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10.1371/journal.ppat.1002337 | IFITM3 Inhibits Influenza A Virus Infection by Preventing Cytosolic Entry | To replicate, viruses must gain access to the host cell's resources. Interferon (IFN) regulates the actions of a large complement of interferon effector genes (IEGs) that prevent viral replication. The interferon inducible transmembrane protein family members, IFITM1, 2 and 3, are IEGs required for inhibition of influe... | Influenza epidemics exact a great toll on world health. Thus research to identify new anti-influenza virus strategies would be useful. Each of our cells contains antiviral factors that work to inhibit infection. A large component of this antiviral program is regulated by the interferon family of signaling molecules. He... | The 2009 H1N1 pandemic provided a strong reminder of the threat that influenza A virus poses to world health (http://www.cdc.gov/h1n1flu/cdcresponse.htm). The most effective means of protection against influenza is the seasonal vaccine. However, if the vaccine does not match the viral strains, its effectiveness can be ... |
10.1371/journal.ppat.1002736 | DNase Sda1 Allows Invasive M1T1 Group A Streptococcus to Prevent TLR9-Dependent Recognition | Group A Streptococcus (GAS) has developed a broad arsenal of virulence factors that serve to circumvent host defense mechanisms. The virulence factor DNase Sda1 of the hyperinvasive M1T1 GAS clone degrades DNA-based neutrophil extracellular traps allowing GAS to escape extracellular killing. TLR9 is activated by unmeth... | Group A Streptococcus (GAS) ranks among the top ten human pathogens causing fatal disease. GAS possesses an arsenal of virulence factors that circumvent the primary mammalian defence strategies, the innate immune system. Toll-like receptors (TLRs), allow the host to detect pathogens by recognizing structures or pattern... | The Gram-positive bacterium Group A Streptococcus (GAS) is a leading human pathogen, annually causing over 700 million cases of superficial infections such as pharyngitis or pyoderma, and more than 650,000 cases of invasive infections, including the potentially lethal conditions of necrotizing fasciitis (NF) and strept... |
10.1371/journal.pgen.1007781 | RNase H1 directs origin-specific initiation of DNA replication in human mitochondria | Human mitochondrial DNA (mtDNA) replication is first initiated at the origin of H-strand replication. The initiation depends on RNA primers generated by transcription from an upstream promoter (LSP). Here we reconstitute this process in vitro using purified transcription and replication factors. The majority of all tra... | Human mitochondria contain a double-stranded DNA genome that codes for key components of the oxidative phosphorylation system. The mitochondrial DNA (mtDNA) is replicated by a replication machinery distinct from that operating in the nucleus and mutations affecting individual replication factors have been associated wi... | Mitochondrial DNA (mtDNA) is a 16.6 kb circular, double-stranded DNA (dsDNA) molecule that contains genes for 13 components of the oxidative phosphorylation (OXPHOS) system as well as the 22 tRNAs and 2 rRNAs required for their translation. The two strands can be separated by CsCl gradient density centrifugation and ar... |
10.1371/journal.pgen.1007435 | A neuronal MAP kinase constrains growth of a Caenorhabditis elegans sensory dendrite throughout the life of the organism | Neurons develop elaborate morphologies that provide a model for understanding cellular architecture. By studying C. elegans sensory dendrites, we previously identified genes that act to promote the extension of ciliated sensory dendrites during embryogenesis. Interestingly, the nonciliated dendrite of the oxygen-sensin... | Lewis Carroll's Alice told the Caterpillar, "Being so many different sizes in a day is very confusing." Like Alice, the cells of our bodies face a problem in size control – they must become the right size and remain that way throughout the life of the organism. This problem is especially relevant for nerve cells (neuro... | Neurons embody the adage that structure determines function in biology. The geometries and lengths of axons and dendrites determine the path and timing of information flow. Dendrites, in particular, are sculpted in ways that control how information is integrated and computed. One well-studied aspect of dendrite morphog... |
10.1371/journal.ppat.1002793 | The Lectin Pathway of Complement Activation Is a Critical Component of the Innate Immune Response to Pneumococcal Infection | The complement system plays a key role in host defense against pneumococcal infection. Three different pathways, the classical, alternative and lectin pathways, mediate complement activation. While there is limited information available on the roles of the classical and the alternative activation pathways of complement... | Streptococcus pneumoniae is a major human pathogen that causes pneumonia, septicemia and meningitis. The host defense against pneumococci is largely dependent on complement, a system of blood proteins which, when activated, attach to bacteria, targeting them for clearance by phagocytes. There are three routes of comple... | Streptococcus pneumoniae infection is a major cause of pneumonia, otitis media, septicemia and meningitis [1], [2]. Complement–driven opsonophagocytosis is a prominent feature of the host response to pneumococcal infections, [3].
Complement provides protection against invading microorganisms through both antibod... |
10.1371/journal.pntd.0001686 | Vasa-Like DEAD-Box RNA Helicases of Schistosoma mansoni | Genome sequences are available for the human blood flukes, Schistosoma japonicum, S. mansoni and S. haematobium. Functional genomic approaches could aid in identifying the role and importance of these newly described schistosome genes. Transgenesis is established for functional genomics in model species, which can lead... | Schistosomes, the blood flukes, are responsible for the major neglected tropical diseases termed schistosomiasis, which afflicts >200 million people in impoverished regions of the developing world. The genome sequence of these parasites has been decoded recently. The DEAD-box family is the largest of RNA helicase famil... | Schistosomiasis is considered the most important of the human helminthiases in terms of morbidity and mortality. It is endemic to 76 countries, affecting an estimated 200 million people with an additional 700 million people at risk of infection [1]–[3]. Draft genome sequences of all three of the major schistosome speci... |
10.1371/journal.pcbi.1000575 | Computational Model of Membrane Fission Catalyzed by ESCRT-III | ESCRT-III proteins catalyze membrane fission during multi vesicular body biogenesis, budding of some enveloped viruses and cell division. We suggest and analyze a novel mechanism of membrane fission by the mammalian ESCRT-III subunits CHMP2 and CHMP3. We propose that the CHMP2-CHMP3 complexes self-assemble into hemi-sp... | Membrane fission is a key step of fundamental intracellular processes such as endocytosis, membrane trafficking, cytokinesis and virus budding. The fission reaction requires substantial energy inputs provided by specialized proteins. Recently, the ESCRT-III proteins have been implicated in membrane budding and fission ... | Membrane fission leading to division of one continuous membrane into two separate ones is ubiquitous in cell physiology. It is one of the crucial events in generation of transport intermediates from plasma membranes and intracellular organelles; steady-state dynamics of the endoplasmic reticulum, mitochondria and Golgi... |
10.1371/journal.pgen.1004823 | Mutation of Npr2 Leads to Blurred Tonotopic Organization of Central Auditory Circuits in Mice | Tonotopy is a fundamental organizational feature of the auditory system. Sounds are encoded by the spatial and temporal patterns of electrical activity in spiral ganglion neurons (SGNs) and are transmitted via tonotopically ordered processes from the cochlea through the eighth nerve to the cochlear nuclei. Upon reachin... | Millions of people suffer from debilitating hearing defects, ranging from a complete inability to detect sound to more subtle changes in how sounds are encoded by the nervous system. Many forms of deafness are due to mutations in genes that impair the development or function of hair cells, which are responsible for cha... | The sense of hearing is mediated by precisely organized neural circuits that encode the frequency content, timing, and intensity of sounds. Frequency information is encoded in the spatial organization of hair cells in the cochlea, with high frequencies detected in the base and low frequencies in the apex. SGNs transmit... |
10.1371/journal.pcbi.1006119 | Assessing the public health impact of tolerance-based therapies with mathematical models | Disease tolerance is a defense strategy against infections that aims at maintaining host health even at high pathogen replication or load. Tolerance mechanisms are currently intensively studied with the long-term goal of exploiting them therapeutically. Because tolerance-based treatment imposes less selective pressure ... | Conventional therapies improve patient health by eliminating the pathogen, or, at least, reducing its burden. Recently, alternative therapies that exploit host tolerance mechanisms have received attention from the medical community as a promising strategy. These treatments aim at reducing the level of illness due to th... | Hosts can respond to infections in various ways. The host can reduce the pathogen replication or load and thus improve its health. In evolutionary ecology, such a response is called “host resistance”. Another possible host response is “disease tolerance”, that induces a state, in which the host, at a given pathogen loa... |
10.1371/journal.pbio.1001452 | Order–Disorder Transitions Govern Kinetic Cooperativity and Allostery of Monomeric Human Glucokinase | Glucokinase (GCK) catalyzes the rate-limiting step of glucose catabolism in the pancreas, where it functions as the body's principal glucose sensor. GCK dysfunction leads to several potentially fatal diseases including maturity–onset diabetes of the young type II (MODY-II) and persistent hypoglycemic hyperinsulinemia o... | Glucokinase is a key metabolic enzyme that functions as the body's principal glucose sensor. Glucokinase regulates the rate at which insulin is secreted by the pancreas by using a unique but poorly understood cooperative kinetic response to increasing glucose concentrations. The physiological importance of this enzyme ... | Human pancreatic glucokinase (GCK) is the body's principal glucose sensor [1]. GCK is a 52 kDa monomeric enzyme that catalyzes the formation of glucose-6-phosphate from glucose and ATP [2]. This chemical transformation represents the rate-limiting step of glucose catabolism in the pancreas, allowing GCK activity to reg... |
10.1371/journal.pcbi.1005282 | Predicting Structure-Function Relations and Survival following Surgical and Bronchoscopic Lung Volume Reduction Treatment of Emphysema | Lung volume reduction surgery (LVRS) and bronchoscopic lung volume reduction (bLVR) are palliative treatments aimed at reducing hyperinflation in advanced emphysema. Previous work has evaluated functional improvements and survival advantage for these techniques, although their effects on the micromechanical environment... | Surgical and, more recently, bronchoscopic lung volume reduction is the only available treatments for patients with advanced stage emphysema. Several large-scale, clinical studies have outlined appropriate selection criteria based on patient outcomes; however, the underlying mechanisms determining disease progression a... | Emphysema, a subtype of chronic obstructive pulmonary disease (COPD), is a progressively destructive lung tissue disease characterized by abnormal and permanent enlargement of airspaces distal to the terminal bronchioles. This largely preventable, yet presently incurable disease is associated with high morbidity and mo... |
10.1371/journal.pbio.1000429 | Cryptic Variation between Species and the Basis of Hybrid Performance | Crosses between closely related species give two contrasting results. One result is that species hybrids may be inferior to their parents, for example, being less fertile [1]. The other is that F1 hybrids may display superior performance (heterosis), for example with increased vigour [2]. Although various hypotheses ha... | A major conundrum in biology is why hybrids between species display two opposing features. On the one hand, hybrids are often more vigorous or productive than their parents, a phenomenon called hybrid vigor or hybrid superiority. On the other hand they often show reduced vigour and fertility, known as hybrid inferiorit... | Crosses between closely related species give two contrasting results [3]. One result is that species hybrids may be inferior to their parents, with reduced fertility or viability [1]. The other is that F1 hybrids may be superior (heterosis), with increased vigour [2],[4]. Hybrid inferiority is commonly explained throug... |
10.1371/journal.pcbi.1005313 | Identifying T Cell Receptors from High-Throughput Sequencing: Dealing with Promiscuity in TCRα and TCRβ Pairing | Characterisation of the T cell receptors (TCR) involved in immune responses is important for the design of vaccines and immunotherapies for cancer and autoimmune disease. The specificity of the interaction between the TCR heterodimer and its peptide-MHC ligand derives largely from the juxtaposed hypervariable CDR3 regi... | Our repertoires of T cell receptors (TCR) give our immune system the ability to recognise a huge diversity of foreign and self antigens, and identifying the TCRs involved in infectious disease, cancer, and autoimmune disease is important for designing vaccines and immunotherapies. The majority of T cells express a TCR ... | The ability of T cells to recognise antigens is conferred by a process of gene rearrangement that generates a diverse repertoire of T cell receptors (TCR), or clonotypes. Identifying the clonotypes involved in responses against pathogens and tumours or those involved in autoimmune disease can guide the design of vaccin... |
10.1371/journal.pcbi.1000440 | PoreWalker: A Novel Tool for the Identification and Characterization of Channels in Transmembrane Proteins from Their Three-Dimensional Structure | Transmembrane channel proteins play pivotal roles in maintaining the homeostasis and responsiveness of cells and the cross-membrane electrochemical gradient by mediating the transport of ions and molecules through biological membranes. Therefore, computational methods which, given a set of 3D coordinates, can automatic... | Transmembrane channel proteins are responsible for the transport of ions and molecules through biological membranes and are pivotal for the physiology of the cell. In fact, their incorrect functioning is involved or related to several diseases (diabetes, myotonia, Parkinson's disease, etc.). Moreover, their specificity... | Transmembrane channel proteins play pivotal roles in maintaining the homeostasis and responsiveness of cells and the cross-membrane electrochemical gradient by mediating the transport of ions and molecules through biological membranes [1]. For instance, aquaporins facilitate the flux of water and small uncharged solute... |
10.1371/journal.pcbi.1002739 | Evolution of Associative Learning in Chemical Networks | Organisms that can learn about their environment and modify their behaviour appropriately during their lifetime are more likely to survive and reproduce than organisms that do not. While associative learning – the ability to detect correlated features of the environment – has been studied extensively in nervous systems... | Whilst one may have believed that associative learning requires a nervous system, this paper shows that chemical networks can be evolved in silico to undertake a range of associative learning tasks with only a small number of reactions. The mechanisms are surprisingly simple. The networks can be analysed using Bayesian... | Here we evolve chemical networks in simulation to undertake associative learning. We define learning as the process by which information about the world is encoded into internal state (a memory-trace) in order to behave more adaptively in the future. Associative learning is learning of a relation between two types of e... |
10.1371/journal.pntd.0003269 | Dengue Virus Infections among Haitian and Expatriate Non-governmental Organization Workers — Léogane and Port-au-Prince, Haiti, 2012 | In October 2012, the Haitian Ministry of Health and the US CDC were notified of 25 recent dengue cases, confirmed by rapid diagnostic tests (RDTs), among non-governmental organization (NGO) workers. We conducted a serosurvey among NGO workers in Léogane and Port-au-Prince to determine the extent of and risk factors for... | Dengue is the most common mosquito-borne viral disease in the world, and caused an estimated 390 million infections and 96 million cases in the tropics and subtropics in 2010. Over the last decade, the number of cases of dengue and the severity of dengue virus infections have increased in the Americas, including the Ca... | Dengue is the most common mosquito-borne viral disease in the world, and resulted in an estimated 390 million infections and 96 million symptomatic cases throughout the tropics and subtropics in 2010 [1], [2]. Over the last decade, the incidence and the severity of dengue have increased in the Americas, including the C... |
10.1371/journal.pbio.2003174 | A damped oscillator imposes temporal order on posterior gap gene expression in Drosophila | Insects determine their body segments in two different ways. Short-germband insects, such as the flour beetle Tribolium castaneum, use a molecular clock to establish segments sequentially. In contrast, long-germband insects, such as the vinegar fly Drosophila melanogaster, determine all segments simultaneously through ... | Different insect species exhibit one of two distinct modes of determining their body segments (known as segmentation) during development: they either use a molecular oscillator to position segments sequentially, or they generate segments simultaneously through a hierarchical gene-regulatory cascade. The sequential mode... | The segmented body plan of insects is established by two seemingly very different modes of development [1–4]. Long-germband insects, such as the vinegar fly D. melanogaster, determine their segments more or less simultaneously during the blastoderm stage, before the onset of gastrulation [5, 6]. The segmental pattern i... |
10.1371/journal.pcbi.1000061 | Distinct Timing Mechanisms Produce Discrete and Continuous Movements | The differentiation of discrete and continuous movement is one of the pillars of motor behavior classification. Discrete movements have a definite beginning and end, whereas continuous movements do not have such discriminable end points. In the past decade there has been vigorous debate whether this classification impl... | A fundamental question in motor control research is whether distinct movement classes exist. Candidate classes are discrete and continuous movement. Discrete movements have a definite beginning and end, whereas continuous movements do not have such discriminable end points. In the past decade there has been vigorous, p... | Discrete movements constitute singularly occurring events preceded and followed by a period without motion (i.e., with zero velocity) for a reasonable amount of time, such as a single finger flexion or flexion-extension cycle [1],[2]. Continuous movements lack such recognizable endpoints, and normally are considered rh... |
10.1371/journal.ppat.1002649 | In Vivo Suppression of HIV by Antigen Specific T Cells Derived from Engineered Hematopoietic Stem Cells | The HIV-specific cytotoxic T lymphocyte (CTL) response is a critical component in controlling viral replication in vivo, but ultimately fails in its ability to eradicate the virus. Our intent in these studies is to develop ways to enhance and restore the HIV-specific CTL response to allow long-term viral suppression or... | There is a desperate need for the development of new therapeutic strategies to eradicate HIV infection. HIV actively subverts the potent natural immune responses against it, particularly cellular cytotoxic T lymphocyte (CTL) responses. The development of a therapy that allows long-lived immune self-containment of HIV a... | Human hematopoietic stem cells (HSCs), through development in the thymus, are capable of producing progeny T cells that generally display one of a vast repertoire of T cell receptors (TCRs). In the case of many non-persistent viral infections, T cells bearing TCRs specific to viral antigens mediate a potent antiviral r... |
10.1371/journal.pgen.1004461 | Cis and Trans Effects of Human Genomic Variants on Gene Expression | Gene expression is a heritable cellular phenotype that defines the function of a cell and can lead to diseases in case of misregulation. In order to detect genetic variations affecting gene expression, we performed association analysis of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) with gene ... | Humans differ in their genetic sequences at millions of positions but only a subset of these differences have a functional effect. In order to detect functional genetic differences, we assessed the impact of common genetic variants on gene expression in 869 individuals and discovered that the expression of many genes i... | Genome-wide association studies (GWAS) have discovered a large number of loci implicated in many complex traits and diseases [1]. The vast majority of variants discovered are found in non-coding regions (88%), which challenges the interpretation of their functional effect [1]. One way to overcome this challenge is to l... |
10.1371/journal.pgen.1000779 | Epigenetic Control of Virulence Gene Expression in Pseudomonas aeruginosa by a LysR-Type Transcription Regulator | Phenotypic variation within an isogenic bacterial population is thought to ensure the survival of a subset of cells in adverse conditions. The opportunistic pathogen Pseudomonas aeruginosa variably expresses several phenotypes, including antibiotic resistance, biofilm formation, and the production of CupA fimbriae. Her... | Bistable switches allow the expression of a gene, or set of genes, to switch from one stable expression state to another and can generate cells with different phenotypes in an isogenic population. In this work we uncover a previously unidentified bistable switch that controls virulence gene expression in the opportunis... | The Gram-negative bacterium Pseudomonas aeruginosa is an opportunistic pathogen of humans. It can cause infection in a wide variety of tissues in the immunocompromised host, and is the leading cause of morbidity and mortality in cystic fibrosis (CF) patients [1]. This breadth of infectious capacity is thought to result... |
10.1371/journal.pcbi.1002127 | Genome-Scale Analysis of Translation Elongation with a Ribosome Flow Model | We describe the first large scale analysis of gene translation that is based on a model that takes into account the physical and dynamical nature of this process. The Ribosomal Flow Model (RFM) predicts fundamental features of the translation process, including translation rates, protein abundance levels, ribosomal den... | Gene translation is a central process in all living organisms. However, this process is still enigmatic, and contradicting conclusions regarding the essential parameters that determine translation rates appear in different studies. We introduce a new approach for modeling the process of translation elongation. Taking i... | Gene translation is a complex process through which an mRNA sequence is decoded by the ribosome to produce a specific protein. The elongation step of this process is an iterative procedure in which each codon in the mRNA sequence is recognized by a specific tRNA, which adds one additional amino-acid to the growing pept... |
10.1371/journal.pgen.1000241 | Essential Role of Chromatin Remodeling Protein Bptf in Early Mouse Embryos and Embryonic Stem Cells | We have characterized the biological functions of the chromatin remodeling protein Bptf (Bromodomain PHD-finger Transcription Factor), the largest subunit of NURF (Nucleosome Remodeling Factor) in a mammal. Bptf mutants manifest growth defects at the post-implantation stage and are reabsorbed by E8.5. Histological anal... | While the chromatin of eukaryotes provides an efficient means to compact large amounts of DNA into a small nucleus, it renders the DNA relatively inaccessible. ATP-dependent chromatin remodeling complexes mobilize nucleosomes and provide a means to gain access to DNA in chromatin. While the biochemical functions of chr... | The packaging of eukaryotic DNA into chromatin provides a general mechanism for the modulation of gene activity and DNA metabolism through alterations of chromatin architecture. The structure and composition of chromatin can be altered by a number of distinct pathways, including post-translational modification of histo... |
10.1371/journal.pbio.0050192 | Myc Dynamically and Preferentially Relocates to a Transcription Factory Occupied by Igh | Transcription in mammalian nuclei is highly compartmentalized in RNA polymerase II-enriched nuclear foci known as transcription factories. Genes in cis and trans can share the same factory, suggesting that genes migrate to preassembled transcription sites. We used fluorescent in situ hybridization to investigate the dy... | Many different types of cancer result from gene translocations. Specifically, two different chromosomes can be joined that fuse growth control genes with powerful regulatory elements, leading to unrestricted control of cell growth. Translocation partner genes must physically encounter each other in the nucleus to under... | Interphase chromosomes are organized in tissue-specific arrangements in nuclei, suggesting that chromosomal position and juxtaposition play a role in gene expression [1–5]. Nonrandom chromosome positioning has also been implicated in the frequency of specific chromosomal translocations. For example, Chromosomes 12 and ... |
10.1371/journal.pcbi.1002032 | How Molecular Motors Are Arranged on a Cargo Is Important for Vesicular Transport | The spatial organization of the cell depends upon intracellular trafficking of cargos hauled along microtubules and actin filaments by the molecular motor proteins kinesin, dynein, and myosin. Although much is known about how single motors function, there is significant evidence that cargos in vivo are carried by multi... | The spatial organization of living cells depends upon a transportation system consisting of molecular motor proteins that act like porters carrying cargos along filaments that are analogous to roads. The breakdown of this transportation system has been associated with neurodegenerative diseases such as Alzheimer's and ... | Cells are highly organized, and much of this organization results from motors that move cargos along microtubules. The single-molecule properties of molecular motors are relatively well understood both experimentally and theoretically. With this as a starting point, we investigated how the presence of the cargo itself ... |
10.1371/journal.pntd.0005800 | The location of Australian Buruli ulcer lesions—Implications for unravelling disease transmission | Buruli ulcer (BU), caused by Mycobacterium ulcerans, is increasing in incidence in Victoria, Australia. To improve understanding of disease transmission, we aimed to map the location of BU lesions on the human body.
Using notification data and clinical records review, we conducted a retrospective observational study of... | Buruli ulcer is an emerging tropical disease that is also increasingly common in the temperate Australian state of Victoria. The mode of transmission of this geographically restricted infection remains elusive. We have accurately mapped the location of 649 PCR-confirmed Buruli lesions affecting 579 patients and display... | Buruli ulcer (BU), listed by the World Health Organisation (WHO) as a neglected tropical disease, is a destructive infection of the subcutaneous tissue caused by the acid-fast bacillus Mycobacterium ulcerans [1,2]. It is endemic in at least 33 countries and is the third most prevalent mycobacterial disease worldwide af... |
10.1371/journal.pbio.1000155 | CFTR Delivery to 25% of Surface Epithelial Cells Restores Normal Rates of Mucus Transport to Human Cystic Fibrosis Airway Epithelium | Dysfunction of CFTR in cystic fibrosis (CF) airway epithelium perturbs the normal regulation of ion transport, leading to a reduced volume of airway surface liquid (ASL), mucus dehydration, decreased mucus transport, and mucus plugging of the airways. CFTR is normally expressed in ciliated epithelial cells of the surfa... | The ciliated epithelium that lines the conducting airways of the lung normally functions to transport hydrated mucus secretions out of the airways to maintain respiratory sterility. Cystic fibrosis (CF) lung disease results from reduced airway surface hydration leading to decreased mucus clearance that precipitates bac... | Cystic fibrosis (CF) is the most common recessive lethal genetic disorder in Caucasian populations and results from a defect in the CFTR gene. Although CF affects many organs, the pulmonary manifestations account for over 90% of the morbidity and mortality [1]. Dysfunction of CFTR in CF airway epithelium perturbs the n... |
10.1371/journal.pntd.0006492 | Molecular characterization of Vibrio cholerae responsible for cholera epidemics in Uganda by PCR, MLVA and WGS | For almost 50 years sub-Saharan Africa, including Uganda, has experienced several outbreaks due to Vibrio cholerae. Our aim was to determine the genetic relatedness and spread of strains responsible for cholera outbreaks in Uganda.
Sixty-three V. cholerae isolates collected from outbreaks in Uganda between 2014 and 201... | Cholera, an acute diarrheal disease, essentially was eliminated in the western world many decades ago, but has continued to cause many deaths in sub-Saharan Africa, South America and Asia. Cholera diagnosis in most countries in sub-Saharan Africa, including Uganda, is by stool culture, serology and biochemical methods.... | Vibrio cholerae remains a major cause of morbidity and mortality globally [1]. There have been seven cholera pandemics since the disease was recognized as a global threat [2]. The English record of pandemics of cholera started in 1816, but cholera as a disease goes back centuries in Indian literature [3]. The organism ... |
10.1371/journal.pbio.1001911 | Structure of a Membrane-Embedded Prenyltransferase Homologous to UBIAD1 | Membrane-embedded prenyltransferases from the UbiA family catalyze the Mg2+-dependent transfer of a hydrophobic polyprenyl chain onto a variety of acceptor molecules and are involved in the synthesis of molecules that mediate electron transport, including Vitamin K and Coenzyme Q. In humans, missense mutations to the p... | The biosynthesis of Vitamin K and Coenzyme Q requires the transfer of a long, hydrophobic moiety known as an isoprenyl onto an aromatic acceptor compound. This process is catalyzed by a family of proteins known as the UbiA proteins, which are embedded in the hydrophobic environment of cell membranes. To understand how ... | Vitamin K is an essential cofactor required for the posttranslational modification of proteins involved in blood-clotting and normal bone metabolism. One of the major forms of vitamin K in humans, menaquinone-4, is produced by cleaving the phytyl group from dietary phylloquinone to produce menadione, which is then modi... |
10.1371/journal.ppat.1001136 | Transforming Growth Factor-β: Activation by Neuraminidase and Role in Highly Pathogenic H5N1 Influenza Pathogenesis | Transforming growth factor-beta (TGF-β), a multifunctional cytokine regulating several immunologic processes, is expressed by virtually all cells as a biologically inactive molecule termed latent TGF-β (LTGF-β). We have previously shown that TGF-β activity increases during influenza virus infection in mice and suggeste... | Transforming growth factor-beta (TGF-β) is a multifunctional protein that serves as a global regulator of immunity by controlling the initiation and resolution of inflammatory responses. A pathogen that can regulate TGF-β activation could promote an immune-privileged state for itself within its host. Indeed, multiple p... | Transforming growth factor-β1 (TGF-β) is the prototypic member of a family of multifunctional cytokines that modulate diverse cellular, developmental, and immunological processes (reviewed in [1]–[3]). TGF-β is secreted by virtually all cells as a biologically inactive molecule termed latent TGF-β (LTGF-β) [4], [5]. Th... |
10.1371/journal.pbio.1000616 | Structural Insight into the Rotational Switching Mechanism of the
Bacterial Flagellar Motor | The bacterial flagellar motor can rotate either clockwise (CW) or
counterclockwise (CCW). Three flagellar proteins, FliG, FliM, and FliN, are
required for rapid switching between the CW and CCW directions. Switching is
achieved by a conformational change in Fl... | The bacterial flagellum is a rotating organelle that governs cell motility. At
the base of each flagellum is a motor powered by the electrochemical potential
difference of specific ions across the cytoplasmic membrane. In response to
environmental stimuli, rot... | Bacteria such as Escherichia coli and Salmonella
enterica swim by rotating multiple flagella, which arise randomly over
the cell surface. Each flagellum is a huge protein complex made up of about 30
different proteins and can be divided into three distinct parts: the ... |
10.1371/journal.pgen.1005855 | Synergistic Control of Kinetochore Protein Levels by Psh1 and Ubr2 | The accurate segregation of chromosomes during cell division is achieved by attachment of chromosomes to the mitotic spindle via the kinetochore, a large multi-protein complex that assembles on centromeres. The budding yeast kinetochore comprises more than 60 different proteins. Although the structure and function of m... | As cells divide, their replicated chromosomes must be correctly allocated to the two nascent daughter cells. This is achieved by the kinetochore, which provides a physical link between the chromosomes and the microtubules that drive their movement. If chromosome separation fails, the resulting cells have an abnormal nu... | Accurate chromosome segregation is necessary for the equal distribution of genetic material between daughter cells during cell division and is achieved by kinetochores which link chromosomes to spindle microtubules [1]. Perturbations of kinetochore function result in aneuploidy, i.e. changes in chromosome number, and g... |
10.1371/journal.ppat.1006057 | The Mouse Cytomegalovirus Gene m42 Targets Surface Expression of the Protein Tyrosine Phosphatase CD45 in Infected Macrophages | The receptor-like protein tyrosine phosphatase CD45 is expressed on the surface of cells of hematopoietic origin and has a pivotal role for the function of these cells in the immune response. Here we report that following infection of macrophages with mouse cytomegalovirus (MCMV) the cell surface expression of CD45 is ... | Human cytomegalovirus (HCMV) is a tenacious pathogen, which can be life-threatening for immunocompromised patients and immunologically immature newborns. The pathogenicity of HCMV is owed to a plethora of immunomodulatory functions that interfere with host defense mechanisms. Such viral functions can teach us about vir... | Cytomegaloviruses (CMVs) possess the largest genomes among the herpesviruses [1–3] and dedicate a substantial portion of their genomic coding capacity to accessory functions that are not directly needed for replication of the DNA genome or as structural components for the assembly of progeny virions [4,5]. Among the ac... |
10.1371/journal.ppat.1002549 | Transcriptional Activation of the Adenoviral Genome Is Mediated by Capsid Protein VI | Gene expression of DNA viruses requires nuclear import of the viral genome. Human Adenoviruses (Ads), like most DNA viruses, encode factors within early transcription units promoting their own gene expression and counteracting cellular antiviral defense mechanisms. The cellular transcriptional repressor Daxx prevents v... | To initiate infection, DNA viruses deliver their genome to the nucleus and express viral genes required for genome replication. Efficient transport is achieved by packing the viral genome as a condensed, transcriptionally inactive nucleo-protein complex. However, for most DNA viruses, including Adenoviruses (Ads), it r... | DNA viruses require the transport of their genome into the nucleus to initiate replication. Cells perceive the introduction of foreign nucleic acids or unscheduled replication as danger signals and activate a DNA damage response that leads to cell cycle arrest and/or apoptosis. To ensure proper replication, DNA viruses... |
10.1371/journal.pcbi.1005359 | Memory replay in balanced recurrent networks | Complex patterns of neural activity appear during up-states in the neocortex and sharp waves in the hippocampus, including sequences that resemble those during prior behavioral experience. The mechanisms underlying this replay are not well understood. How can small synaptic footprints engraved by experience control lar... | Synaptic plasticity is the basis for learning and memory, and many experiments indicate that memories are imprinted in synaptic connections. However, basic mechanisms of how such memories are retrieved and consolidated remain unclear. In particular, how can one-shot learning of a sequence of events achieve a sufficient... | The idea of sequential activation of mental concepts and neural populations has deep roots in the history of the cognitive sciences [1–3] as well as its share of criticism [4]. In one of the most influential works in neuroscience, Donald Hebb extended this concept by suggesting that neurons that fire simultaneously sho... |
10.1371/journal.pntd.0002332 | Polyethyleneimine Mediated DNA Transfection in Schistosome Parasites and Regulation of the WNT Signaling Pathway by a Dominant-Negative SmMef2 | Schistosomiasis is a serious global problem and the second most devastating parasitic disease following malaria. Parasitic worms of the genus Schistosoma are the causative agents of schistosomiasis and infect more than 240 million people worldwide. The paucity of molecular tools to manipulate schistosome gene expressio... | Schistosomiasis is a global disease infecting more than 240 million people worldwide and is ranked second only to malaria in global health importance. The causative agents of human schistosomiasis are parasitic worms that ingest red blood cells and can live for decades producing hundreds of eggs daily. There is one pri... | The use of transgenesis and other technological advances has had a powerful impact in the molecular characterization and functional analysis of gene function in model organisms [1], [2]. However, like many parasitic worms, the natural characteristics of the schistosome (its complex life cycle involving multiple hosts, ... |
10.1371/journal.ppat.1007204 | Asymmetric antiviral effects of ebolavirus antibodies targeting glycoprotein stem and glycan cap | Recent studies suggest that some monoclonal antibodies (mAbs) specific for ebolavirus glycoprotein (GP) can protect experimental animals against infections. Most mAbs isolated from ebolavirus survivors appeared to target the glycan cap or the stalk region of the viral GP, which is the envelope protein and the only anti... | Recent progress in isolation of mAbs from survivors of filovirus infections suggests that the human adaptive immune system is capable of producing strong antibody responses. However, the effects of mAbs with different epitope specificity on individual steps of filovirus infection are still unclear. We evaluated a panel... | Filoviruses are enveloped, filamentous-like viruses with non-segmented RNA genome of negative polarity. The Ebolavirus genus of the Filoviridae family includes five species: Ebola (EBOV), Sudan (SUDV), Bundibugyo (BDBV), Taï Forest (TAFV) and Reston (RESTV) viruses. Most of these viruses are responsible for highly leth... |
10.1371/journal.pntd.0003693 | A DNA Vaccine against Yellow Fever Virus: Development and Evaluation | Attenuated yellow fever (YF) virus 17D/17DD vaccines are the only available protection from YF infection, which remains a significant source of morbidity and mortality in the tropical areas of the world. The attenuated YF virus vaccine, which is used worldwide, generates both long-lasting neutralizing antibodies and st... | DNA and other nucleic acid vaccine technologies are advancing quickly, and new potent delivery methods are demonstrating great potential in human clinical trials. In this manuscript, we report a highly protective DNA vaccine against the yellow fever virus. This vaccine was engineered with a molecular adjuvant technolog... | The yellow fever (YF) virus is considered the prototype member of the family Flaviviridae, which includes several other viruses of medical importance, such as the dengue, Japanese encephalitis, tick-borne encephalitis and West Nile viruses [1]. According to the World Health Organization (WHO), more than 200,000 cases o... |
10.1371/journal.pcbi.1000119 | Intrinsic Gain Modulation and Adaptive Neural Coding | In many cases, the computation of a neural system can be reduced to a receptive field, or a set of linear filters, and a thresholding function, or gain curve, which determines the firing probability; this is known as a linear/nonlinear model. In some forms of sensory adaptation, these linear filters and gain curve adju... | Many neurons are known to achieve a wide dynamic range by adaptively changing their computational input/output function according to the input statistics. These adaptive changes can be very rapid, and it has been suggested that a component of this adaptation could be purely input-driven: even a fixed neural system can ... | An f-I curve, defined as the mean firing rate in response to a stationary mean current input, is one of the simplest ways to characterize how a neuron transforms a stimulus into a spike train output as a function of the magnitude of a single stimulus parameter. Recently, the dependence of f-I curves on other input stat... |
10.1371/journal.pcbi.1005437 | Stimulus-specific adaptation in a recurrent network model of primary auditory cortex | Stimulus-specific adaptation (SSA) occurs when neurons decrease their responses to frequently-presented (standard) stimuli but not, or not as much, to other, rare (deviant) stimuli. SSA is present in all mammalian species in which it has been tested as well as in birds. SSA confers short-term memory to neuronal respons... | We present a possible mechanism for the way auditory cortex emphasizes stimuli that are deviant within a regular, repetitive sequence. This enhancement is strong and widespread in auditory cortex, but not in its major thalamic input, the ventral division of the medial geniculate body. In contrast with previous models, ... | Stimulus-specific adaptation (SSA) is the decrease in responses to a repeating stimulus (standard) that does not generalize to another, rarely-occurring stimulus (deviant). SSA is a robust and widespread finding in the auditory system. It has been demonstrated in single neurons in primary auditory cortex (A1) of anesth... |
10.1371/journal.ppat.1003930 | The Secreted Triose Phosphate Isomerase of Brugia malayi Is Required to Sustain Microfilaria Production In Vivo | Human lymphatic filariasis is a major tropical disease transmitted through mosquito vectors which take up microfilarial larvae from the blood of infected subjects. Microfilariae are produced by long-lived adult parasites, which also release a suite of excretory-secretory products that have recently been subject to in-d... | Triose phosphate isomerase (TPI) is a ubiquitous and highly conserved enzyme in intracellular glucose metabolism. Surprisingly, the human lymphatic filariai nematode parasite Brugia malayi, releases TPI into the extracellular environment, suggesting a role in helminth survival in the mammalian host. We first establishe... | Continued survival of parasitic helminths within their mammalian host requires that they neutralise potentially protective immune responses, generate energy and reproduce. Filarial nematodes are particularly long-lived, tissue-dwelling parasites which evade immunity and maintain transmission over many years [1]. Over 1... |
10.1371/journal.pgen.1002435 | The Drosophila melanogaster Seminal Fluid Protease “Seminase” Regulates Proteolytic and Post-Mating Reproductive Processes | Proteases and protease inhibitors have been identified in the ejaculates of animal taxa ranging from invertebrates to mammals and form a major protein class among Drosophila melanogaster seminal fluid proteins (SFPs). Other than a single protease cascade in mammals that regulates seminal clot liquefaction, no proteolyt... | Proteases can destroy, activate, or otherwise modulate the function of other proteins. In seminal fluid, many proteins have to be activated or degraded after mating; proteolysis is an effective way to accomplish this because seminal fluid proteins act outside of the cell, where most other regulatory processes cannot be... | Proteolysis regulators are a component of the seminal fluid of many animal taxa, including insects and other invertebrates [1]–[7], fish [8]–[10], birds [11], [12], and mammals [13]–[18]. However, the mechanisms by which seminal proteases act, and most of the processes they affect, in mated females are poorly understoo... |
10.1371/journal.pgen.1004985 | A Rolling Circle Replication Mechanism Produces Multimeric Lariats of Mitochondrial DNA in Caenorhabditis elegans | Mitochondrial DNA (mtDNA) encodes respiratory complex subunits essential to almost all eukaryotes; hence respiratory competence requires faithful duplication of this molecule. However, the mechanism(s) of its synthesis remain hotly debated. Here we have developed Caenorhabditis elegans as a convenient animal model for ... | Defects in the mitochondrial DNA (mtDNA) that encodes protein subunits of the respiratory complexes may cause severe metabolic disease in humans. Such defects are often caused by errors during mtDNA synthesis, motivating ongoing studies of this process. The nematode Caenorhabditis elegans has been proposed as a model f... | Caenorhabditis elegans is a ubiquitous model animal often employed in studies of aging and metabolic disease, processes intimately associated with mitochondrial health. However, comparatively little is known of mtDNA maintenance in this organism [1,2].
Early studies of mitochondrial DNA (mtDNA) replication in mammalia... |
10.1371/journal.pcbi.1003640 | A Normative Theory of Forgetting: Lessons from the Fruit Fly | Recent experiments revealed that the fruit fly Drosophila melanogaster has a dedicated mechanism for forgetting: blocking the G-protein Rac leads to slower and activating Rac to faster forgetting. This active form of forgetting lacks a satisfactory functional explanation. We investigated optimal decision making for an ... | The dominant perception of forgetting in science and society is that it is a nuisance in achieving better memory performance. However, recent experiments in the fruit fly show that the forgetting rate is biochemically adapted to the environment, raising doubts that slower forgetting per se is a desirable feature. Here ... | Drosophila melanogaster forgets [1], [2]. In itself this is unremarkable because forgetting as a behavioral phenomenon appears in any adaptive system of limited capacity; storing new associations will lead to interference with existing memories. Forgetting, in this sense, is just the flip side of learning. When capacit... |
10.1371/journal.pcbi.1004796 | BIITE: A Tool to Determine HLA Class II Epitopes from T Cell ELISpot Data | Activation of CD4+ T cells requires the recognition of peptides that are presented by HLA class II molecules and can be assessed experimentally using the ELISpot assay. However, even given an individual’s HLA class II genotype, identifying which class II molecule is responsible for a positive ELISpot response to a give... | When studying the host immune response, a central question is: “which peptides elicit CD4+ T cell responses?” ELISpot assays are used to assess if subjects have responded to a given peptide. However, to determine which of the HLA-II molecules coded by the host HLA genotype is responsible for the reaction requires addit... | Adaptive immunity relies on the recognition of non-self peptides by T cell receptors to mount an effective response against an infection. Both self and non-self peptides are presented on the cell surface by human leucocyte antigen complex (HLA) molecules using two pathways: the HLA class I pathway presents cytosolic pe... |
10.1371/journal.ppat.1002580 | Calcium Influx Rescues Adenylate Cyclase-Hemolysin from Rapid Cell Membrane Removal and Enables Phagocyte Permeabilization by Toxin Pores | Bordetella adenylate cyclase toxin-hemolysin (CyaA) penetrates the cytoplasmic membrane of phagocytes and employs two distinct conformers to exert its multiple activities. One conformer forms cation-selective pores that permeabilize phagocyte membrane for efflux of cytosolic potassium. The other conformer conducts extr... | The adenylate cyclase toxin (CyaA) of pathogenic Bordetellae eliminates the first line of host innate immune defense by inhibiting the oxidative burst and complement-mediated opsonophagocytic killing of bacteria. The toxin penetrates myeloid phagocytes, such as neutrophil, macrophage or dendritic cells, and subverts th... | By instantaneously disrupting bactericidal functions of host phagocytes, the adenylate cyclase toxin-hemolysin (CyaA, ACT, or AC-Hly) plays a major role in virulence of pathogenic Bordetellae [1]. The toxin rapidly paralyzes phagocytes [1], [2] by translocating across their cytoplasmic membrane an N-terminal adenylate ... |
10.1371/journal.pntd.0006011 | Clinico-pathological features of erythema nodosum leprosum: A case-control study at ALERT hospital, Ethiopia | Leprosy reactions are a significant cause of morbidity in leprosy population. Erythema nodosum leprosum (ENL) is an immunological complication affecting approximately 50% of patients with lepromatous leprosy (LL) and 10% of borderline lepromatous (BL) leprosy. ENL is associated with clinical features such as skin lesio... | Leprosy reactions (Type 1 and 2) are important causes of nerve damage and illness. Erythema Nodosum Leprosum (ENL) also called type 2 reactions is a severe multisystem immune-mediated complication of borderline and lepromatous leprosy. ENL causes high morbidity and mortality and usually requires urgent medical attentio... | Leprosy is a disease caused by Mycobacterium leprae, an intracellular acid-fast bacillus[1]. It mainly infects the skin and peripheral nerves[2]. The disease manifests with a spectrum of clinical pictures ranging from the localized tuberculoid leprosy (TT) to the generalized lepromatous leprosy (LL) types forming the t... |
10.1371/journal.pcbi.1000892 | Frequency-Dependent Selection Predicts Patterns of Radiations and Biodiversity | Most empirical studies support a decline in speciation rates through time, although evidence for constant speciation rates also exists. Declining rates have been explained by invoking pre-existing niches, whereas constant rates have been attributed to non-adaptive processes such as sexual selection and mutation. Trends... | Ecological opportunity, or filling a pre-existing unoccupied adaptive zone, is considered the dominant mechanism explaining the initial explosion of diversity. Although this type of niche filling can explain rates of diversification in some lineages, it is not sufficient for a radiation to occur. Instead of attributing... | Speciation is one of the most complex phenomena in nature, yet the effects of its tempo and mode for biodiversity patterns are still controversial [1], [2]. Pre-existing niches is considered the dominant mechanism explaining the initial explosion of diversity observed in radiations [3]–[7]. In contrast, non-adaptive ra... |
10.1371/journal.pcbi.1000810 | Polarizable Water Model for the Coarse-Grained MARTINI Force Field | Coarse-grained (CG) simulations have become an essential tool to study a large variety of biomolecular processes, exploring temporal and spatial scales inaccessible to traditional models of atomistic resolution. One of the major simplifications of CG models is the representation of the solvent, which is either implicit... | Many biomolecular processes involve charged species moving between regions of high polarity, such as the water phase, and regions of lower polarity, such as the lipid membrane. Due to the change in electrostatic screening between these two environments, the strength of the interactions between the moving charge and the... | Since the first introduction of physics-based coarse-grained (CG) models in computational biology [1], CG models have become increasingly popular in the simulation of complex biological systems [2]. They significantly reduce the computational complexity in comparison to all-atom (AA) models and allow sampling over much... |
10.1371/journal.pcbi.1005700 | Extracting replicable associations across multiple studies: Empirical Bayes algorithms for controlling the false discovery rate | In almost every field in genomics, large-scale biomedical datasets are used to report associations. Extracting associations that recur across multiple studies while controlling the false discovery rate is a fundamental challenge. Here, we propose a new method to allow joint analysis of multiple studies. Given a set of ... | When analyzing results from multiple studies, extracting replicated associations is the first step towards making new discoveries. The standard approach for this task is to use meta-analysis methods, which usually make an underlying null hypothesis that a gene has no effect in all studies. On the other hand, in replica... | Confidence in reported findings is a prerequisite for advancing any scientific field. Such confidence is achieved by showing replication of discoveries in new studies [1]. In recent years studies have shown low reproducibility of results in several domains, including economics [2], psychology [3], medicine [4], and bio... |
10.1371/journal.pntd.0004680 | The Role of Serotype Interactions and Seasonality in Dengue Model Selection and Control: Insights from a Pattern Matching Approach | The epidemiology of dengue fever is characterized by highly seasonal, multi-annual fluctuations, and the irregular circulation of its four serotypes. It is believed that this behaviour arises from the interplay between environmental drivers and serotype interactions. The exact mechanism, however, is uncertain. Constrai... | The fluctuations of multi-serotype infectious diseases are often highly irregular and hard to predict. Previous theoretical approaches have attempted to disentangle the drivers that may underlie this behaviour in dengue dynamics with variable success. Here, we examine the role of such drivers using a pattern-oriented m... | With a 30-fold increase in incidence over the last five decades, dengue poses an increasing threat to about two thirds of the world population [1]. Dengue, caused by a group of viruses belonging to the Flavivirus genera, circulates in four major serotypes (DENV 1–4) [2], and manifests in a wide spectrum of clinical for... |
10.1371/journal.pbio.2000598 | Authorization of Animal Experiments Is Based on Confidence Rather than Evidence of Scientific Rigor | Accumulating evidence indicates high risk of bias in preclinical animal research, questioning the scientific validity and reproducibility of published research findings. Systematic reviews found low rates of reporting of measures against risks of bias in the published literature (e.g., randomization, blinding, sample s... | Scientific validity of research findings depends on scientific rigor, including measures to avoid bias, such as random allocation of animals to treatment groups (randomization) and assessing outcome measures without knowing to which treatment groups the animals belong (blinding). However, measures against bias are rare... | Reproducibility is a fundamental principle of the scientific method and distinguishes scientific evidence from mere anecdote. The advancement of basic as well as applied research depends on the reproducibility of the findings, and can be seriously hampered if reproducibility is poor. However, accumulating evidence indi... |
10.1371/journal.pgen.1005493 | The Dynamic Genome and Transcriptome of the Human Fungal Pathogen Blastomyces and Close Relative Emmonsia | Three closely related thermally dimorphic pathogens are causal agents of major fungal diseases affecting humans in the Americas: blastomycosis, histoplasmosis and paracoccidioidomycosis. Here we report the genome sequence and analysis of four strains of the etiological agent of blastomycosis, Blastomyces, and two speci... | Dimorphic fungal pathogens including Blastomyces are the cause of major fungal diseases in North and South America. The genus Emmonsia includes species infecting small mammals as well as a newly emerging pathogenic species recently reported in HIV-positive patients in South Africa. Here, we synthesize both genome seque... | Blastomyces is a genus of a thermally dimorphic fungal pathogen, which is the etiological agent of blastomycosis, a lung infection that can become a systemic mycosis. In North America, Blastomyces is endemic in the Ohio and Mississippi river valleys, the Great Lakes region, and the St. Lawrence River [1]. Within Blasto... |
10.1371/journal.pgen.1006273 | Glucose Sensor MdHXK1 Phosphorylates and Stabilizes MdbHLH3 to Promote Anthocyanin Biosynthesis in Apple | Glucose induces anthocyanin accumulation in many plant species; however, the molecular mechanism involved in this process remains largely unknown. Here, we found that apple hexokinase MdHXK1, a glucose sensor, was involved in sensing exogenous glucose and regulating anthocyanin biosynthesis. In vitro and in vivo assays... | Glucose is considered as a major regulatory molecule in addition to being essential metabolic nutrients and structural components in higher plants. As is well known, hexokinase1 (HXK1) is a glucose sensor that integrates diverse signals to govern gene expression and plant growth in response to environmental cues. Previ... | In higher plants, sugars function as major regulatory molecules in addition to being essential metabolic nutrients and structural components. Sugars control gene expression to affect developmental and metabolic processes during the entire plant life cycle and function in response to biotic and abiotic stresses [1–3]. T... |
10.1371/journal.pntd.0002059 | Dog Bite Histories and Response to Incidents in Canine Rabies-Enzootic KwaZulu-Natal, South Africa | The objective of this paper is to report evaluated observations from survey records captured through a cross-sectional observational study regarding canine populations and dog owners in rabies enzootic KwaZulu-Natal province, South Africa. Our aim was to evaluate respondent knowledge of canine rabies and response to do... | Canine rabies has been enzootic to KwaZulu-Natal province, South Africa since the mid-1970's. Vaccination requirements for domestic species and animal control laws enforced in industrialized countries frequently eliminate the need for rabies post exposure prophylaxis (PEP) when an animal bite occurs. Rabies deaths in A... | Rabies kills tens of thousands of people in developing countries each year, and it is estimated that almost half of global rabies incidences occur in Africa [1]–[2]. However, one major factor compounding the problems of rabies is a high probability of disease underreporting. Studies in Tanzania, for example, indicated ... |
10.1371/journal.ppat.1000061 | Suppression of Plant Resistance Gene-Based Immunity by a Fungal Effector | The innate immune system of plants consists of two layers. The first layer, called basal resistance, governs recognition of conserved microbial molecules and fends off most attempted invasions. The second layer is based on Resistance (R) genes that mediate recognition of effectors, proteins secreted by pathogens to sup... | In agriculture, the most environmentally friendly way to combat plant diseases is to make use of the innate immune system of plants, for instance by crossing into crop varieties polymorphic resistance genes that occur in natural populations of the crop plant or its close relatives. Plant pathogens, however, have co-evo... | Long periods of co-evolution of plants and microorganisms have led to complex mechanisms of attack and defence, involving the innate immune system of plants and virulence factors of pathogens [1]. The first layer of plant defence, called basal immunity, is based on recognition of conserved microbial molecules but can b... |
10.1371/journal.pgen.1004236 | CYP6 P450 Enzymes and ACE-1 Duplication Produce Extreme and Multiple Insecticide Resistance in the Malaria Mosquito Anopheles gambiae | Malaria control relies heavily on pyrethroid insecticides, to which susceptibility is declining in Anopheles mosquitoes. To combat pyrethroid resistance, application of alternative insecticides is advocated for indoor residual spraying (IRS), and carbamates are increasingly important. Emergence of a very strong carbama... | Malaria control depends heavily on only four classes of insecticide to which Anopheles mosquitoes are increasingly resistant. It is important to manage insecticide application carefully to minimise increases in resistance, for example by using different compounds in combination or rotation. Recently, mosquitoes resista... | Malaria mortality has decreased substantially in sub-Saharan Africa over the last decade, attributed in part to a massive scale-up in insecticide-based vector control interventions [1]. As the only insecticide class approved for treatment of bednets (ITNs) and the most widely used for indoor residual spraying (IRS), py... |
10.1371/journal.pgen.1006976 | Northeast African genomic variation shaped by the continuity of indigenous groups and Eurasian migrations | Northeast Africa has a long history of human habitation, with fossil-finds from the earliest anatomically modern humans, and housing ancient civilizations. The region is also the gate-way out of Africa, as well as a portal for migration into Africa from Eurasia via the Middle East and the Arabian Peninsula. We investig... | Northeast Africa has geographic and historical links to Eurasia via the Middle East and the Arabian Peninsula, but the demographic history of the region itself has been more elusive. We investigate genomic diversity of northeast African populations and found a clear bimodal distribution of variation, correlated with ge... | The Nile River Valley and northeast Africa have experienced a long history of human habitation. The region harbored some of the most ancient civilizations in the world and contains fossil finds of the earliest anatomically modern humans [1–3]. Agriculture has a long history in the Nile River valley, and crops of potent... |
10.1371/journal.pgen.1005491 | The Saccharomyces cerevisiae AMPK, Snf1, Negatively Regulates the Hog1 MAPK Pathway in ER Stress Response | Accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER) causes ER stress. Snf1, the Saccharomyces cerevisiae ortholog of AMP–activated protein kinase (AMPK), plays a crucial role in the response to various environmental stresses. However, the role of Snf1 in ER stress response remains poorly un... | All organisms are always exposed to several environmental stresses, including ultraviolet, heat, and chemical compounds. Therefore, every cell possesses defense mechanisms to maintain their survival under stressed conditions. Numerous studies have shown that a family of protein kinases plays a principal role in adaptiv... | The endoplasmic reticulum (ER) is the cellular organelle responsible for the folding and modification of newly synthesized secretory or membrane proteins. Environmental or developmental changes which perturb ER homeostasis, or genetic alterations causing production of irreversibly misfolded proteins lead to an accumula... |
10.1371/journal.pntd.0005635 | Safety and efficacy of short course combination regimens with AmBisome, miltefosine and paromomycin for the treatment of visceral leishmaniasis (VL) in Bangladesh | AmBisome therapy for VL has an excellent efficacy and safety profile and has been adopted as a first-line regimen in Bangladesh. Second-line treatment options are limited and should preferably be given in short course combinations in order to prevent the development of resistant strains. Combination regimens including ... | Treatment is one of the key strategies for visceral leishmaniasis control and elimination. Historically a number of monotherapy drugs for VL treatment were used in Bangladesh, including pentavalent antimonials, amphotericin B deoxycholate (AmB), and miltefosine (MF). With the limited number of drugs available, it was n... | World-wide, 200,000–400,000 new cases of visceral leishmaniasis (VL) occur annually [1]. The majority of these cases occur in South Asia; mainly in Bihar, India and neighbouring regions of Nepal, and in the highly endemic Mymensingh province of Bangladesh.
Before the introduction of single-dose AmBisome, miltefosine w... |
10.1371/journal.pmed.1002540 | Comorbidity health pathways in heart failure patients: A sequences-of-regressions analysis using cross-sectional data from 10,575 patients in the Swedish Heart Failure Registry | Optimally treated heart failure (HF) patients often have persisting symptoms and poor health-related quality of life. Comorbidities are common, but little is known about their impact on these factors, and guideline-driven HF care remains focused on cardiovascular status. The following hypotheses were tested: (i) comorb... | Heart failure is an increasingly common condition, and patients often experience persistent symptoms and poor quality of life, even when they are receiving the best possible treatment for their heart failure.
Most heart failure patients have other conditions that dominate their health experience, yet heart failure trea... | Heart failure (HF) is a complex clinical syndrome of multiple symptoms, functional impairments, and poor health-related quality of life (HRQoL). With modern therapies, HF patients are now living longer but with a potentially higher symptom burden [1] that can be worse compared to people with other chronic diseases incl... |
10.1371/journal.pgen.1005276 | The DnaA Protein Is Not the Limiting Factor for Initiation of Replication in Escherichia coli | The bacterial replication cycle is driven by the DnaA protein which cycles between the active ATP-bound form and the inactive ADP-bound form. It has been suggested that DnaA also is the main controller of initiation frequency. Initiation is thought to occur when enough ATP-DnaA has accumulated. In this work we have per... | Cell cycle regulation of the bacterium Escherichia coli has been studied for many years, and its understanding is complicated by the fact that overlapping replication cycles occur during growth in rich media. Under such conditions cells initiate several copies of the chromosome. The active form of the CDC6-like DnaA pr... | The ORC- and CDC6-like prokaryotic initiator protein DnaA has been studied extensively for many years, but it is still not clear whether the protein contributes to actual regulation of the initiation of replication or whether it works as a cell cycle motor which “licenses” initiation at regular intervals. In E.coli the... |
10.1371/journal.pcbi.1003359 | Direct Solution of the Chemical Master Equation Using Quantized Tensor Trains | The Chemical Master Equation (CME) is a cornerstone of stochastic analysis and simulation of models of biochemical reaction networks. Yet direct solutions of the CME have remained elusive. Although several approaches overcome the infinite dimensional nature of the CME through projections or other means, a common featur... | Stochastic models of chemical networks are necessary to quantitatively describe random fluctuations and other probabilistic phenomena within living cells. The Chemical Master Equation (CME) describes the time evolution of molecular abundance probabilities in these models, and is a basis for many stochastic simulation a... | In spite of the success of continuous-variable deterministic models in describing many biological phenomena, discrete stochastic models are often necessary to describe biological phenomena inside living cells where random motion of reacting species introduces randomness in both the order and timing of biochemical react... |
10.1371/journal.ppat.1003234 | Lymphotoxin Signaling Is Initiated by the Viral Polymerase in HCV-linked Tumorigenesis | Exposure to hepatitis C virus (HCV) typically results in chronic infection that leads to progressive liver disease ranging from mild inflammation to severe fibrosis and cirrhosis as well as primary liver cancer. HCV triggers innate immune signaling within the infected hepatocyte, a first step in mounting of the adaptiv... | Hepatitis C affects nearly 200 million people worldwide. It results from the failure of the immune system to control the hepatitis C virus (HCV) replication and spread, leading to progressive liver disease that can culminate in fibrosis, cirrhosis and cancer. The inflammatory cells that infiltrate the diseased liver fu... | Persistent HCV infection affects about 170 million people worldwide [1] and is one of the most common causes of chronic liver disease [2]. Infected individuals typically suffer from chronic liver inflammation that can last several decades and lead to progressive fibrotic liver that can culminate in hepatic cirrhosis an... |
10.1371/journal.ppat.1000057 | Primate Lentiviral Vpx Commandeers DDB1 to Counteract a Macrophage Restriction | Primate lentiviruses encode four “accessory proteins” including Vif, Vpu, Nef, and Vpr/Vpx. Vif and Vpu counteract the antiviral effects of cellular restrictions to early and late steps in the viral replication cycle. We present evidence that the Vpx proteins of HIV-2/SIVSM promote virus infection by antagonizing an an... | Defense against infection by the primate lentiviruses HIV/SIV is mediated primarily by antibodies that can neutralize the virus and by cytotoxic cells that can recognize and kill other virus-infected cells. However, in the past several years, research has revealed the existence of an additional line of host defense aga... | The genomes of primate and non-primate lentiviruses encode “accessory” proteins from short open reading frames which are absent from the genomes of simple retroviruses [1]. The function of two of the accessory proteins, the Vif and Vpu proteins, have been defined: Vif antagonizes the antiviral activity of cellular Apob... |
10.1371/journal.pgen.1008327 | SMAX1/SMXL2 regulate root and root hair development downstream of KAI2-mediated signalling in Arabidopsis | Karrikins are smoke-derived compounds presumed to mimic endogenous signalling molecules (KAI2-ligand, KL), whose signalling pathway is closely related to that of strigolactones (SLs), important regulators of plant development. Both karrikins/KLs and SLs are perceived by closely related α/β hydrolase receptors (KAI2 and... | Karrikins are plant signaling compounds from smoke, which induce germination of fire-following plants. They likely mimic endogenous plant hormones (KAI2-ligand, KL), because Arabidopsis karrikin receptor mutants display shoot developmental phenotypes. Perception of karrikins/KL is very similar to that of another plant ... | Plant roots continually integrate environmental information to make decisions about their development, and to optimize their growth for optimal nutrient uptake and anchorage. Increased lateral root formation and root hair growth are necessary to compensate for low nutrient availability in the soil by increasing the roo... |
10.1371/journal.ppat.1007816 | Host-specialized fibrinogen-binding by a bacterial surface protein promotes biofilm formation and innate immune evasion | Fibrinogen is an essential part of the blood coagulation cascade and a major component of the extracellular matrix in mammals. The interface between fibrinogen and bacterial pathogens is an important determinant of the outcome of infection. Here, we demonstrate that a canine host-restricted skin pathogen, Staphylococcu... | Many bacterial pathogens are specialized for a single host-species and rarely cause infections of other hosts. Our understanding of the bacterial factors underpinning host-specificity are limited. Here we demonstrate that a canine host-restricted bacterial pathogen, Staphylococcus pseudintermedius, produces a surface p... | Many bacteria evolve strict mutualistic relationships with their host species with limited capacity to colonize and cause disease in other hosts. In contrast, other bacteria have the ability to expand into new host-species leading to the emergence of new pathogenic clones. Our understanding of the bacterial and host fa... |
10.1371/journal.pcbi.1006166 | Variability in pulmonary vein electrophysiology and fibrosis determines arrhythmia susceptibility and dynamics | Success rates for catheter ablation of persistent atrial fibrillation patients are currently low; however, there is a subset of patients for whom electrical isolation of the pulmonary veins alone is a successful treatment strategy. It is difficult to identify these patients because there are a multitude of factors affe... | Atrial fibrillation is the most commonly encountered cardiac arrhythmia, affecting a significant portion of the population. Currently, ablation is the most effective treatment but success rates are less than optimal, being 70% one-year post-treatment. There is a large effort to find better ablation strategies to perman... | Success rates for catheter ablation of persistent atrial fibrillation (AF) patients are currently low; however, there is a subset of patients for whom pulmonary vein isolation (PVI) alone is a successful treatment strategy [1]. PVI ablation may work by preventing triggered beats from entering the left atrial body, or b... |
10.1371/journal.pmed.1002085 | Dietary Diversity, Diet Cost, and Incidence of Type 2 Diabetes in the United Kingdom: A Prospective Cohort Study | Diet is a key modifiable risk factor for multiple chronic conditions, including type 2 diabetes (T2D). Consuming a range of foods from the five major food groups is advocated as critical to healthy eating, but the association of diversity across major food groups with T2D is not clear and the relationship of within-foo... | Diet is a known modifiable risk factor for chronic diseases, and poor quality diets are linked with risk of type 2 diabetes.
A varied diet is advocated as being critical to healthy eating, but people can vary in consumption of different food groups, and also of different subtypes within major food groups.
We analysed s... | Non-communicable diseases present a significant challenge to both high-income and low-income countries, with growing numbers of people experiencing the health and economic burden of one or more chronic conditions [1]. Diet is a key modifiable risk factor for multiple chronic diseases, with poor quality diets being a le... |
10.1371/journal.pntd.0000196 | Decision Tree Algorithms Predict the Diagnosis and Outcome of Dengue Fever in the Early Phase of Illness | Dengue is re-emerging throughout the tropical world, causing frequent recurrent epidemics. The initial clinical manifestation of dengue often is confused with other febrile states confounding both clinical management and disease surveillance. Evidence-based triage strategies that identify individuals likely to be in th... | Dengue illness appears similar to other febrile illness, particularly in the early stages of disease. Consequently, diagnosis is often delayed or confused with other illnesses, reducing the effectiveness of using clinical diagnosis for patient care and disease surveillance. To address this shortcoming, we have studied ... | Dengue fever/dengue haemorrhagic fever (DF/DHF) is a re-emerging disease throughout the tropical world. The disease is caused by four closely related dengue viruses, which are transmitted by the Aedes mosquitoes, principally Aedes aegypti [1]. DHF and dengue shock syndrome (DSS) represent the severe end of the disease ... |
10.1371/journal.pgen.1005309 | Temporal Coordination of Carbohydrate Metabolism during Mosquito Reproduction | Hematophagous mosquitoes serve as vectors of multiple devastating human diseases, and many unique physiological features contribute to the incredible evolutionary success of these insects. These functions place high-energy demands on a reproducing female mosquito, and carbohydrate metabolism (CM) must be synchronized w... | Mosquitoes transmit numerous devastating human diseases due to their obligatory hematophagy that is required for the efficient reproduction. Metabolism must be synchronized with high energetic needs of a female mosquito for host seeking, blood feeding and rapid egg development. Each reproductive cycle is divided into t... | The ability of multicellular organisms to maintain metabolic homeostasis and respond to changing energy requirements during development, reproduction and stress represents an essential adaptation critical for survival and evolutionary success. Thus, it is important to decipher regulatory mechanisms coordinating metabol... |
10.1371/journal.pbio.2004470 | Full mutational mapping of titratable residues helps to identify proton-sensors involved in the control of channel gating in the Gloeobacter violaceus pentameric ligand-gated ion channel | The Gloeobacter violaceus ligand-gated ion channel (GLIC) has been extensively studied by X-ray crystallography and other biophysical techniques. This provided key insights into the general gating mechanism of pentameric ligand-gated ion channel (pLGIC) signal transduction. However, the GLIC is activated by lowering th... | Pentameric ligand-gated ion channels are an important class of receptors that are involved in many neurological diseases. They have been extensively studied but a full understanding of their mechanism of action has yet to be achieved. In an effort to bypass obstacles in the research of human receptors, bacterial versio... | Pentameric ligand-gated ion channels (pLGICs) are key players of neuronal communication. They promote either cell depolarization or hyperpolarization with the passive permeation of ions through an intrinsic channel, whose opening is stabilized by the binding of specific neurotransmitters. pLGICs are ubiquitously expres... |
10.1371/journal.pgen.1003151 | A Synthetic Interaction Screen Identifies Factors Selectively Required for Proliferation and TERT Transcription in p53-Deficient Human Cancer Cells | Numerous genetic and epigenetic alterations render cancer cells selectively dependent on specific genes and regulatory pathways, and represent potential vulnerabilities that can be therapeutically exploited. Here we describe an RNA interference (RNAi)–based synthetic interaction screen to identify genes preferentially ... | The conversion of a normal cell into a cancer cell involves activating genes that promote cancer growth (oncogenes) and/or inactivating genes that normally act to inhibit cancer growth (tumor suppressor genes). The tumor suppressor gene p53 is the most frequently mutated gene in human cancers, being inactivated in appr... | The p53 tumor suppressor (also called TP53; NP_000537.3) plays a pivotal role in regulating multiple cellular processes including cell cycle arrest, apoptosis, cell metabolism and senescence (reviewed in [1]). Activated p53 can either induce cell cycle arrest and inhibit cell growth or promote cell apoptosis depending ... |
10.1371/journal.pntd.0003816 | Differential Activation of Human Monocytes and Lymphocytes by Distinct Strains of Trypanosoma cruzi | Trypanosoma cruzi strains are currently classified into six discrete typing units (DTUs) named TcI to VI. It is known that these DTUs have different geographical distribution, as well as biological features. TcI and TcII are major DTUs found in patients from northern and southern Latin America, respectively. Our hypoth... | Chagas disease remains a major public health problem in Latin America with over 13 million people infected. It is believed that the host immune response and genetic diversity of the parasite play an important role in the progression of Chagas disease, which presents a variety of clinical forms ranging from indeterminat... | Human infection with the protozoan parasite, Trypanosoma cruzi, leads to Chagas disease, which presents as a spectrum of clinical forms, ranging from a relatively mild form (indeterminate), to a severe heart disease that affects approximately 30% of the infected individuals. Chagas disease is endemic to Latin America a... |
10.1371/journal.ppat.1006405 | Elevated catalase expression in a fungal pathogen is a double-edged sword of iron | Most fungal pathogens of humans display robust protective oxidative stress responses that contribute to their pathogenicity. The induction of enzymes that detoxify reactive oxygen species (ROS) is an essential component of these responses. We showed previously that ectopic expression of the heme-containing catalase enz... | The pathogenic yeast Candida albicans faces multiple challenges within its human host. These include the need to protect itself against the toxic oxidants used by the host to kill invading microbes, and the need to scavenge iron, an essential micronutrient that is limiting in certain tissues. The iron-containing enzyme... | Of the circa three million fungal species that are thought to inhabit our planet [1], only a relatively small number have been reported to cause infections in humans. (About 400 species are described in the Atlas of Clinical Fungi [2].) Nevertheless, there is an increasing awareness that these fungal pathogens impose a... |
10.1371/journal.pntd.0001801 | Severe Hemorrhagic Fever in Strain 13/N Guinea Pigs Infected with Lujo Virus | Lujo virus (LUJV) is a novel member of the Arenaviridae family that was first identified in 2008 after an outbreak of severe hemorrhagic fever (HF). In what was a small but rapidly progressing outbreak, this previously unknown virus was transmitted from the critically ill index patient to 4 attending healthcare workers... | The pathogenic arenaviruses are a diverse group of human pathogens capable of causing a wide range of human illness ranging from encephalitis to severe hemorrhagic fever throughout the New and Old World. In 2008, a previously unknown virus (now named Lujo virus) caused a high case fatality outbreak (80%) in southern Af... | Beginning in the 1930s, novel pathogenic arenaviruses have been increasingly recognized as emerging threats to human health [1], [2], [3], [4], [5], [6], [7], [8], [9], [10]. During the 1960s and 1970s, several previously unknown arenaviruses emerged as a significant public health threats and causes of a severe and oft... |
10.1371/journal.pntd.0005792 | Adding tsetse control to medical activities contributes to decreasing transmission of sleeping sickness in the Mandoul focus (Chad) | Gambian sleeping sickness or HAT (human African trypanosomiasis) is a neglected tropical disease caused by Trypanosoma brucei gambiense transmitted by riverine species of tsetse. A global programme aims to eliminate the disease as a public health problem by 2020 and stop transmission by 2030. In the South of Chad, the ... | A global programme aims to eliminate Gambian sleeping sickness (Human African Trypanosomiasis, HAT) as a public health problem by 2020. Gambian HAT is a neglected tropical disease caused by trypanosomes spread by tsetse flies and its control has relied largely on detection and treatment of human cases. In the Mandoul f... | Human African Trypanosomiasis (HAT), also called sleeping sickness, is an endemic neglected tropical disease found in sub-Saharan Africa, caused by subspecies of Trypanosoma brucei transmitted by tsetse flies (Glossina). There is no vaccine against this lethal disease, and treatment is difficult with 1–2 weeks hospital... |
10.1371/journal.ppat.1000341 | An Epstein-Barr Virus Anti-Apoptotic Protein Constitutively Expressed in Transformed Cells and Implicated in Burkitt Lymphomagenesis: The Wp/BHRF1 Link | Two factors contribute to Burkitt lymphoma (BL) pathogenesis, a chromosomal translocation leading to c-myc oncogene deregulation and infection with Epstein-Barr virus (EBV). Although the virus has B cell growth–transforming ability, this may not relate to its role in BL since many of the transforming proteins are not e... | Cancer almost always develops through the cumulative effects of several independent changes in the target cell. For certain tumors, one step in the chain involves infection of the cell with a particular type of virus. The best example is Burkitt lymphoma (BL), a tumor of B lymphocytes which develops through the combine... | Burkitt lymphoma (BL) is a human tumor of B cell origin whose pathogenesis involves complementation between a defined cellular genetic change, translocation of the c-myc oncogene into an active immunoglobulin (Ig) locus, and a B cell-transforming virus, Epstein-Barr virus (EBV) [1],[2]. C-myc deregulation appears to be... |
10.1371/journal.pgen.1007949 | Parental legacy, demography, and admixture influenced the evolution of the two subgenomes of the tetraploid Capsella bursa-pastoris (Brassicaceae) | Allopolyploidy is generally perceived as a major source of evolutionary novelties and as an instantaneous way to create isolation barriers. However, we do not have a clear understanding of how two subgenomes evolve and interact once they have fused in an allopolyploid species nor how isolated they are from their relati... | Allopolyploid species have two or more sets of chromosomes that originate from hybridization of different species. It remains largely unknown how the two genomes evolve in the same organism and how strongly their evolutionary trajectory depends on the initial differences between the two parental species and the specifi... | Allopolyploidy, the origin of polyploids from two different ancestral lineages, poses serious evolutionary challenges since the presence of two divergent sub-genomes may lead to perturbation of meiosis, conflicts in gene expression regulation, protein-protein interactions, and transposable element suppression [1–3]. Wh... |
10.1371/journal.pgen.1002923 | Genome-Wide Association Studies Identify Heavy Metal ATPase3 as the Primary Determinant of Natural Variation in Leaf Cadmium in Arabidopsis thaliana | Understanding the mechanism of cadmium (Cd) accumulation in plants is important to help reduce its potential toxicity to both plants and humans through dietary and environmental exposure. Here, we report on a study to uncover the genetic basis underlying natural variation in Cd accumulation in a world-wide collection o... | Cadmium (Cd) is a potentially toxic metal pollutant that threatens food quality and human health in many regions of the world. Plants have evolved mechanisms for the acquisition of essential metals such as zinc and iron from the soil. Though often quite specific, such mechanisms can also lead to the accumulation of Cd ... | Cadmium (Cd) is a significant pollutant and naturally occurring trace element that is potentially toxic to both plants and animals, including humans. The human body receives Cd from many sources, but mainly from food, drinking water and smoking [1]–[3]. An important step for Cd to enter the human food chain is its accu... |
10.1371/journal.pgen.1005750 | The Nuclear Matrix Protein Megator Regulates Stem Cell Asymmetric Division through the Mitotic Checkpoint Complex in Drosophila Testes | In adult Drosophila testis, asymmetric division of germline stem cells (GSCs) is specified by an oriented spindle and cortically localized adenomatous coli tumor suppressor homolog 2 (Apc2). However, the molecular mechanism underlying these events remains unclear. Here we identified Megator (Mtor), a nuclear matrix pro... | Like many stem cells, the adult Drosophila male GSC often divides asymmetrically to produce one new stem cell and one gonialblast. The asymmetric division of GSC is specified by perpendicular orientation of the mitotic spindle to the hub-GSC interface and localization of Apc2. Here we show that Tpr/Mtor regulates GSC s... | Germline stem cells (GSCs) from the Drosophila testis provide one of the best genetic systems to study stem cell regulation. At the tip of the Drosophila testis (apex) is a germinal proliferation center, which contains the germline and somatic stem cells that maintain spermatogenesis (Fig 1A) [1–5]. Each GSC is encyste... |
10.1371/journal.pcbi.1000710 | Interplay between Pleiotropy and Secondary Selection Determines Rise and Fall of Mutators in Stress Response | Mutators are clones whose mutation rate is about two to three orders of magnitude higher than the rate of wild-type clones and their roles in adaptive evolution of asexual populations have been controversial. Here we address this problem by using an ab initio microscopic model of living cells, which combines population... | The dramatic rise of mutators has been found to accompany adaptation of bacteria in response to many kinds of stress. Two views on the evolutionary origin of this phenomenon emerged: the pleiotropic hypothesis positing that it is a byproduct of environmental stress or other specific stress response mechanisms and the s... | Bacterial populations often respond to various stresses by inducing mutagenesis whereby mutator clones rise to fixation, at least transiently, during adaptation to stressful environments [1]–[5]. The rise of mutator clones has been observed as a universal response regardless of the nature of stress, despite the diversi... |
10.1371/journal.pntd.0000879 | Control of Tungiasis through Intermittent Application of a Plant-Based Repellent: An Intervention Study in a Resource-Poor Community in Brazil | Tungiasis, an ectoparasitosis caused by the female sand flea Tunga penetrans, is an important health problem in many impoverished communities in the tropics. Sand flea disease is associated with a broad spectrum of clinical pathology and severe sequels are frequent. Treatment options are limited.
We assessed the effect... | Tungiasis is a parasitic skin disease caused by the female sand flea Tunga penetrans. The disease is frequent in resource-poor communities in South America and sub-Saharan Africa and affects the poorest of the poor. Sand flea disease is associated with a considerable morbidity and may lead to tetanus in non-vaccinated ... | Tungiasis is a common, but neglected health problem in economically disadvantaged communities in tropical and subtropical countries [1]–[5]. The female sand flea Tunga penetrans penetrates into the epidermis of its host, undergoes a peculiar hypertrophy, expels several hundred eggs for a period of three weeks, and even... |
10.1371/journal.pntd.0007701 | Long-term retrospective assessment of a transmission hotspot for human alveolar echinococcosis in mid-west China | Human alveolar echinococcosis caused by infection with Echinococcus multilocularis is one of the most potentially pathogenic helminthic zoonoses. Transmission occurs involving wildlife cycles typically between fox and small mammal intermediate hosts. In the late 1980s/early 1990s a large focus of human AE was identifie... | Human alveolar echinococcosis caused by infection with Echinococcus multilocularis is one of the most potentially pathogenic helminthic zoonoses. Transmission occurs involving wildlife cycles typically between fox and small mammal intermediate hosts. A large focus of human alveolar echinococcosis was identified in the ... | Zoonotic infections that involve domesticated animals and/or wildlife hosts are of increasing concern globally, especially in resource-poor rural communities, and they are usually difficult to monitor, treat and control [1]. Chronic zoonotic parasitic helminthic infections such as trematodiases, cysticercosis and echin... |
10.1371/journal.pbio.1000256 | ZBED6, a Novel Transcription Factor Derived from a Domesticated DNA Transposon Regulates IGF2 Expression and Muscle Growth | A single nucleotide substitution in intron 3 of IGF2 in pigs abrogates a binding site for a repressor and leads to a 3-fold up-regulation of IGF2 in skeletal muscle. The mutation has major effects on muscle growth, size of the heart, and fat deposition. Here, we have identified the repressor and find that the protein, ... | The molecular identification of genes and mutations affecting complex traits and disorders has proven to be very challenging in humans as well as in model organisms. These so-called quantitative traits arise from interactions between two or more genes and their environment, and can be mapped to their underlying genes v... | Strong selection for lean growth in the domestic pigs during the last 60 years has resulted in increased muscle growth and reduced fat deposition. Quantitative trait locus (QTL) mapping using an intercross between the European Wild Boar and Large White domestic pigs identified the most important locus that has responde... |
10.1371/journal.pgen.1003996 | NCYM, a Cis-Antisense Gene of MYCN, Encodes a De Novo Evolved Protein That Inhibits GSK3β Resulting in the Stabilization of MYCN in Human Neuroblastomas | The rearrangement of pre-existing genes has long been thought of as the major mode of new gene generation. Recently, de novo gene birth from non-genic DNA was found to be an alternative mechanism to generate novel protein-coding genes. However, its functional role in human disease remains largely unknown. Here we show ... | The MYCN oncogene has a central role in the genesis and progression of neuroblastomas, and its amplification is associated with an unfavorable prognosis. We have found that NCYM, a MYCN cis-antisense RNA, is translated in humans to a de novo evolved protein. NCYM inhibits GSK3β to stabilize MYCN, whereas MYCN induces N... | Gene evolution has long been thought to arise from pre-existing genes through duplication or rearrangement followed by rapid divergence [1]–[5]. De novo gene birth from non-coding genomic regions has been generally believed to be exceptionally rare [1]. However, recent studies using genome-wide analyses have suggested ... |
10.1371/journal.pbio.2006537 | Vocal practice regulates singing activity–dependent genes underlying age-independent vocal learning in songbirds | The development of highly complex vocal skill, like human language and bird songs, is underlain by learning. Vocal learning, even when occurring in adulthood, is thought to largely depend on a sensitive/critical period during postnatal development, and learned vocal patterns emerge gradually as the long-term consequenc... | How is plasticity associated with vocal learning regulated during a critical period? Although there are abundant studies on the critical period in sensory systems, which are passively regulated by the external environment, few studies have manipulated the sensorimotor experience through the entire critical period. Thus... | Both human speech and birdsong are acquired through vocal learning [1,2]. This learning process is achieved through sensory learning to memorize model sounds and sensorimotor learning based on matching auditory inputs and motor output to the model sounds by iterative self-motivated practice of vocalization. However, ne... |
10.1371/journal.pntd.0000617 | Serotype-Specific Differences in the Risk of Dengue Hemorrhagic Fever: An Analysis of Data Collected in Bangkok, Thailand from 1994 to 2006 | It is unclear whether dengue serotypes differ in their propensity to cause severe disease. We analyzed differences in serotype-specific disease severity in children presenting for medical attention in Bangkok, Thailand.
Prospective studies were conducted from 1994 to 2006. Univariate and multivariate logistic and multi... | The four dengue viruses (DENV) represent the most common human arbovirus infections in the world and are currently a challenging problem, particularly in the tropical and subtropical regions of Asia and the Americas. Infection with DENV may produce symptoms of varying severity. While access to care, appropriate interve... | Dengue virus (DENV) is an increasing problem in tropical and sub-tropical countries, where Aedes spp mosquitoes transmit the virus primarily in urban or semi-urban settings. Infection with DENV may result in a sub-clinical infection, undifferentiated fever, dengue fever (DF), dengue hemorrhagic fever (DHF), or dengue s... |
10.1371/journal.pntd.0002702 | Determinants of Heterogeneous Blood Feeding Patterns by Aedes aegypti in Iquitos, Peru | Heterogeneous mosquito biting results in different individuals in a population receiving an uneven number of bites. This is a feature of many vector-borne disease systems that, if understood, could guide preventative control efforts toward individuals who are expected to contribute most to pathogen transmission. We aim... | We studied the biting habits of Aedes aegypti, the principal vector of dengue virus, to determine why certain people are bitten more often by this day-active mosquito. Over one year in dengue-endemic Iquitos, Peru, we collected blood fed mosquitoes from 19 households. Mosquito blood meals were then matched to household... | Mosquito blood feeding behavior is epidemiologically important because of its central role in determining which vertebrate hosts and mosquitoes are exposed to a pathogen. Aedes aegypti, the principal mosquito vector of dengue (DENV) and urban yellow fever viruses [1] is highly anthropophilic, feeding predominantly on p... |
10.1371/journal.pntd.0003114 | Re-emergence of Rabies in the Guangxi Province of Southern China | Human rabies cases in the Guangxi province of China decreased from 839 in 1982 to 24 in 1995, but subsequently underwent a sharp increase, and has since maintained a high level.
3,040 brain samples from normal dogs and cats were collected from 14 districts of Guangxi and assessed by RT-PCR. The brain samples showed an ... | Rabies is a worldwide zoonosis disease and is of considerable public health threat and hazard. The Guangxi province of southern China is a severe rabies epidemic region. Human rabies cases decreased from 839 in 1982 to 24 in 1995 in Guangxi as a result of a dog vaccination campaign. However, the number subsequently und... | Rabies is a fatal enzootic viral infection of the central nervous system. The disease is widespread throughout the world, and is a serious public health problem in developing countries. The WHO reported that human mortality from endemic canine rabies is estimated to be 55000 deaths per year in Asia and Africa, with 56%... |
10.1371/journal.pbio.1001467 | Integration of Canonical and Noncanonical Wnt Signaling Pathways Patterns the Neuroectoderm Along the Anterior–Posterior Axis of Sea Urchin Embryos | Patterning the neuroectoderm along the anterior–posterior (AP) axis is a critical event in the early development of deuterostome embryos. However, the mechanisms that regulate the specification and patterning of the neuroectoderm are incompletely understood. Remarkably, the anterior neuroectoderm (ANE) of the deuterost... | The initial regulatory state of most cells in many deuterostome embryos, including those of vertebrates and sea urchins, supports anterior neural fate specification. It is important to restrict this neurogenic potential to the anterior end of the embryo during early embryogenesis, but the molecular mechanisms by which ... | Wnt signaling pathways play fundamental roles in many developmental processes. One of the earliest and most crucial of these roles is the activation of gene regulatory programs that specify different cell fates along the embryo's primary anterior–posterior (AP) axis. Recent comparative analyses suggest that Wnt/β-caten... |
10.1371/journal.ppat.1005020 | Type VI Secretion System Transports Zn2+ to Combat Multiple Stresses and Host Immunity | Type VI secretion systems (T6SSs) are widespread multi-component machineries that translocate effectors into either eukaryotic or prokaryotic cells, for virulence or for interbacterial competition. Herein, we report that the T6SS-4 from Yersinia pseudotuberculosis displays an unexpected function in the transportation o... | One unique feature of type VI secretion system is the presence of multiple distinct systems in certain bacterial species. It is well established that some of these systems function to compete for their living niches among diverse bacterial species, whilst the activity of many such transporters remains unknown. Because ... | Specialized protein secretion systems are essential for many bacteria to survive in interactions with their hosts or within specific environmental niches. Among these, type VI secretion system (T6SS) is a complex macromolecular apparatus found in more than 25% of sequenced Gram-negative bacteria genomes, ranging from p... |
10.1371/journal.pntd.0004080 | Household Socioeconomic and Demographic Correlates of Cryptosporidium Seropositivity in the United States | Cryptosporidium are parasitic protozoa that infect humans, domestic animals, and wildlife globally. In the United States, cryptosporidiosis occurs in an estimated 750,000 persons annually, and is primarily caused by either of the Cryptosporidium parvum genotypes 1 and 2, exposure to which occurs through ingestion of fo... | We examined if and how social inequality in the United States influences seropositivity to Cryptosporidium parvum. By using nationwide data on parasite seropositivity, demographics, and household metrics of socioeconomic status provided through the National Health and Nutritional Examination Survey, we quantified how m... | Cryptosporidium are parasitic protozoa that infect humans, domestic animals, and wildlife globally [1]. In humans, cryptosporidiosis is a major cause of global diarrheal illness, and in the United States an estimated 750000 cases occur annually [2]. Although direct mortality from Cryptosporidium infection is rare and o... |
10.1371/journal.pgen.1002987 | A Mimicking-of-DNA-Methylation-Patterns Pipeline for Overcoming the Restriction Barrier of Bacteria | Genetic transformation of bacteria harboring multiple Restriction-Modification (R-M) systems is often difficult using conventional methods. Here, we describe a mimicking-of-DNA-methylation-patterns (MoDMP) pipeline to address this problem in three difficult-to-transform bacterial strains. Twenty-four putative DNA methy... | Approximately 95% of the genome-sequenced bacteria harbor Restriction-Modification (R-M) systems. R-M systems usually occur in pairs, i.e., DNA methyltransferases (MTases) and restriction endonucleases (REases). REases can degrade invading DNA to protect the cell from infection by phages. This protecting machinery has ... | Experimental genetic manipulation has been an essential tool for gaining insight into the significance of bacterial metabolism, physiology and pathogenesis [1], [2] and has been instrumental in developing microbial biotechnology [3]. To date, only a limited proportion of the laboratory culturable bacterial species are ... |
10.1371/journal.pntd.0006429 | Microdeletion on chromosome 8p23.1 in a familial form of severe Buruli ulcer | Buruli ulcer (BU), the third most frequent mycobacteriosis worldwide, is a neglected tropical disease caused by Mycobacterium ulcerans. We report the clinical description and extensive genetic analysis of a consanguineous family from Benin comprising two cases of unusually severe non-ulcerative BU. The index case was t... | Buruli ulcer (BU) is a tropical infectious disease caused by Mycobacterium ulcerans. Although being the third most common mycobacterial disease in the world after tuberculosis and leprosy, BU remains a neglected tropical disease and an emerging health emergency in several developing countries. It causes profound skin u... | Buruli ulcer (BU), caused by Mycobacterium ulcerans, is the third most frequent mycobacteriosis worldwide, after tuberculosis and leprosy [1]. It mostly affects rural areas of tropical countries. No reliable estimate of global incidence is currently available but West Africa, annually reporting several thousand of case... |
10.1371/journal.pntd.0006074 | Csseverin inhibits apoptosis through mitochondria-mediated pathways triggered by Ca2 + dyshomeostasis in hepatocarcinoma PLC cells | Numerous experimental and epidemiological studies have demonstrated a link between Clonorchis sinensis (C. sinensis) infestation and cholangiocarcinoma (CCA) as well as hepatocellular carcinoma (HCC). The underlying molecular mechanism involved in the malignancy of CCA and HCC has not yet been addressed. Csseverin, a c... | Multiple studies have contributed to the association between Clonorchis sinensis (C. sinensis) infestation and cholangiocarcinoma (CCA) as well as hepatocellular carcinoma (HCC) in past years. However, studies on the underlying pathogenic mechanisms of C. sinensis lag behind those of other parasitic diseases. The excre... | Clonorchis sinensis (C. sinensis) causes clonorchiasis, which is widely distributed in East Asia with heavily endemic zones in China, Taiwan, Vietnam, Russia, and Korea[1]. C. sinensis was reclassified as a group-I biocarcinogen for cholangiocarcinoma (CCA) by the International Agency for Research on Cancer (IARC) in 2... |
10.1371/journal.ppat.1002969 | Rhinovirus Attenuates Non-typeable Hemophilus influenzae-stimulated IL-8 Responses via TLR2-dependent Degradation of IRAK-1 | Bacterial infections following rhinovirus (RV), a common cold virus, are well documented, but pathogenic mechanisms are poorly understood. We developed animal and cell culture models to examine the effects of RV on subsequent infection with non-typeable Hemophilus influenzae (NTHi). We focused on NTHI-induced neutrophi... | Rhinovirus (RV) is responsible for the majority of common colds. RV infection is also associated with hospitalizations for lower respiratory tract illness, a significant proportion of which are accompanied by bacterial infections including acute otitis media, sinusitis and pneumonia. However, the mechanisms by which RV... | Respiratory infection by one pathogen can alter the innate immunity to unrelated pathogens long after resolution of the first infection. This can affect the pathogen clearance and increase disease severity [1]. Severe illness or death due to bacterial infection following viral influenza is one of the most well-document... |
10.1371/journal.pmed.1002019 | Estimating the Risk of Chronic Pain: Development and Validation of a Prognostic Model (PICKUP) for Patients with Acute Low Back Pain | Low back pain (LBP) is a major health problem. Globally it is responsible for the most years lived with disability. The most problematic type of LBP is chronic LBP (pain lasting longer than 3 mo); it has a poor prognosis and is costly, and interventions are only moderately effective. Targeting interventions according t... | A minority of patients who experience an episode of low back pain develop persistent (chronic) pain.
Offering tests and treatments to all these patients exposes high numbers of low-risk patients to unnecessary intervention, which is very costly and potentially harmful.
A tool to help healthcare practitioners accurately... | Low back pain (LBP) is a major global health problem that, compared to all other diseases and health conditions, is responsible for the most years lived with disability, an estimated 80 million years lived with disability in 2010 [1]. The costs of care, investigations, and lost productivity associated with LBP are a si... |
10.1371/journal.pntd.0000235 | Age-Related Alteration of Arginase Activity Impacts on Severity of Leishmaniasis | The leishmaniases are a group of vector-borne parasitic diseases that represent a major international public health problem; they belong to the most neglected tropical diseases and have one of the highest rates of morbidity and mortality. The clinical outcome of infection with Leishmania parasites depends on a variety ... | It is well documented that ageing alters many aspects of immune responses; however, a causal relation between impaired immune functions in ageing individuals and the response to infection has not been established. Experimental leishmaniasis is an excellent model to analyse protective and pathological immune responses. ... | Infections with protozoan parasites inflict an immense toll on the developing world; they are major causes of morbidity and mortality and impede economic development. Leishmaniases are vector-borne diseases, the parasites being transmitted by bites of blood feeding female sandflies and causing different disease manifes... |
10.1371/journal.ppat.1007589 | Sensing of cell-associated HTLV by plasmacytoid dendritic cells is regulated by dense β-galactoside glycosylation | Human T Lymphotropic virus (HTLV) infection can persist in individuals resulting, at least in part, from viral escape of the innate immunity, including inhibition of type I interferon response in infected T-cells. Plasmacytoid dendritic cells (pDCs) are known to bypass viral escape by their robust type I interferon pro... | Human T Lymphotropic virus type (HTLV) establishes persistent infections, leading to adult T-cell Leukemia, a life-threatening cancer in chronically-infected individuals. Viral persistence likely results from a failure of immune responses to eradicate viral replication, a least in part, by viral escape from innate immu... | Human T-Lymphotropic Virus type 1 (HTLV-1) infects over an estimation of 5–10 million people. HTLV-1 is mainly present in Japan, central Africa, Caribbean and South America [1,2]. After a long period of clinical latency, HTLV-1 infection leads, in a fraction of infected individuals, either to Adult T-cell Leukemia/Lymp... |
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