd.0005219 | CD4/CD8 Ratio and KT Ratio Predict Yellow Fever Vaccine Immunogenicity in HIV-Infected Patients | HIV-infected individuals have deficient responses to Yellow Fever vaccine (YFV) and may be at higher risk for adverse events (AE). Chronic immune activation–characterized by low CD4/CD8 ratio or high indoleamine 2,3-dioxygenase-1 (IDO) activity—may influence vaccine response in this population.
We prospectively assesse... | Yellow Fever (YF) vaccine is considered one of the most effective vaccines ever produced. However, previous studies suggest that HIV impairs YF vaccine response. In this study, we assessed if HIV infection impacts the risk of adverse events and could reduce antibody response to YF vaccine. We explored if laboratory mar... | Effective antiretroviral treatment (ART) drastically improved clinical outcomes for people living with HIV. However, these patients still present increased risk of death, higher prevalence of comorbidities, and impaired responses to vaccines [1–6]. Prior studies have shown impaired Yellow Fever vaccine (YFV) immunogeni... |
10.1371/journal.pcbi.1002905 | Viral Capsid Proteins Are Segregated in Structural Fold Space | Viral capsid proteins assemble into large, symmetrical architectures that are not found in complexes formed by their cellular counterparts. Given the prevalence of the signature jelly-roll topology in viral capsid proteins, we are interested in whether these functionally unique capsid proteins are also structurally uni... | Viruses are increasingly viewed not as pathogens that parasitize all domains of life, but as useful nanoplatforms for synthetic maneuvers in a wide range of biomedical and materials science applications. One of the most well-known examples of virus-based nanotools developed so far features viral capsules as therapeutic... | Viral capsid proteins protect the viral genome by forming a closed protein shell around it. Most of currently found viral shells with known structure are spherical in shape and observe icosahedral symmetry [1]. Comprised of a large number of proteins, such large, symmetrical complexes assume a geometrically sophisticat... |
10.1371/journal.ppat.1003643 | Inherited Prion Disease A117V Is Not Simply a Proteinopathy but Produces Prions Transmissible to Transgenic Mice Expressing Homologous Prion Protein | Prions are infectious agents causing fatal neurodegenerative diseases of humans and animals. In humans, these have sporadic, acquired and inherited aetiologies. The inherited prion diseases are caused by one of over 30 coding mutations in the human prion protein (PrP) gene (PRNP) and many of these generate infectious p... | Prions are infectious agents causing incurable brain disease in humans and animals. Prion diseases are by definition transmissible, which means that it should be possible to experimentally transfer disease from patient brain tissue to laboratory animals by inoculation. While many forms of prion disease have been shown ... | According to the widely accepted “protein-only” hypothesis [1], an abnormal isoform (PrPSc) of host-encoded cellular prion protein (PrPC) is the principal, and possibly the sole, constituent of the transmissible agent or prion [2]. Prions exist in multiple strains which are thought to represent distinct polymeric forms... |
10.1371/journal.pcbi.1000305 | Timing the Emergence of Resistance to Anti-HIV Drugs with Large Genetic Barriers | New antiretroviral drugs that offer large genetic barriers to resistance, such as the recently approved inhibitors of HIV-1 protease, tipranavir and darunavir, present promising weapons to avert the failure of current therapies for HIV infection. Optimal treatment strategies with the new drugs, however, are yet to be e... | The ability of HIV to rapidly acquire mutations responsible for resistance to administered drugs underlies the failure of current antiretroviral therapies for HIV infection. The recent advent of drugs that offer large genetic barriers to resistance, e.g., tipranavir and darunavir, presents a new opportunity to devise t... | Current antiretroviral therapies for HIV infection often fail to elicit lasting virological responses in patients because of the emergence of multidrug resistant strains of HIV [1],[2]. The enormous replication rate and the high mutation and recombination rates of HIV [3]–[7] propel the acquisition of mutations that co... |
10.1371/journal.pgen.1006335 | Family Based Whole Exome Sequencing Reveals the Multifaceted Role of Notch Signaling in Congenital Heart Disease | Left-ventricular outflow tract obstructions (LVOTO) encompass a wide spectrum of phenotypically heterogeneous heart malformations which frequently cluster in families. We performed family based whole-exome and targeted re-sequencing on 182 individuals from 51 families with multiple affected members. Central to our appr... | Left-ventricular outflow tract obstructions comprise a group of developmental heart disorders that are genetically and phenotypically heterogeneous, with no single gene accounting for the majority of cases. In order to identify mutations contributing to disease, we selected patients from 51 families with a history of c... | Left-ventricular outflow tract obstructions (LVOTO) comprise a group of cardiac malformations that restrict blood flow in the left portion of the heart. This heterogeneous subclass of cardiac malformations is commonly associated with aortic valve disease and early onset aortopathy, including severe stenosis and aortic ... |
10.1371/journal.ppat.1002613 | Structural Basis for Type VI Secretion Effector Recognition by a Cognate Immunity Protein | The type VI secretion system (T6SS) has emerged as an important mediator of interbacterial interactions. A T6SS from Pseudomonas aeruginosa targets at least three effector proteins, type VI secretion exported 1–3 (Tse1–3), to recipient Gram-negative cells. The Tse2 protein is a cytoplasmic effector that acts as a poten... | Bacterial species have been at war with each other for over a billion years. During this period they have evolved many pathways for besting the competition; one of the most recent of these to be described is the type VI secretion system (T6SS). The T6SS of Pseudomonas aeruginosa is a complex machine that the bacterium ... | The type VI secretion system (T6SS) is a multifaceted protein export pathway that is widely distributed in Gram-negative Proteobacteria [1], [2]. With a minimal functional requirement for the products of at least 13 genes, this secretion machine rivals the complexity of the more extensively characterized type III and I... |
10.1371/journal.ppat.1002777 | Candida albicans Scavenges Host Zinc via Pra1 during Endothelial Invasion | The ability of pathogenic microorganisms to assimilate essential nutrients from their hosts is critical for pathogenesis. Here we report endothelial zinc sequestration by the major human fungal pathogen, Candida albicans. We hypothesised that, analogous to siderophore-mediated iron acquisition, C. albicans utilises an ... | The capacity of disease-causing microbes to acquire nutrients from their host is one of the most fundamental aspects of infection. Host organisms therefore restrict microbial access to certain key nutrients in a process known as nutritional immunity. Recently, it was found that infected vertebrates sequester zinc from ... | Assimilation of essential nutrients by pathogenic microorganisms from their host environment is one of the most fundamental aspects of infection. Host organisms therefore restrict microbial access to certain key nutrients in a process termed nutritional immunity. The mechanisms of iron sequestration, together with the ... |
10.1371/journal.ppat.1000664 | Inclusion Biogenesis and Reactivation of Persistent Chlamydia trachomatis Requires Host Cell Sphingolipid Biosynthesis | Chlamydiae are obligate intracellular pathogens that must coordinate the acquisition of host cell-derived biosynthetic constituents essential for bacterial survival. Purified chlamydiae contain several lipids that are typically found in eukaryotes, implying the translocation of host cell lipids to the chlamydial vacuol... | The genus Chlamydia is composed of a group of obligate intracellular bacterial pathogens that cause several human diseases of medical significance. C. trachomatis is the most commonly encountered sexually transmitted pathogen, as well as the leading cause of preventable blindness worldwide. The prevalence of chlamydial... | The genus Chlamydia is composed of obligate intracellular prokaryotic pathogens that cause a range of clinical sequelae in humans encompassing ocular, genital, and respiratory tract infections. Consequences of subsequent chronic disease include blindness, infertility, arthritis, and possible coronary heart disease [1],... |
10.1371/journal.ppat.1007709 | Nlrp3 inflammasome activation and Gasdermin D-driven pyroptosis are immunopathogenic upon gastrointestinal norovirus infection | Norovirus infection is the leading cause of food-borne gastroenteritis worldwide, being responsible for over 200,000 deaths annually. Studies with murine norovirus (MNV) showed that protective STAT1 signaling controls viral replication and pathogenesis, but the immune mechanisms that noroviruses exploit to induce patho... | Gastrointestinal norovirus infections form a serious socio-economic worldwide problem, with about 684 million cases annually worldwide and mortality occurring both in underdeveloped countries and in immunocompromised patients. Despite the urgent global need, no specific treatments are available for norovirus induced ga... | Human norovirus infection is the most common cause of food-borne gastroenteritis worldwide, responsible for an estimated 684 million cases per year [1]. While norovirus gastroenteritis is self-limiting in immunocompetent individuals, it can evolve to a seriously debilitating and even life-threatening infection in condi... |
10.1371/journal.pcbi.1005945 | Identifying human diamine sensors for death related putrescine and cadaverine molecules | Pungent chemical compounds originating from decaying tissue are strong drivers of animal behavior. Two of the best-characterized death smell components are putrescine (PUT) and cadaverine (CAD), foul-smelling molecules produced by decarboxylation of amino acids during decomposition. These volatile polyamines act as ‘ne... | The distinctive dead smell comes largely from molecules like cadaverine and putrescine that are produced during decomposition of organic tissues. These volatile compounds act as powerful chemical signals important for the survival of a wide range of species. Previous studies have identified the trace amine-associated r... | Olfaction is the major neurosensory function by which many species explore the chemical composition of their natural environments to locate food, avoid potentially harmful situations, recognize territory, identify members of their own group or predators, and choose a mate. Notable among the many olfactory signals is th... |
10.1371/journal.pcbi.1002079 | Generative Embedding for Model-Based Classification of fMRI Data | Decoding models, such as those underlying multivariate classification algorithms, have been increasingly used to infer cognitive or clinical brain states from measures of brain activity obtained by functional magnetic resonance imaging (fMRI). The practicality of current classifiers, however, is restricted by two major... | Neurological and psychiatric spectrum disorders are typically defined in terms of particular symptom sets, despite increasing evidence that the same symptom may be caused by very different pathologies. Pathophysiological classification and effective treatment of such disorders will increasingly require a mechanistic un... | Recent years have seen a substantial increase in the use of functional neuroimaging data for investigating healthy brain function and detecting abnormalities. The most popular type of analysis is statistical parametric mapping (SPM), a mass-univariate encoding model of fMRI data in which the statistical relationship be... |
10.1371/journal.pgen.1007427 | Paired Immunoglobulin-like Type 2 Receptor Alpha G78R variant alters ligand binding and confers protection to Alzheimer's disease | Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA) is a cell surface inhibitory receptor that recognizes specific O-glycosylated proteins and is expressed on various innate immune cell types including microglia. We show here that a common missense variant (G78R, rs1859788) of PILRA is the likely causal allele for... | Alzheimer’s disease (AD) is a devastating neurodegenerative disorder resulting from a complex interaction of environmental and genetic risk factors. Despite considerable progress in defining the genetic component of AD risk, understanding the biology of common variant associations is a challenge. We find that PILRA G78... | Alzheimer’s disease (AD) results from a complex interaction of environmental and genetic risk factors [1]. Proposed environmental risk factors include a history of head trauma [2–4] and infection [5–7]. In recent years, large-scale genome-wide association studies (GWAS) and family-based studies have made considerable p... |
10.1371/journal.pntd.0006335 | Group A Streptococcus pharyngitis and pharyngeal carriage: A meta-analysis | Antibiotic treatment of Group A Streptococcus (GAS) pharyngitis is important in acute rheumatic fever (ARF) prevention, however clinical guidelines for prescription vary. GAS carriers with acute viral infections may receive antibiotics unnecessarily. This review assessed the prevalence of GAS pharyngitis and carriage i... | Treating sore throats caused by Group A Streptococcus infections (GAS pharyngitis) with antibiotics is important for preventing acute rheumatic fever (ARF). It is impossible to distinguish patients with true GAS pharyngitis infections from GAS carriers with pharyngitis caused by viral infections when throat swab cultur... | Acute pharyngitis is a common cause of doctor’s visits across the world.[1] Most pharyngitis episodes (40–80%) are caused by self-limiting viral infections. Group A Streptococcus (GAS) infection is the most common bacterial cause of pharyngitis, responsible for approximately15-30% of cases.[2] In a small minority of pa... |
10.1371/journal.ppat.1005701 | CRISPR/Cas9-Mediated Genome Editing of Herpesviruses Limits Productive and Latent Infections | Herpesviruses infect the majority of the human population and can cause significant morbidity and mortality. Herpes simplex virus (HSV) type 1 causes cold sores and herpes simplex keratitis, whereas HSV-2 is responsible for genital herpes. Human cytomegalovirus (HCMV) is the most common viral cause of congenital defect... | Herpesviruses are large DNA viruses that are carried by almost 100% of the adult human population. Herpesviruses include several important human pathogens, such as herpes simplex viruses (HSV) type 1 and 2 (causing cold sores and genital herpes, respectively), human cytomegalovirus (HCMV; the most common viral cause of... | Herpesviruses are large DNA viruses that cause widespread, lifelong infections; most adults carry multiple herpesviruses [1]. The herpesvirus family is divided into three subfamilies, the Alpha-, Beta- and Gammaherpesvirinae. The subfamily of Alphaherpesvirinae includes the herpes simplex virus type 1 and type 2 (HSV-1... |
10.1371/journal.pgen.1005008 | Elevated In Vivo Levels of a Single Transcription Factor Directly Convert Satellite Glia into Oligodendrocyte-like Cells | Oligodendrocytes are the myelinating glia of the central nervous system and ensure rapid saltatory conduction. Shortage or loss of these cells leads to severe malfunctions as observed in human leukodystrophies and multiple sclerosis, and their replenishment by reprogramming or cell conversion strategies is an important... | Developmental or acquired defects of oligodendrocytes or their myelin sheaths impairs saltatory nerve conduction in the central nervous system and thus leads to severe neurological diseases. Strategies to regenerate or replace these cells require a deeper understanding of the regulatory processes that underlie their ge... | Transcription factor-mediated reprogramming is currently the method of choice for the generation of induced pluripotent stem (iPS) cells [1]. It is also used to directly convert one cell type into another. Successful conversion depends on the choice of transcription factors, but is also influenced by the proteomic cons... |
10.1371/journal.pntd.0002488 | Barriers to Treatment Access for Chagas Disease in Mexico | According to World Health Organization (WHO) prevalence estimates, 1.1 million people in Mexico are infected with Trypanosoma cruzi, the etiologic agent of Chagas disease (CD). However, limited information is available about access to antitrypanosomal treatment. This study assesses the extent of access in Mexico, analy... | Chagas disease is a vector-borne disease caused by the parasite Trypanosoma cruzi. The disease is most frequently transmitted by triatomine insects but can also be passed through blood donation or from mother to child at birth. Experts estimate that 8 million people are infected with Chagas disease globally and that 1.... | Chagas disease is a vector-borne, parasitic disease with a prevalence of 8 million infections globally. The disease is responsible for as many as 15,000 deaths per year [1], [2], largely concentrated among the poor in Latin America, and a recent study found that the disease is also responsible for substantial losses in... |
10.1371/journal.ppat.1005685 | Biosynthesis of Antibiotic Leucinostatins in Bio-control Fungus Purpureocillium lilacinum and Their Inhibition on Phytophthora Revealed by Genome Mining | Purpureocillium lilacinum of Ophiocordycipitaceae is one of the most promising and commercialized agents for controlling plant parasitic nematodes, as well as other insects and plant pathogens. However, how the fungus functions at the molecular level remains unknown. Here, we sequenced two isolates (PLBJ-1 and PLFJ-1) ... | Purpureocillium lilacinum, a well-known bio-control agent against various plant pathogens in agriculture, can produce antibiotic leucinostatins—peptaibiotic with extensive biological activities, including antimalarial, antiviral, antibacterial, antifungal, and antitumor activities, as well as phytotoxic. We have sequen... | Plant parasitic nematodes with wide host ranges cause enormous crop and economic losses amounting to $157 billion annually worldwide [1, 2]. Biological control by fungi has become increasingly popular due to nematicides’ risks of environmental toxicity and adverse effects on human health [3]. One of the most promising ... |
10.1371/journal.pbio.1001456 | Disease Ecology, Biodiversity, and the Latitudinal Gradient in Income | While most of the world is thought to be on long-term economic growth paths, more than one-sixth of the world is roughly as poor today as their ancestors were hundreds of years ago. The majority of the extremely poor live in the tropics. The latitudinal gradient in income is highly suggestive of underlying biophysical ... | While most of the world is thought to be growing economically, more than one-sixth of the world is roughly as poor today as their ancestors were hundreds of years ago. The extremely poor live largely in the tropics. This latitudinal gradient in income suggests that there are biophysical factors, such as the burden of d... | Despite long-term economic growth trajectories for most countries, extreme poverty persists for more than one-sixth of the world. The distribution of wealth and poverty has a clear geographic signature. Along with 93% of the global burden of vector-borne and parasitic diseases (VBPDs), the tropics host 41 of the 48 “le... |
10.1371/journal.ppat.1000065 | Targeting of Pseudorabies Virus Structural Proteins to Axons Requires Association of the Viral Us9 Protein with Lipid Rafts | The pseudorabies virus (PRV) Us9 protein plays a central role in targeting viral capsids and glycoproteins to axons of dissociated sympathetic neurons. As a result, Us9 null mutants are defective in anterograde transmission of infection in vivo. However, it is unclear how Us9 promotes axonal sorting of so many viral pr... | Alpha herpesviruses are common mammalian pathogens (e.g. herpes simplex and chickenpox virus infect humans). These viruses enter and spread in and out of the mammalian nervous system, a defining hallmark of their lifecycle and potential pathogenesis. Neurons are polarized cells, and the movement of certain cellular pro... | Neurons are highly polarized cells with distinct biochemical and functional properties particular to the cell body (soma), dendrites, and the axon. Soluble, cytosolic proteins likely move into axons and dendrites by bulk flow, while membrane proteins are highly restricted to the somatodendritic membrane, the axonal mem... |
10.1371/journal.pbio.2002690 | Common genes associated with antidepressant response in mouse and man identify key role of glucocorticoid receptor sensitivity | Response to antidepressant treatment in major depressive disorder (MDD) cannot be predicted currently, leading to uncertainty in medication selection, increasing costs, and prolonged suffering for many patients. Despite tremendous efforts in identifying response-associated genes in large genome-wide association studies... | Major depression is the second leading cause of disability worldwide. However, only one-third of patients with depression benefit from the first antidepressant compound they are prescribed. It is a fundamental problem that the outcomes of individual antidepressant treatments are still highly unpredictable. In clinical ... | A “one size fits all” approach is not effective or efficient in the treatment of major depressive disorder (MDD). Although it would be ideal to tailor available treatments to individual patients [1], patient-level antidepressant treatment outcomes are still highly unpredictable [2]. Identification of biomarkers predict... |
10.1371/journal.pcbi.0030032 | Repressor Dimerization in the Zebrafish Somitogenesis Clock | The oscillations of the somitogenesis clock are linked to the fundamental process of vertebrate embryo segmentation, yet little is known about their generation. In zebrafish, it has been proposed that Her proteins repress the transcription of their own mRNA. However, in its simplest form, this model is incompatible wit... | Vertebrate embryos acquire a segmented structure along the anteroposterior axis. Segmentation is critical for patterning of other structures (such as nerves, vertebrae, muscles, and blood vessels) and occurs by the rhythmic separation of balls of cells, called somites, from the anterior end of their precursor tissue, c... | A somitogenesis clock, linked to the vertebrate segmentation process, has been uncovered in mouse, chick, and zebrafish [1]. Genes involved show oscillatory expression in the presomitic mesoderm (PSM) and are mostly related to the Notch pathway in all three species. In zebrafish PSM, oscillatory genes include her1 and ... |
10.1371/journal.pntd.0006640 | Clinical, environmental, and behavioral characteristics associated with Cryptosporidium infection among children with moderate-to-severe diarrhea in rural western Kenya, 2008–2012: The Global Enteric Multicenter Study (GEMS) | Cryptosporidium is a leading cause of moderate-to-severe diarrhea (MSD) in young children in Africa. We examined factors associated with Cryptosporidium infection in MSD cases enrolled at the rural western Kenya Global Enteric Multicenter Study (GEMS) site from 2008-2012.
At health facility enrollment, stool samples we... | Cryptosporidium is an important cause of childhood diarrhea. Research on cryptosporidiosis in countries where it is endemic remains limited; few studies have comprehensively examined risk factors for children in Kenya and similar settings. We examined characteristics associated with Cryptosporidium in children with mod... | The Global Enteric Multicenter Study (GEMS) was undertaken to assess the burden and etiology of moderate-to-severe diarrhea (MSD) in seven countries, three in South Asia and four in sub-Saharan Africa. In all African sites, Cryptosporidium was the second-highest enteric pathogen attributable to infant MSD; in GEMS Keny... |
10.1371/journal.pntd.0007709 | Leprosy in elderly people and the profile of a retrospective cohort in an endemic region of the Brazilian Amazon | Leprosy has a global presence; more than 180 thousand new cases were registered in 2013, 15% of which were found in the Americas. The elderly are a very susceptible demographic in terms of developing illnesses, mainly because of characteristics natural to the senescence of the human organism. This study’s goals were to... | Leprosy, despite being an ancient disease, still represents a challenge to public health systems today. There are still just a few studies about it, particularly among the elderly. It is known that they constitute a very heterogeneous group in terms of immune response to infections, alterations to the peripheral nervou... | Poverty is closely related to the occurrence of Neglected Tropical Diseases (NTDs), and leprosy has high endemicity mainly in Africa, the Americas, Southeast Asia and the Eastern Pacific, where social and economic inequalities reflect adverse conditions of life and health for the population [1]. Brazil is number two in... |
10.1371/journal.pmed.1002601 | The San Diego 2007 wildfires and Medi-Cal emergency department presentations, inpatient hospitalizations, and outpatient visits: An observational study of smoke exposure periods and a bidirectional case-crossover analysis | The frequency and intensity of wildfires is anticipated to increase as climate change creates longer, warmer, and drier seasons. Particulate matter (PM) from wildfire smoke has been linked to adverse respiratory and possibly cardiovascular outcomes. Children, older adults, and persons with underlying respiratory and ca... | Large wildfires are becoming more frequent and are expected to increase with climate change. Smoke from wildfires can cause health problems, especially for children, older persons, and people who already have respiratory or heart problems.
Researchers had access to data on emergency department visits, hospitalizations,... | Large forest fires have become more frequent in the Western United States since the 1980s [1–3]. Under most future climate scenarios, the frequency and size of wildfires in the southwestern states are expected to increase [4]. Climate models predict up to a 74% increase in area burned in California and a possible doubl... |
10.1371/journal.pcbi.1005348 | THE REAL McCOIL: A method for the concurrent estimation of the complexity of infection and SNP allele frequency for malaria parasites | As many malaria-endemic countries move towards elimination of Plasmodium falciparum, the most virulent human malaria parasite, effective tools for monitoring malaria epidemiology are urgent priorities. P. falciparum population genetic approaches offer promising tools for understanding transmission and spread of the dis... | Monitoring malaria epidemiology is critical for evaluating the impact of interventions and designing strategies for control and elimination. Population genetics has been used to inform malaria epidemiology, but it is limited by the fact that a fundamental metric needed for most analyses—the frequency of alleles in a po... | Malaria has declined significantly over the past decade, but continues to cause half a million deaths annually [1]. Calls for elimination have shifted research efforts towards developing new approaches for transmission reduction, including the identification of source and sink regions and hotspots that sustain transmis... |
10.1371/journal.pcbi.1000952 | HIV Promoter Integration Site Primarily Modulates Transcriptional Burst Size Rather Than Frequency | Mammalian gene expression patterns, and their variability across populations of cells, are regulated by factors specific to each gene in concert with its surrounding cellular and genomic environment. Lentiviruses such as HIV integrate their genomes into semi-random genomic locations in the cells they infect, and the re... | Cellular gene expression is a fundamentally stochastic process due to the intrinsic randomness of the underlying biochemical reactions involved. The resulting stochastically generated expression heterogeneities have important biological consequences and also encode information about the underlying dynamics that generat... | The life cycle dynamics of HIV-1 within a host are shaped by numerous apparently stochastic processes, from the statistics of immune cell infection in humans, to mutation during reverse transcription, semi-random integration of the proviral DNA into the host-cell chromosome, and stochastic viral gene expression thereaf... |
10.1371/journal.ppat.1001097 | The Microbiota Mediates Pathogen Clearance from the Gut Lumen after Non-Typhoidal Salmonella Diarrhea | Many enteropathogenic bacteria target the mammalian gut. The mechanisms protecting the host from infection are poorly understood. We have studied the protective functions of secretory antibodies (sIgA) and the microbiota, using a mouse model for S. typhimurium diarrhea. This pathogen is a common cause of diarrhea in hu... | Numerous pathogens infect the gut. Protection against these infections is mediated by mucosal immune defenses including secreted IgA as well as by the competing intestinal microbiota. However, so far the relative importance of these two different defense mechanisms remains unclear. We addressed this question using the ... | Bacterial diarrhea is a global cause of morbidity and mortality. In most cases, the acute disease symptoms cease after a few days and the pathogen is eliminated from the gut. However, the mechanisms eliminating enteropathogenic bacteria from the gut lumen are poorly understood. Most “classical” effector mechanisms of t... |
10.1371/journal.ppat.1004811 | Plasma Membrane Profiling Defines an Expanded Class of Cell Surface Proteins Selectively Targeted for Degradation by HCMV US2 in Cooperation with UL141 | Human cytomegalovirus (HCMV) US2, US3, US6 and US11 act in concert to prevent immune recognition of virally infected cells by CD8+ T-lymphocytes through downregulation of MHC class I molecules (MHC-I). Here we show that US2 function goes far beyond MHC-I degradation. A systematic proteomic study using Plasma Membrane P... | As the largest human herpesvirus, HCMV is a paradigm of viral immune evasion and has evolved multiple mechanisms to evade immune detection and enable survival. The HCMV genes US2, US3, US6 and US11 promote virus persistence by their ability to downregulate cell surface MHC. We developed ‘Plasma Membrane Profiling’ (PMP... | HCMV is the prototype betaherpesvirus and an important human pathogen. Following primary infection, HCMV persists for the lifetime of the host under constant control by the host immune system. In the face of this selective pressure, HCMV has evolved multiple mechanisms to evade immune detection and has emerged as a par... |
10.1371/journal.pbio.2000841 | Nonlatching positive feedback enables robust bimodality by decoupling expression noise from the mean | Fundamental to biological decision-making is the ability to generate bimodal expression patterns where 2 alternate expression states simultaneously exist. Here, we use a combination of single-cell analysis and mathematical modeling to examine the sources of bimodality in the transcriptional program controlling HIV’s fa... | A central and recurring feature of cell-fate regulating circuits is their ability to generate bimodal expression—2 alternate expression states that exist simultaneously—with each state corresponding to a different cell fate. To understand the mechanisms enabling bimodality in a natural decision-making circuit, we exami... | Bimodality is a recurring feature in many biological fate-selection programs [1], such as the HIV active-versus-latent decision (Fig 1A). Bimodal expression is a population-wide distribution pattern comprises 2 gene-expression modes, each corresponding to a specific fate path [2]. The mechanisms that can generate bimod... |
10.1371/journal.pgen.1000973 | Sgs1 and Exo1 Redundantly Inhibit Break-Induced Replication and De Novo Telomere Addition at Broken Chromosome Ends | In budding yeast, an HO endonuclease-inducible double-strand break (DSB) is efficiently repaired by several homologous recombination (HR) pathways. In contrast to gene conversion (GC), where both ends of the DSB can recombine with the same template, break-induced replication (BIR) occurs when only the centromere-proxim... | A chromosomal double-strand break (DSB) poses a severe threat to genome integrity, and budding yeast cells use several homologous recombination mechanisms to repair the break. In gene conversion (GC), both ends of the DSB share homology to an intact donor locus, and the break is repaired by copying the donor to create ... | DNA double-strand breaks (DSBs) are generated by normal cellular processes including DNA replication or by exposure to DNA damaging agents or ionizing radiation. To maintain cell viability and preserve genomic integrity, cells employ multiple pathways of homologous recombination (HR) to repair DSBs [1]–[4]. A key initi... |
10.1371/journal.ppat.1003932 | Unifying Viral Genetics and Human Transportation Data to Predict the Global Transmission Dynamics of Human Influenza H3N2 | Information on global human movement patterns is central to spatial epidemiological models used to predict the behavior of influenza and other infectious diseases. Yet it remains difficult to test which modes of dispersal drive pathogen spread at various geographic scales using standard epidemiological data alone. Evol... | What explains the geographic dispersal of emerging pathogens? Reconstructions of evolutionary history from pathogen gene sequences offer qualitative descriptions of spatial spread, but current approaches are poorly equipped to formally test and quantify the contribution of different potential explanatory factors, such ... | The emergence and worldwide dispersal of novel human pathogens is increasingly challenging global public health [1]. Notable recent examples include novel influenza strains, severe acute respiratory syndrome (SARS) virus and Methicillin-resistant Staphylococcus aureus, which all exploit today's complex and voluminous t... |
10.1371/journal.pmed.1002531 | Causes of death and infant mortality rates among full-term births in the United States between 2010 and 2012: An observational study | While the high prevalence of preterm births and its impact on infant mortality in the US have been widely acknowledged, recent data suggest that even full-term births in the US face substantially higher mortality risks compared to European countries with low infant mortality rates. In this paper, we use the most recent... | High infant mortality rates in the US compared to other high-income countries have been well documented in the literature.
Most of this literature primarily attributes high infant mortality in the US to the high rates of prematurity.
Relatively little is known regarding the survival of infants born full-term.
We compar... | Despite some progress made in recent years, infant mortality rates in the US continue to be high compared to other high-income countries [1]. According to the latest estimates, the US currently ranks 44th among 199 countries of all income levels, with an infant mortality rate of 5.6 deaths per 1,000 live births in 2015... |
10.1371/journal.pcbi.1003767 | Quantitatively Characterizing the Ligand Binding Mechanisms of Choline Binding Protein Using Markov State Model Analysis | Protein-ligand recognition plays key roles in many biological processes. One of the most fascinating questions about protein-ligand recognition is to understand its underlying mechanism, which often results from a combination of induced fit and conformational selection. In this study, we have developed a three-pronged ... | Molecular recognition plays important roles in numerous biological processes including gene regulation, cell signaling and enzymatic activity. It has been suggested that molecular recognition employs a variety of mechanisms, ranging from induced fit to conformational selection. In many realistic systems, conformational... | Protein-ligand recognition plays a key role in many aspects of biological processes, such as enzyme catalysis, substrate translocation, and drug therapy [1]. Current studies indicate two prevailing models to address the recognition process: the induced fit model (where ligand binding induces conformational changes of t... |
10.1371/journal.pntd.0007169 | The diversity, evolution and ecology of Salmonella in venomous snakes | Reptile-associated Salmonella bacteria are a major, but often neglected cause of both gastrointestinal and bloodstream infection in humans globally. The diversity of Salmonella enterica has not yet been determined in venomous snakes, however other ectothermic animals have been reported to carry a broad range of Salmone... | Salmonella enterica is a remarkable bacterial species that causes Neglected Tropical Diseases globally. The burden of disease is greatest in some of the most poverty-afflicted regions of Africa, where salmonellosis frequently causes bloodstream infection with fatal consequences. The bacteria have the ability to colonis... | Salmonella is a clinically relevant bacterial pathogen that poses a significant burden upon public health worldwide [1–4]. Two groups of Salmonella serovars have clinical relevance with distinct host-specificity and disease manifestations. Typhoidal Salmonella is restricted to human hosts and presents as a systemic inf... |
10.1371/journal.pgen.1005804 | Pedigree- and SNP-Associated Genetics and Recent Environment are the Major Contributors to Anthropometric and Cardiometabolic Trait Variation | Genome-wide association studies have successfully identified thousands of loci for a range of human complex traits and diseases. The proportion of phenotypic variance explained by significant associations is, however, limited. Given the same dense SNP panels, mixed model analyses capture a greater proportion of phenoty... | Unravelling overall trait architecture of complex traits and diseases is important for phenotype prediction and disease prevention and correct modelling of the trait will further aid discovery of causative loci. Here we take advantage of genome-wide data and a large family-based study to examine the role of common gene... | Phenotypic variation for a quantitative trait is attributable to the summed effects of genetic and environmental influences together with any covariances and interactions. The proportion of phenotypic variance contributed by genetic variation is termed the heritability (h2) [1]. The heritability scales the influence of... |
10.1371/journal.pgen.1006369 | Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis | Despite recent advances in our understanding of the pathogenesis of ectodermal dysplasias (EDs), the molecular basis of many of these disorders remains unknown. In the present study, we aimed at elucidating the genetic basis of a new form of ED featuring facial dysmorphism, scalp hypotrichosis and hypodontia. Using who... | Ectodermal dysplasias refer to a large group of inherited disorders characterized by developmental defects in tissues of ectodermal origin. The study of these conditions has been instrumental in the discovery of biological pathways involved in the regulation of epithelial tissue morphogenesis. In this report, through t... | Ectodermal dysplasias refer to a large clinically and genetically heterogeneous group of disorders characterized by developmental defects affecting tissues of ectodermal origin [1]. These conditions therefore feature various combinations of cutaneous, nail, hair, dental or limb anomalies which demarcate the various sub... |
10.1371/journal.pgen.1006650 | SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer | Hepatocellular carcinoma (HCC) is the fifth most common solid tumor in the world and the third leading cause of cancer-associated deaths. A Sleeping Beauty-mediated transposon mutagenesis screen previously identified mutations that cooperate with MYC to accelerate liver tumorigenesis. This revealed a tumor suppressor r... | Liver cancer is the third leading cause of cancer-associated deaths worldwide with limited responses to targeted therapies. An unbiased forward genetic screen previously revealed a tumor suppressor role for the Steroid Receptor Coactivator 2 (Src-2) in liver cancer driven by the MYC oncogene. Yet, SRC-2 has been shown ... | Hepatocellular carcinoma (HCC) is the fifth most common solid tumor and the third leading cause of cancer-related deaths, resulting in approximately 700,000 deaths per year worldwide [1]. Liver tumorigenesis occurs in settings of chronic inflammation, cirrhosis, or glycogen storage disease [2, 3]. Previous studies have... |
10.1371/journal.pntd.0006415 | Quantification of pathogenic Leptospira in the soils of a Brazilian urban slum | Leptospirosis is an important zoonotic disease that causes considerable morbidity and mortality globally, primarily in residents of urban slums. While contact with contaminated water plays a critical role in the transmission of leptospirosis, little is known about the distribution and abundance of pathogenic Leptospira... | Leptospirosis is a globally distributed zoonotic disease that disproportionately affects vulnerable populations in urban slums. The disease is transmitted by direct contact with water, soil, or mud that has been contaminated with infected urine shed from chronically infected animals. Despite the critical role the envir... | Leptospirosis is a life-threatening, zoonotic disease of global importance, with more than 1 million cases and approximately 60,000 deaths estimated annually, predominately in developing tropical countries [1]. The disease is caused by spirochetes of the genus Leptospira, which contains 35 species, 13 of which in the p... |
10.1371/journal.pgen.1007473 | RES complex is associated with intron definition and required for zebrafish early embryogenesis | Pre-mRNA splicing is a critical step of gene expression in eukaryotes. Transcriptome-wide splicing patterns are complex and primarily regulated by a diverse set of recognition elements and associated RNA-binding proteins. The retention and splicing (RES) complex is formed by three different proteins (Bud13p, Pml1p and ... | RES complex is essential for splicing in yeast but its function and role during vertebrate development are unknown. Here, we combined genetic loss-of-function mutants with transcriptomic analysis and found that a subset of introns is particularly affected in RES complex knock-out background. Those introns display the m... | Splicing is critical step in eukaryotic gene expression and is an important source of transcriptomic complexity [1]. Splicing is carried out by the spliceosome, a large macromolecular complex that includes five small nuclear ribonucleoproteins (snRNPs; U1, U2, U4, U5 and U6) and hundreds of core and accessory proteins ... |
10.1371/journal.pgen.1004699 | daf-31 Encodes the Catalytic Subunit of N Alpha-Acetyltransferase that Regulates Caenorhabditis elegans Development, Metabolism and Adult Lifespan | The Caenorhabditis elegans dauer larva is a facultative state of diapause. Mutations affecting dauer signal transduction and morphogenesis have been reported. Of these, most that result in constitutive formation of dauer larvae are temperature-sensitive (ts). The daf-31 mutant was isolated in genetic screens looking fo... | The development of a living organism is influenced by the environmental conditions such as nutrient availability. Under starvation conditions, the C. elegans larvae will enter a special developmental stage called dauer larva. An insulin-like signaling pathway controls dauer formation as well as adult lifespan by inhibi... | Animal development is a complex process that involves hierarchical gene regulatory networks and is influenced by environmental conditions. When food is abundant, the post-embryonic development of C. elegans consists of four larval stages (L1–L4) and the adult. During the L1 stage, environmental factors determine whethe... |
10.1371/journal.pntd.0005829 | Heterologous expression of the antimyotoxic protein DM64 in Pichia pastoris | Snakebite envenomation is a neglected condition that constitutes a public health problem in tropical and subtropical countries, including Brazil. Interestingly, some animals are resistant to snake envenomation due to the presence of inhibitory glycoproteins in their serum that target toxic venom components. DM64 is an ... | Snakebite envenomation causes medical emergencies that, depending on the species responsible for the bite, involve different organs and tissues. Envenomation by snakebite is a worldwide problem, and Brazil presents a high incidence of Bothrops bites. Bothrops venoms cause pathological alterations with prominent local e... | Accidents involving venomous snakes are medical emergencies that are often neglected in many tropical and subtropical countries [1]. Several epidemiological studies have tried to estimate the true burden of snakebite envenoming in the world. Overall, they have reported up to 5 million snake bites/envenoming per year, i... |
10.1371/journal.pcbi.1002887 | Linking Proteomic and Transcriptional Data through the Interactome and Epigenome Reveals a Map of Oncogene-induced Signaling | Cellular signal transduction generally involves cascades of post-translational protein modifications that rapidly catalyze changes in protein-DNA interactions and gene expression. High-throughput measurements are improving our ability to study each of these stages individually, but do not capture the connections betwee... | The ways in which cells respond to changes in their environment are controlled by networks of physical links among the proteins and genes. The initial signal of a change in conditions rapidly passes through these networks from the cytoplasm to the nucleus, where it can lead to long-term alterations in cellular behavior... | Cellular signaling and transcription are tightly integrated processes that underlie many short- and long-term cellular responses to the environment. Dysregulation of these molecular events has been implicated in diverse diseases including neurodegeneration [1], [2], metabolic disorders [3], and every stage of tumor dev... |
10.1371/journal.pcbi.1000888 | MetMap Enables Genome-Scale Methyltyping for Determining Methylation States in Populations | The ability to assay genome-scale methylation patterns using high-throughput sequencing makes it possible to carry out association studies to determine the relationship between epigenetic variation and phenotype. While bisulfite sequencing can determine a methylome at high resolution, cost inhibits its use in comparati... | In the vertebrates, methylation of cytosine residues in DNA regulates gene activity in concert with proteins that associate with DNA. Large-scale genomewide comparative studies that seek to link specific methylation patterns to disease will require hundreds or thousands of samples, and thus economical methods that assa... | New methods that assay epigenetic modifications over the whole genome promise to reveal insights into cell differentiation and development [1]–[15]. Moreover, incorporation of genome-scale epigenetic data into case-control studies is now becoming feasible, and has the potential to be a powerful tool in the study of dis... |
10.1371/journal.pgen.1002806 | TDP-1/TDP-43 Regulates Stress Signaling and Age-Dependent Proteotoxicity in Caenorhabditis elegans | TDP-43 is a multifunctional nucleic acid binding protein linked to several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia. To learn more about the normal biological and abnormal pathological role of this protein, we turned to Caenorhabditis elegans and its orthologu... | TAR DNA Binding Protein 43 (TDP-43) is implicated in several human age-dependent neurodegenerative disorders, but until now little was known about TDP-43's role in the aging process. Here we used the nematode Caenorhabditis elegans to study the role of the TDP-43 orthologue tdp-1 in aging and neurodegeneration. In this... | TDP-1 is the Caenorhabditis elegans orthologue of the multifunctional DNA/RNA binding protein TDP-43 (TAR DNA Binding Protein 43). Mutations and accumulations of TDP-43 have been found in patients with Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia, and in a growing number of neurodegenerative disorders [... |
10.1371/journal.pgen.1002449 | An siRNA Screen in Pancreatic Beta Cells Reveals a Role for Gpr27 in Insulin Production | The prevalence of type 2 diabetes in the United States is projected to double or triple by 2050. We reasoned that the genes that modulate insulin production might be new targets for diabetes therapeutics. Therefore, we developed an siRNA screening system to identify genes important for the activity of the insulin promo... | Pancreatic beta cells are the only physiologic source of insulin. When these cells are destroyed in type 1 diabetics, there is uncontrolled hyperglycemia from complete insulin deficiency. In type 2 diabetes, these same cells fail to increase insulin secretion to compensate for peripheral insulin resistance leading to r... | Nearly 13% of American adults have diabetes and these numbers continue to rise, mostly from an increase in type 2 diabetes [1], [2]. Although insulin resistance is a cardinal feature of type 2 diabetes, most people with insulin resistance do not develop diabetes because their pancreatic beta cells are able to compensat... |
10.1371/journal.pgen.1008212 | Longevity is determined by ETS transcription factors in multiple tissues and diverse species | Ageing populations pose one of the main public health crises of our time. Reprogramming gene expression by altering the activities of sequence-specific transcription factors (TFs) can ameliorate deleterious effects of age. Here we explore how a circuit of TFs coordinates pro-longevity transcriptional outcomes, which re... | Understanding the basic biology of ageing may help us to reduce the burden of ill-health that old age brings. Ageing is modulated by changes to gene expression, which are orchestrated by the coordinate activity of proteins called transcription factors (TFs). E-twenty six (ETS) TFs are a large family with cellular funct... | Ageing is characterised by a steady systematic decline in biological function, and increased likelihood of disease[1]. Understanding the basic biology of ageing therefore promises to help improve the overall health of older people, who constitute an ever-increasing proportion of our populations. In experimental systems... |
10.1371/journal.pbio.1000604 | A High Precision Survey of the Molecular Dynamics of Mammalian Clathrin-Mediated Endocytosis | Dual colour total internal reflection fluorescence microscopy is a powerful tool for decoding the molecular dynamics of clathrin-mediated endocytosis (CME). Typically, the recruitment of a fluorescent protein–tagged endocytic protein was referenced to the disappearance of spot-like clathrin-coated structure (CCS), but ... | The molecular machinery of clathrin-mediated endocytosis concentrates receptors at the cell surface in a patch of membrane that curves into a vesicle, pinches off, and internalizes membrane cargo and a tiny volume of extracellular fluid. We know that dozens of proteins are involved in this process, but precisely when a... | Clathrin-mediated endocytosis (CME) is the principal means by which mammalian cells internalize cell surface receptors (reviewed in [1]). Some 40 years of electron microscopy (EM), genetic, and biochemical studies are distilled in the canonical model of CME [2] (reviewed in Figure S1). Here, interaction of receptors wi... |
10.1371/journal.pgen.1000633 | Regulation of Ubx Expression by Epigenetic Enhancer Silencing in Response to Ubx Levels and Genetic Variation | For gene products that must be present in cells at defined concentrations, expression levels must be tightly controlled to ensure robustness against environmental, genetic, and developmental noise. By studying the regulation of the concentration-sensitive Drosophila melanogaster Hox gene Ultrabithorax (Ubx), we found t... | Gene expression is generally governed by cis-regulatory elements, also called enhancers. For genes whose expression levels must be tightly controlled, enhancer activities must be tightly regulated. In this work, we show that enhancers that control the expression of the Hox gene Ultrabithorax (Ubx) in Drosophila are reg... | The transcriptional control of gene expression in eukaryotes is governed by cis-regulatory elements, also known as enhancers, that integrate cell-type and temporal information by binding combinations of transcription factors. Genes that exhibit complex expression patterns are typically controlled by multiple cis-regula... |
10.1371/journal.pntd.0002604 | Analysis of the Vaccine Potential of Plasmid DNA Encoding Nine Mycolactone Polyketide Synthase Domains in Mycobacterium ulcerans Infected Mice | There is no effective vaccine against Buruli ulcer. In experimental footpad infection of C57BL/6 mice with M. ulcerans, a prime-boost vaccination protocol using plasmid DNA encoding mycolyltransferase Ag85A of M. ulcerans and a homologous protein boost has shown significant, albeit transient protection, comparable to t... | Buruli ulcer (BU) is an infectious disease, characterized by deep, ulcerating skin lesions, particularly on arms and legs, which are provoked by a toxin. BU is caused by a microbe of the genus that also cause tuberculosis and leprosy. The 33 countries where Buruli ulcer has been detected, especially in West Africa, hav... | Buruli ulcer (BU) is a necrotizing bacterial skin disease caused by Mycobacterium ulcerans. M. ulcerans produces a diffusible macrolide toxin, called mycolactone (ML) which is essential for bacterial virulence [1]. BU has been documented in 33 countries worldwide, although most of the cases occur in West Africa, primar... |
10.1371/journal.pgen.1001022 | Widespread Presence of Human BOULE Homologs among Animals and Conservation of Their Ancient Reproductive Function | Sex-specific traits that lead to the production of dimorphic gametes, sperm in males and eggs in females, are fundamental for sexual reproduction and accordingly widespread among animals. Yet the sex-biased genes that underlie these sex-specific traits are under strong selective pressure, and as a result of adaptive ev... | While sexual reproduction is widespread among animals, it remains enigmatic to what extent sexual reproduction is conserved and when sex-specific gametogenesis (spermatogenesis and oogenesis) originated in animals. Here we demonstrate the presence of the reproductive-specific protein Boule throughout bilaterally-symmet... | Evolution of sexual reproduction, consisting of the origin and maintenance of sex, has been a central focus of evolutionary biology since the time of Darwin. The origin of sex has generally been simplified to the question of the origin of meiosis, which is known to have a single origin among all eukaryotes [1], [2]. Ho... |
10.1371/journal.pgen.1000372 | Loss of Myotubularin Function Results in T-Tubule Disorganization in Zebrafish and Human Myotubular Myopathy | Myotubularin is a lipid phosphatase implicated in endosomal trafficking in vitro, but with an unknown function in vivo. Mutations in myotubularin cause myotubular myopathy, a devastating congenital myopathy with unclear pathogenesis and no current therapies. Myotubular myopathy was the first described of a growing list... | Congenital myopathies are inherited muscle conditions typically presenting in early childhood. They are individually rare, but as a group are likely as common as conditions such as muscular dystrophy. The zebrafish is an emerging experimental system for the study of myopathies. We have utilized the zebrafish to develop... | Myotubular myopathy is a severe, X-linked congenital myopathy with onset in infancy [1]. It is characterized by profound neonatal hypotonia and skeletal muscle weakness. It is associated with substantial mortality, with approximately half of all affected boys dying in the first year of life [2]. Surviving children have... |
10.1371/journal.pbio.1001564 | Control of Translation and miRNA-Dependent Repression by a Novel Poly(A) Binding Protein, hnRNP-Q | Translation control often operates via remodeling of messenger ribonucleoprotein particles. The poly(A) binding protein (PABP) simultaneously interacts with the 3′ poly(A) tail of the mRNA and the eukaryotic translation initiation factor 4G (eIF4G) to stimulate translation. PABP also promotes miRNA-dependent deadenylat... | The regulation of mRNA translation and stability is of paramount importance for almost every cellular function. In eukaryotes, the poly(A) binding protein (PABP) is a central regulator of both global and mRNA-specific translation. PABP simultaneously interacts with the 3′ poly(A) tail of the mRNA and the eukaryotic tra... | Proteins that form dynamic multiprotein complexes with eukaryotic mRNAs play important roles in the control of gene expression [1]. The composition and architecture of messenger ribonucleoprotein particles (mRNPs) largely determines their distribution between different subcellular structures (i.e., polysomes, stress gr... |
10.1371/journal.pgen.1006579 | Reduced Insulin/Insulin-Like Growth Factor Receptor Signaling Mitigates Defective Dendrite Morphogenesis in Mutants of the ER Stress Sensor IRE-1 | Neurons receive excitatory or sensory inputs through their dendrites, which often branch extensively to form unique neuron-specific structures. How neurons regulate the formation of their particular arbor is only partially understood. In genetic screens using the multidendritic arbor of PVD somatosensory neurons in the... | Sensory neurons sample their environment through highly branched structures termed dendritic arbors or trees. The precise patterning of dendritic arbors is important for the proper functioning of the nervous system, and evidence indicates an involvement of sensory neurons in neuropsychiatric disease such as autism spec... | During their development neurons can form complex dendritic branching patterns. The specific arbor morphologies of different neuron types are thought to have evolved to mediate the acquisition and processing of distinct inputs [1]. Defective arbor morphologies in brain neurons are a common cellular symptom in many neur... |
10.1371/journal.pcbi.1003256 | Reassessing Google Flu Trends Data for Detection of Seasonal and Pandemic Influenza: A Comparative Epidemiological Study at Three Geographic Scales | The goal of influenza-like illness (ILI) surveillance is to determine the timing, location and magnitude of outbreaks by monitoring the frequency and progression of clinical case incidence. Advances in computational and information technology have allowed for automated collection of higher volumes of electronic data an... | In November 2008, Google Flu Trends was launched as an open tool for influenza surveillance in the United States. Engineered as a system for early detection and daily monitoring of the intensity of seasonal influenza epidemics, Google Flu Trends uses internet search data and a proprietary algorithm to provide a surroga... | Influenza remains a paradox for public health: While influenza epidemics are expected seasonally in temperate climates, their exact timing and severity remain largely unpredictable, making them a challenge to ongoing preparedness, surveillance and response efforts [1]. Surveillance efforts for influenza seek to determi... |
10.1371/journal.pgen.1005135 | Turning Saccharomyces cerevisiae into a Frataxin-Independent Organism | Frataxin (Yfh1 in yeast) is a conserved protein and deficiency leads to the neurodegenerative disease Friedreich’s ataxia. Frataxin is a critical protein for Fe-S cluster assembly in mitochondria, interacting with other components of the Fe-S cluster machinery, including cysteine desulfurase Nfs1, Isd11 and the Isu1 sc... | Frataxin was discovered because mutations in the corresponding gene cause the neurodegenerative disease Friedreich’s ataxia. The finding that frataxin protein physically associates with scaffold proteins Isu1/IscU places it squarely in the pathway of Fe-S cluster assembly. Fe-S clusters are essential cofactors for many... | Frataxin is a highly conserved protein that is found in both prokaryotic and eukaryotic organisms [1]. The protein was originally identified based on its connection to Friedreich’s ataxia, which is an inherited neurodegenerative and cardiodegenerative disease resulting from a deficiency of frataxin [2]. Recently a mito... |
10.1371/journal.pcbi.1006883 | 3D computational models explain muscle activation patterns and energetic functions of internal structures in fish swimming | How muscles are used is a key to understanding the internal driving of fish swimming. However, the underlying mechanisms of some features of the muscle activation patterns and their differential appearance in different species are still obscure. In this study, we explain the muscle activation patterns by using 3D compu... | For undulatory swimming, fish form posteriorly traveling waves of body bending by activating their muscles sequentially along the body. However, experimental observations have shown that the muscle activation wave does not simply match the bending wave. Researchers have previously computed the torque required for muscl... | During the undulatory swimming of fish, a backward-traveling wave of body bending is formed to push against the water and generate propulsion. Muscle is the executor of the neural control and the source of mechanical power in fish swimming. Therefore, how muscles are used is a key question in understanding the control ... |
10.1371/journal.ppat.1000940 | Epstein-Barr Virus-Encoded LMP2A Induces an Epithelial–Mesenchymal Transition and Increases the Number of Side Population Stem-like Cancer Cells in Nasopharyngeal Carcinoma | It has been recently reported that a side population of cells in nasopharyngeal carcinoma (NPC) displayed characteristics of stem-like cancer cells. However, the molecular mechanisms underlying the modulation of such stem-like cell populations in NPC remain unclear. Epstein-Barr virus was the first identified human tum... | Epstein-Barr virus (EBV) infects about 90% of people worldwide and persists benignly as a latent infection. However, EBV is associated with different types of human cancer. Nasopharyngeal carcinoma (NPC) is the most commonly known EBV associated cancer and expresses a well defined set of latent viral genes, including L... | Nasopharyngeal carcinoma (NPC) is the most frequent head and neck tumor in Guangdong, South China, where the incidence peaks at 50 per 100,000, but is rare in the Western world (1 per 100,000) [1], [2]. NPC is a highly malignant cancer which often invades adjacent regions and metastasizes to regional lymph nodes and di... |
10.1371/journal.pgen.1007830 | Global transcriptional regulation of innate immunity by ATF-7 in C. elegans | The nematode Caenorhabditis elegans has emerged as a genetically tractable animal host in which to study evolutionarily conserved mechanisms of innate immune signaling. We previously showed that the PMK-1 p38 mitogen-activated protein kinase (MAPK) pathway regulates innate immunity of C. elegans through phosphorylation... | Innate immunity is the first line of defense against invading microbes across metazoans. Caenorhabditis elegans lacks adaptive immunity and is therefore particularly dependent on mounting an innate immune response against pathogens. A major component of this response is the conserved PMK-1/p38 MAPK signaling cascade, t... | Convergent genetic studies of host defense of Drosophila melanogaster and mammalian innate immune signaling revealed a commonality in signaling pathways of innate immunity that has helped motivate the study of pathogen resistance mechanisms in genetically tractable host organisms such as Caenorhabditis elegans [1]. The... |
10.1371/journal.pgen.1007578 | The roles of SMYD4 in epigenetic regulation of cardiac development in zebrafish | SMYD4 belongs to a family of lysine methyltransferases. We analyzed the role of smyd4 in zebrafish development by generating a smyd4 mutant zebrafish line (smyd4L544Efs*1) using the CRISPR/Cas9 technology. The maternal and zygotic smyd4L544Efs*1 mutants demonstrated severe cardiac malformations, including defects in le... | SMYD4 belongs to a SET and MYND domain-containing lysine methyltransferase. In zebrafish, smyd4 is ubiquitously expressed in early embryos and becomes enriched in the developing heart at 48 hours post-fertilization (hpf). We generated a smyd4 mutant zebrafish line (smyd4L544Efs*1) using the CRISPR/Cas9 technology. The ... | Protein post-translational modifications (PTMs) are critical for the biological function of proteins. Histone modification is a common epigenetic mechanism that plays essential roles in the regulation of chromatin structure and gene expression. Different types of histone modifications, which are mediated by a series of... |
10.1371/journal.ppat.1006010 | Pyrimidine Salvage Enzymes Are Essential for De Novo Biosynthesis of Deoxypyrimidine Nucleotides in Trypanosoma brucei | The human pathogenic parasite Trypanosoma brucei possess both de novo and salvage routes for the biosynthesis of pyrimidine nucleotides. Consequently, they do not require salvageable pyrimidines for growth. Thymidine kinase (TK) catalyzes the formation of dTMP and dUMP and is one of several salvage enzymes that appear ... | Human pathogenic trypanosomatids are responsible for several life threatening diseases, together infecting 20 million people, while treatment is complicated by poor drug therapies. The unique biology of these organisms has led to the need for different drug therapies to be developed for each. Identification of enzymati... | The parasitic trypanosomatids are vector-borne single-celled eukaryotic pathogens that cause significant disease and mortality in tropical and subtropical countries [1]. Human African trypanosomiasis (HAT), Leishmaniasis and Chagas disease affect 20 million people combined, but control is hampered by lack of good drugs... |
10.1371/journal.pgen.1002486 | Precocious Metamorphosis in the Juvenile Hormone–Deficient Mutant of the Silkworm, Bombyx mori | Insect molting and metamorphosis are intricately governed by two hormones, ecdysteroids and juvenile hormones (JHs). JHs prevent precocious metamorphosis and allow the larva to undergo multiple rounds of molting until it attains the proper size for metamorphosis. In the silkworm, Bombyx mori, several “moltinism” mutati... | The number of larval instars in insects varies greatly across insect taxa and can even vary at the intraspecific level. However, little is known about how the number of larval instars is fixed in each species or modified by the environment. The silkworm, Bombyx mori, provides a unique bioresource for investigating this... | The number of larval instars in insects varies greatly across insect taxa, and can even vary at the intraspecific level [1], [2], [3]. In general, phylogenetically higher insects tend to have fewer larval instars (three to eight) compared to species from basal lineages, such as Ephemeroptera, Odonata and Plecoptera (mo... |
10.1371/journal.pcbi.1002309 | Tuning the Mammalian Circadian Clock: Robust Synergy of Two Loops | The circadian clock is accountable for the regulation of internal rhythms in most living organisms. It allows the anticipation of environmental changes during the day and a better adaptation of physiological processes. In mammals the main clock is located in the suprachiasmatic nucleus (SCN) and synchronizes secondary ... | Most organisms have evolved an internal clock which allows them to anticipate and react to the light/dark daily rhythm and is able to generate oscillation with a circa 24 hour rhythm. A molecular network involving feedback loops is responsible for the rhythm generation. A large number of clock-controlled genes pass on ... | Circadian rhythms can be found in most organisms, from bacteria to humans and are a fundamental property of living cells [1]. These endogenous rhythms provide a way to anticipate external cues and to adapt molecular and behavioural processes to specific day-times with the advantage of temporally separating incompatible... |
10.1371/journal.pcbi.0030181 | Organization and Evolution of Primate Centromeric DNA from Whole-Genome Shotgun Sequence Data | The major DNA constituent of primate centromeres is alpha satellite DNA. As much as 2%–5% of sequence generated as part of primate genome sequencing projects consists of this material, which is fragmented or not assembled as part of published genome sequences due to its highly repetitive nature. Here, we develop comput... | Centromeric DNA has been described as the last frontier of genomic sequencing; such regions are typically poorly assembled during the whole-genome shotgun sequence assembly process due to their repetitive complexity. This paper develops a computational algorithm to systematically extract data regarding primate centrome... | Alpha-satellite is the only functional DNA sequence associated with all naturally occurring human centromeres. Alpha satellite consists of tandem repetitions of a 171-bp AT-rich sequence motif (called a monomer). In humans, two distinct forms of alpha-satellite are recognized based on their organization and sequence pr... |
10.1371/journal.ppat.1006774 | The amino-terminus of the hepatitis C virus (HCV) p7 viroporin and its cleavage from glycoprotein E2-p7 precursor determine specific infectivity and secretion levels of HCV particle types | Viroporins are small transmembrane proteins with ion channel activities modulating properties of intracellular membranes that have diverse proviral functions. Hepatitis C virus (HCV) encodes a viroporin, p7, acting during assembly, envelopment and secretion of viral particles (VP). HCV p7 is released from the viral pol... | Viroporins are small transmembrane viral proteins with ion channel activities modulating properties of intracellular membranes, which impacts several fundamental biological processes such as trafficking, ion fluxes as well as connections and exchanges between organelles. Hepatitis C virus (HCV) encodes a viroporin, p7,... | Hepatitis C virus (HCV) infection is a major cause of chronic liver diseases worldwide. With 180 million people persistently infected, chronic HCV infection induces liver diseases such as liver cirrhosis and hepatocellular carcinoma. Although new direct antiviral agents are now able to eradicate the virus in most patie... |
10.1371/journal.pbio.1001823 | In Vivo Time-Resolved Microtomography Reveals the Mechanics of the Blowfly Flight Motor | Dipteran flies are amongst the smallest and most agile of flying animals. Their wings are driven indirectly by large power muscles, which cause cyclical deformations of the thorax that are amplified through the intricate wing hinge. Asymmetric flight manoeuvres are controlled by 13 pairs of steering muscles acting dire... | A blowfly's wingbeat is 50 times shorter than a blink of a human eye, and is controlled by numerous tiny steering muscles—some of which are as thin as a human hair. To visualize the movements of these muscles and the deformations of the surrounding exoskeleton, we developed a technique to allow us to look inside the in... | Insects are the smallest and most agile of all flying animals. These attributes are taken to extremes in the dipteran flies, whose single pair of wings enable a range of dramatic flight manoeuvres, from turning on the spot, or flying backwards, to even landing on ceilings. The blowfly Calliphora vicina routinely pulls ... |
10.1371/journal.pgen.1001227 | The DNA Damage Response Pathway Contributes to the Stability of Chromosome III Derivatives Lacking Efficient Replicators | In eukaryotic chromosomes, DNA replication initiates at multiple origins. Large inter-origin gaps arise when several adjacent origins fail to fire. Little is known about how cells cope with this situation. We created a derivative of Saccharomyces cerevisiae chromosome III lacking all efficient origins, the 5ORIΔ-ΔR fra... | Loss of genome integrity underlies aspects of aging and human disease. During DNA replication, two parallel signaling pathways play important roles in the maintenance of genome integrity. One pathway detects DNA damage, while the other senses replication stress. Both pathways activate responses that include arrest of c... | In eukaryotic chromosomes, DNA replication initiates at multiple origins, specified by cis-acting sequences called replicators. In the budding yeast, Saccharomyces cerevisiae, replicators are termed ARS elements and were identified by their ability to promote extrachromosomal maintenance of plasmids. Chromosomal replic... |
10.1371/journal.pgen.1007517 | Sequence features governing aggregation or degradation of prion-like proteins | Enhanced protein aggregation and/or impaired clearance of aggregates can lead to neurodegenerative disorders such as Alzheimer’s Disease, Huntington’s Disease, and prion diseases. Therefore, many protein quality control factors specialize in recognizing and degrading aggregation-prone proteins. Prions, which generally ... | Protein aggregation is associated with a variety of diseases, including Alzheimer’s disease and Amyotrophic Lateral Sclerosis. Cells possess a number of factors that can recognize aggregation-prone protein features and prevent aggregation. One common way this is achieved is through the pre-emptive degradation of aggreg... | Protein misfolding disorders involve the conversion of native proteins into non-native, deleterious forms. Some misfolded proteins form highly ordered amyloid aggregates, stabilized by intermolecular cross-β sheets. Once formed, these aggregates can convert remaining soluble proteins to the aggregated form via a templa... |
10.1371/journal.pgen.1000615 | Phosphofructo-1-Kinase Deficiency Leads to a Severe Cardiac and Hematological Disorder in Addition to Skeletal Muscle Glycogenosis | Mutations in the gene for muscle phosphofructo-1-kinase (PFKM), a key regulatory enzyme of glycolysis, cause Type VII glycogen storage disease (GSDVII). Clinical manifestations of the disease span from the severe infantile form, leading to death during childhood, to the classical form, which presents mainly with exerci... | Type VII glycogen storage disease (GSDVII), or Tarui disease, is a rare genetic disorder characterized by glycogen accumulation in skeletal muscle. The molecular cause is loss of activity of the muscle isoform of phosphofructokinase (PFK), which phosphorylates fructose-6-phosphate to fructose-1,6-bisphosphate, commitin... | Phosphofructo-1-kinase (PFK) is a tetrameric enzyme that phosphorylates fructose-6-phosphate to fructose-1,6-bisphosphate, committing glucose to glycolysis. Three PFK isoenzymes, encoded by separate genes, have been identified in mammals: muscle-type (PFKM), liver-type (PFKL), and platelet-type (PFKP), all of which are... |
10.1371/journal.pntd.0001041 | A Phase Two Randomised Controlled Double Blind Trial of High Dose
Intravenous Methylprednisolone and Oral Prednisolone versus Intravenous Normal
Saline and Oral Prednisolone in Individuals with Leprosy Type 1 Reactions and/or
Nerve Function Impairment | Leprosy Type 1 reactions are a major cause of nerve damage and the
preventable disability that results. Type 1 reactions are treated with oral
corticosteroids and there are few data to support the optimal dose and
duration of treatment. Type 1 reac... | Leprosy is caused by a bacterium and is curable with a combination of antibiotics
known as multi-drug therapy that patients take for six or 12 months. However a
significant proportion of leprosy patients experience inflammation in their skin
and/or nerves, whi... | Leprosy is a chronic granulomatous infection principally affecting the skin and
peripheral nerves caused by the obligate intracellular organism
Mycobacterium leprae
[2]. The disease
causes skin lesions and neuropathy. Complications secondary to the neu... |
10.1371/journal.pgen.1006748 | Dysregulation of INF2-mediated mitochondrial fission in SPOP-mutated prostate cancer | Next-generation sequencing of the exome and genome of prostate cancers has identified numerous genetic alternations. SPOP (Speckle-type POZ Protein) was one of the most frequently mutated genes in primary prostate cancer, suggesting SPOP is a potential driver of prostate cancer development and progression. However, how... | Prostate cancer is the leading cause of global cancer-related death. The development of improved diagnoses and novel therapies has been confounded by significant patient heterogeneity. During recent years, significant progress has been made in identifying the molecular alterations in prostate cancer using next-generati... | Large-scale exome/genome sequencing studies have recently revealed that recurrent mutations in the SPOP gene occur in up to 15% of prostate cancers [1–4]. Interestingly, the SPOP mutant subset of prostate cancers had some notable molecular features, including mutual exclusivity with ERG gene rearrangement, elevated lev... |
10.1371/journal.ppat.1002897 | Vector-Borne Transmission Imposes a Severe Bottleneck on an RNA Virus Population | RNA viruses typically occur in genetically diverse populations due to their error-prone genome replication. Genetic diversity is thought to be important in allowing RNA viruses to explore sequence space, facilitating adaptation to changing environments and hosts. Some arboviruses that infect both a mosquito vector and ... | The ability of arboviruses to perpetuate in nature given that they must infect two disparate hosts (the mosquito vector and the vertebrate host) remains a mystery. We studied how viral genetic diversity is impacted by the dual host transmission cycle. Our studies of an enzootic cycle using Venezuelan equine encephaliti... | RNA virus replication is characterized by a high frequency of mutation, which leads to genetically diverse populations. This diversity is thought to enable RNA viruses to effectively survive within the host (i.e. escape or evade immune responses), to be transmitted, and to potentially adapt to new hosts or vectors. Whi... |
10.1371/journal.pntd.0003055 | Emergence of Coxiella burnetii in Ruminants on Reunion Island? Prevalence and Risk Factors | Q fever is a widespread zoonosis that is caused by Coxiella burnetii (C. burnetii), and ruminants are identified as the main sources of human infections. Some human cases have been described, but very limited information was available about Q fever in ruminants on Reunion Island, a tropical island in the Indian Ocean. ... | Q fever is a disease that could be transmitted from animals (cattle, sheep and goats) to humans and caused by a bacterium called Coxiella burnetii (C. burnetii). Some human cases exhibiting characteristic clinical signs of that disease have been detected on Reunion Island, a tropical island in the Indian Ocean, but to ... | Q fever is a widespread zoonosis that is caused by Coxiella burnetii (C. burnetii), an obligate intracellular bacterium [1]–[4]. The reservoir includes mammals, birds and arthropods, mainly ticks [5]. Ruminants (sheep, goats and cattle) are identified as the main sources of human infections [6], [7]. Humans are infecte... |
10.1371/journal.pcbi.1003666 | Augmenting Microarray Data with Literature-Based Knowledge to Enhance Gene Regulatory Network Inference | Gene regulatory networks are a crucial aspect of systems biology in describing molecular mechanisms of the cell. Various computational models rely on random gene selection to infer such networks from microarray data. While incorporation of prior knowledge into data analysis has been deemed important, in practice, it ha... | We have developed a methodology that combines standard computational analysis of gene expression data with knowledge in the literature to identify pathways of gene and protein interactions. We extract the knowledge from PubMed citations using a tool (SemRep) that identifies specific relationships between genes or prote... | Gene regulatory networks (GRNs) are DNA-encoded regulatory subsystems in the genome that coordinate input from activator and repressor transcription factors to control various biological functions, including development, cell differentiation, and response to environmental cues. They provide a systems level illustration... |
10.1371/journal.pgen.1002181 | Pervasive Sign Epistasis between Conjugative Plasmids and Drug-Resistance Chromosomal Mutations | Multidrug-resistant bacteria arise mostly by the accumulation of plasmids and chromosomal mutations. Typically, these resistant determinants are costly to the bacterial cell. Yet, recently, it has been found that, in Escherichia coli bacterial cells, a mutation conferring resistance to an antibiotic can be advantageous... | Bacteria can become resistant to antibiotics by spontaneous mutation of chromosomal genes or through the acquisition of horizontally mobile genetic elements, mainly conjugative plasmids. Plasmid-borne resistance is widespread among bacterial pathogens. Plasmids generally entail a cost to the host, associated with the r... | Multidrug resistance is a major hurdle for modern medicine, putting at risk commonplace medical practices [1] and the treatment of infection by bacterial pathogens [2]. Bacteria can become resistant by spontaneous mutation of chromosomal genes or through the acquisition of horizontally mobile genetic elements [1]. In t... |
10.1371/journal.pntd.0000729 | Cyclosporin A Treatment of Leishmania donovani Reveals Stage-Specific Functions of Cyclophilins in Parasite Proliferation and Viability | Cyclosporin A (CsA) has important anti-microbial activity against parasites of the genus Leishmania, suggesting CsA-binding cyclophilins (CyPs) as potential drug targets. However, no information is available on the genetic diversity of this important protein family, and the mechanisms underlying the cytotoxic effects o... | Visceral leishmanisasis, also known as Kala Azar, is caused by the protozoan parasite Leishmania donovani. The L. donovani infectious cycle comprises two developmental stages, a motile promastigote stage that proliferates inside the digestive tract of the phlebotomine insect host, and a non-motile amastigote stage that... | The cyclophilin (CyP) protein family consists of highly conserved proteins that share a common signature region of approximately 109 amino acids, the cyclophilin-like domain (CLD, Prosite access number: PS50072). The CLD carries the peptidylprolyl isomerase (PPIase) activity characteristic of CyPs [1], which has been i... |
10.1371/journal.pcbi.1006423 | The physiological variability of channel density in hippocampal CA1 pyramidal cells and interneurons explored using a unified data-driven modeling workflow | Every neuron is part of a network, exerting its function by transforming multiple spatiotemporal synaptic input patterns into a single spiking output. This function is specified by the particular shape and passive electrical properties of the neuronal membrane, and the composition and spatial distribution of ion channe... | The peak conductance of many ion channel types measured in any given animal is highly variable across neurons, both within and between neuronal populations. The current view is that this occurs because a neuron needs to adapt its intrinsic electrophysiological properties either to maintain the same operative range in t... | Any given neuron in the brain is part of a network, in which it exerts its action by transforming the input it receives into an output. This function is specified by the particular shape and passive electrical properties of the neuronal membrane, the composition and spatial distribution of ion channels across its proce... |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.