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10.1371/journal.ppat.1003626 | Small RNA sX13: A Multifaceted Regulator of Virulence in the Plant Pathogen Xanthomonas | Small noncoding RNAs (sRNAs) are ubiquitous posttranscriptional regulators of gene expression. Using the model plant-pathogenic bacterium Xanthomonas campestris pv. vesicatoria (Xcv), we investigated the highly expressed and conserved sRNA sX13 in detail. Deletion of sX13 impinged on Xcv virulence and the expression of... | Since the discovery of the first regulatory RNA in 1981, hundreds of small RNAs (sRNAs) have been identified in bacteria. Although sRNA-mediated control of virulence was demonstrated for numerous animal- and human-pathogenic bacteria, sRNAs and their functions in plant-pathogenic bacteria have been enigmatic. We discov... | The survival and prosperity of bacteria depends on their ability to adapt to a variety of environmental cues such as nutrient availability, osmolarity and temperature. Besides the adaptation to the environment by transcriptional regulation of gene expression bacteria express regulatory RNAs that modulate expression on ... |
10.1371/journal.pntd.0007406 | Provision of deworming intervention to pregnant women by antenatal services in countries endemic for soil-transmitted helminthiasis | The World Health Organization has recently reemphasized the importance of providing preventive chemotherapy to women of reproductive age in countries endemic for soil-transmitted helminthiasis as they are at heightened risk of associated morbidity. The Demographic and Health Surveys (DHS) Program is responsible for col... | Soil-transmitted helminths are intestinal worms that cause significant suffering among the poorest communities in the world. They are transmitted via contaminated water, food or soil, all of which result from poor sanitation. Children and women of reproductive age are at heightened risk of related morbidities such as m... | Soil-transmitted helminthiasis (STH) are caused by the intestinal worms Ascaris lumbricoides (roundworm,) Trichuris trichiura (whipworm), Necator americanus and Ancylostoma duodenale (hookworm). STH are transmitted when individuals come in contact with environment contaminated by faeces containing nematode eggs. The pa... |
10.1371/journal.pgen.1007679 | Mechanisms of acquired resistance to rapalogs in metastatic renal cell carcinoma | The mechanistic target of rapamycin (mTOR) is an established therapeutic target in renal cell carcinoma (RCC). Mechanisms of secondary resistance to rapalog therapy in RCC have not been studied previously. We identified six patients with metastatic RCC who initially responded to mTOR inhibitor therapy and then progress... | Mammalian target of rapamycin (mTOR) inhibitors, everolimus and temsirolimus, are FDA-approved for treatment of metastatic renal cell carcinoma (mRCC), but molecular mechanisms of acquired or secondary resistance to these agents are unknown. We evaluated six mRCC patients with available pre-treatment specimens who were... | Both everolimus and temsirolimus, analogs of rapamycin termed rapalogs, are FDA-approved and in common used for treatment of metastatic RCC based on seminal randomized clinical trials [1–3]. However, these drugs are known to cause disease stabilization in most cases, with a 5% objective response rate by standard RECIST... |
10.1371/journal.pntd.0007404 | Pregnancy outcomes and mother-to-child transmission rate in HTLV-1/2 infected women attending two public hospitals in the metropolitan area of Rio de Janeiro | HTLV-1/2 are transmitted sexually, by whole cell blood products and from mother-to-child (MTC), mainly through breastfeeding. HTLV-1/2 prevalence in pregnant women is high in Rio de Janeiro, however there were no local studies addressing the rate of adverse pregnancy outcomes (APO) and MTC transmission. The aim was to ... | HTLV-1/2 are retroviruses transmitted by sex, blood products and from mother to child (MTC), mainly through breastfeeding. There is currently no vaccine, treatment or cure. Although it’s mostly asymptomatic it can cause disabling and even lethal diseases in carriers. The prevalence of HTLV-1/2 in pregnant women at the ... | Human T-lymphotropic virus types 1 and 2 (HTLV-1/2) are human oncogenic retroviruses first identified in the early 1980’s [1]. There are six subtypes of HTLV-1 (A to F), which have no impact on the clinical expression of the disease [2]. There are two other types of HTLV (3 and 4); but there is no evidence of their pat... |
10.1371/journal.ppat.1005339 | EBNA2 Drives Formation of New Chromosome Binding Sites and Target Genes for B-Cell Master Regulatory Transcription Factors RBP-jκ and EBF1 | Epstein-Barr Virus (EBV) transforms resting B-lymphocytes into proliferating lymphoblasts to establish latent infections that can give rise to malignancies. We show here that EBV-encoded transcriptional regulator EBNA2 drives the cooperative and combinatorial genome-wide binding of two master regulators of B-cell fate,... | Epstein-Barr Virus (EBV) reprograms host cell transcription through multiple mechanisms. Here, we show that EBV-encoded transcriptional co-activator EBNA2 drives the formation of new chromosome binding sites for host cell factors RBP-jκ and EBF1. The formation of these new sites is EBNA2-dependent. These newly formed s... | Tumor viruses encode many factors that mimic and alter host cell processes. Epstein-Barr Virus (EBV) is a human tumor virus associated with various lymphoid and epithelial cell malignancies, including Burkitt’s lymphoma, nasopharyngeal carcinoma, and lymphoproliferative disorders in the immunosuppressed [1, 2]. EBV can... |
10.1371/journal.pbio.2002909 | The rostromedial tegmental nucleus is essential for non-rapid eye movement sleep | The rostromedial tegmental nucleus (RMTg), also called the GABAergic tail of the ventral tegmental area, projects to the midbrain dopaminergic system, dorsal raphe nucleus, locus coeruleus, and other regions. Whether the RMTg is involved in sleep–wake regulation is unknown. In the present study, pharmacogenetic activat... | Sleep–wake behavior is controlled by networks of neurons and neurotransmitters in the brain. There are multiple populations of wake-promoting neurons, but few sleep-promoting neurons have been identified. In this study, we revealed that the rostromedial tegmental nucleus, the GABAergic tail of the ventral tegmental are... | Dopamine (DA) produced by neurons in the midbrain plays a key role in processing reward, aversive, and cognitive signals [1]. Abnormal DA is closely associated with neuropsychiatric disorders such as Parkinson disease, schizophrenia, and substance abuse. Severe sleep disturbances have been observed in nearly all of the... |
10.1371/journal.pcbi.1004628 | The Essential Complexity of Auditory Receptive Fields | Encoding properties of sensory neurons are commonly modeled using linear finite impulse response (FIR) filters. For the auditory system, the FIR filter is instantiated in the spectro-temporal receptive field (STRF), often in the framework of the generalized linear model. Despite widespread use of the FIR STRF, numerous... | Understanding how the brain solves sensory problems can provide useful insight for the development of automated systems such as speech recognizers and image classifiers. Recent developments in nonlinear regression and machine learning have produced powerful algorithms for characterizing the input-output relationship of... | Encoding models provide a powerful, objective means to evaluate our understanding of how sensory neural systems represent complex natural stimuli [1, 2]. An encoding model describes any time-varying neural signal (single- or multiunit activity [3, 4], local field potential [5], hemodynamic activity [6], or behavior [7]... |
10.1371/journal.pgen.1006969 | A mutation in Nischarin causes otitis media via LIMK1 and NF-κB pathways | Otitis media (OM), inflammation of the middle ear (ME), is a common cause of conductive hearing impairment. Despite the importance of the disease, the aetiology of chronic and recurrent forms of middle ear inflammatory disease remains poorly understood. Studies of the human population suggest that there is a significan... | Otitis media (OM) is the most common cause of deafness in children and is primarily characterised by inflammation of the middle ear. It is the most common cause of surgery in children in the developed world, with many children developing recurrent and chronic forms of OM undergoing tympanostomy tube insertion. There is... | Otitis media (OM) is characterised by inflammation of the middle ear (ME), often associated with a conductive hearing impairment, and is the commonest cause of hearing loss in children. It is perceived by many to be a transient affliction that in reality places a substantial social, medical and economic burden on healt... |
10.1371/journal.pgen.1004020 | TATN-1 Mutations Reveal a Novel Role for Tyrosine as a Metabolic Signal That Influences Developmental Decisions and Longevity in Caenorhabditis elegans | Recent work has identified changes in the metabolism of the aromatic amino acid tyrosine as a risk factor for diabetes and a contributor to the development of liver cancer. While these findings could suggest a role for tyrosine as a direct regulator of the behavior of cells and tissues, evidence for this model is curre... | In people, elevated blood levels of the amino acid tyrosine are seen in obese individuals, and these elevations represent a novel risk factor for the development of diabetes. The enzyme tyrosine aminotransferase, which removes tyrosine from the body, has also been identified as a tumor suppressor gene, and this enzyme ... | The aromatic amino acid tyrosine serves many metabolic roles including being a building block for protein synthesis, a source of energy, and a precursor for the synthesis of melanin and several neurotransmitters including dopamine and other catecholamines. Beyond these currently known functions for tyrosine, recent wor... |
10.1371/journal.pntd.0007191 | The importance of extracellular vesicle purification for downstream analysis: A comparison of differential centrifugation and size exclusion chromatography for helminth pathogens | Robust protocols for the isolation of extracellular vesicles (EVs) from the rest of their excretory-secretory products are necessary for downstream studies and application development. The most widely used purification method of EVs for helminth pathogens is currently differential centrifugation (DC). In contrast, size... | Recent pathogen research has identified extracellular vesicle (EV) release from many organisms. EVs are small membrane bound organelles, which have different origins, sizes and composition. It is important that the optimal EV purification method is realised in order to obtain high quality EVs to have confidence in unde... | Extracellular vesicle (EV) purification is challenging to standardise due to the diversity of sample composition producing EVs (cell cultures and body fluids), the need for high recovery of functional EVs, the quality of EV preparation and the simplicity of isolation [1–5]. Therefore, there is no current gold standard ... |
10.1371/journal.pgen.1004986 | Sequence Features and Transcriptional Stalling within Centromere DNA Promote Establishment of CENP-A Chromatin | Centromere sequences are not conserved between species, and there is compelling evidence for epigenetic regulation of centromere identity, with location being dictated by the presence of chromatin containing the histone H3 variant CENP-A. Paradoxically, in most organisms CENP-A chromatin generally occurs on particular ... | The kinetochore directs the separation of chromosomes and is assembled at a special region of the chromosome—the centromere. DNA is wrapped around particles called nucleosomes, which contain histone proteins. The nucleosomes at centromeres are specialized, and contain the centromere-specific histone CENP-A. CENP-A nucl... | Centromeres are the chromosomal sites upon which kinetochores are assembled to ensure accurate segregation of sister chromatids into daughter cells. Most kinetochores are built upon a specialized type of chromatin in which canonical histone H3 is replaced by the histone variant CENP-A. Although the centromere-kinetocho... |
10.1371/journal.pcbi.1004362 | Prediction of Functionally Important Phospho-Regulatory Events in Xenopus laevis Oocytes | The African clawed frog Xenopus laevis is an important model organism for studies in developmental and cell biology, including cell-signaling. However, our knowledge of X. laevis protein post-translational modifications remains scarce. Here, we used a mass spectrometry-based approach to survey the phosphoproteome of th... | Proteins can be modified during their life-cycle in order to regulate their function. The addition of a phosphate group is one of the most abundant and well understood protein modifications. Recent technological developments are now allowing us to uncover thousands of phosphorylation sites within proteins in a single e... | Protein function can be regulated by post-translational modifications (PTMs) by altering diverse protein properties such as their localization, activity or interactions. Protein phosphorylation is one of the most well studied PTMs with over 50 years of research since the pioneering work of Krebs and Fischer on glycogen... |
10.1371/journal.pgen.1003993 | Quantifying Missing Heritability at Known GWAS Loci | Recent work has shown that much of the missing heritability of complex traits can be resolved by estimates of heritability explained by all genotyped SNPs. However, it is currently unknown how much heritability is missing due to poor tagging or additional causal variants at known GWAS loci. Here, we use variance compon... | Heritable diseases have an unknown underlying “genetic architecture” that defines the distribution of effect-sizes for disease-causing mutations. Understanding this genetic architecture is an important first step in designing disease-mapping studies, and many theories have been developed on the nature of this distribut... | While association studies have been successful in finding a large number of significant variants for many complex traits, they have individually explained relatively little of the total heritability, motivating analyses that seek to identify this so-called “missing” heritability [1]–[3]. One hypothesis is that addition... |
10.1371/journal.pbio.0050232 | ISWI Regulates Higher-Order Chromatin Structure and Histone H1 Assembly In Vivo | Imitation SWI (ISWI) and other ATP-dependent chromatin-remodeling factors play key roles in transcription and other processes by altering the structure and positioning of nucleosomes. Recent studies have also implicated ISWI in the regulation of higher-order chromatin structure, but its role in this process remains poo... | Chromatin-remodeling factors such as ISWI play a role in transcription and other nuclear processes by altering the structure and positioning of nucleosomes (the protein–DNA complexes that organize chromatin). Recent studies have suggested that chromatin-remodeling factors can also influence higher-order chromatin struc... | The packaging of DNA into chromatin is critical for the organization and expression of eukaryotic genomes. The basic unit of chromatin structure—the nucleosome—can repress transcription by blocking the access of transcription factors and other regulatory proteins to DNA [1]. Interactions between nucleosomes lead to the... |
10.1371/journal.ppat.1005025 | A Unique Human Norovirus Lineage with a Distinct HBGA Binding Interface | Norovirus (NoV) causes epidemic acute gastroenteritis in humans, whereby histo-blood group antigens (HBGAs) play an important role in host susceptibility. Each of the two major genogroups (GI and GII) of human NoVs recognizes a unique set of HBGAs through a distinct binding interface that is conserved within a genogrou... | Human norovirus (huNoV) has diverged into two major lineages (GI and GII) selected by the host histo-blood group antigens (HBGAs). Both lineages further diverge into various sub-lineages (genotypes) that recognize different ABH and Lewis antigens through a common HBGA binding interface shared among strains within each ... | Noroviruses (NoVs) are a group of non-enveloped, single stranded, positive-sense RNA viruses that constitute the Norovirus genus in the family Caliciviridae. NoVs are genetically diverse, containing six genogroups (GI to GVI) with over 35 genetic genotypes. NoVs exhibit wide host tropisms causing diseases in various ma... |
10.1371/journal.pgen.1002761 | The Histone Demethylase Jhdm1a Regulates Hepatic Gluconeogenesis | Hepatic gluconeogenesis is required for maintaining blood glucose homeostasis; yet, in diabetes mellitus, this process is unrestrained and is a major contributor to fasting hyperglycemia. To date, the impacts of chromatin modifying enzymes and chromatin landscape on gluconeogenesis are poorly understood. Through cataly... | Histones are small proteins that are essential for packaging and ordering genetic information (DNA) into high-order chromatin structures. Methylation of specific lysine residues of histones alters chromatin structure, serving as an important epigenetic mechanism for regulation of gene expression. The dynamic nature of ... | Hepatic glucose production is critical for the maintenance of normal blood levels to meet whole-body fuel requirements. In the early phase of postabsorptive state, circulating glucose is supplied from breakdown of liver glycogen stores. When fasting progresses, gluconeogenesis, which utilizes non-carbohydrate precursor... |
10.1371/journal.pbio.1000248 | Patterning of the Dorsal-Ventral Axis in Echinoderms: Insights into the Evolution of the BMP-Chordin Signaling Network | Formation of the dorsal-ventral axis of the sea urchin embryo relies on cell interactions initiated by the TGFβ Nodal. Intriguingly, although nodal expression is restricted to the ventral side of the embryo, Nodal function is required for specification of both the ventral and the dorsal territories and is able to resto... | During early development of many organisms, patterning along the dorsal-ventral axis is regulated by the activities of two signaling centers located on the ventral and dorsal sides of the embryo. One of these centers produces growth factors of the BMP family that act as morphogens, whereas the other center secretes BMP... | Genetic and molecular studies carried out in vertebrates and invertebrates have shown that dorsal-ventral (D/V) patterning in bilaterians is regulated by a remarkably conserved patterning system which relies on production of secreted BMP inhibitors such as Chordin (Sog in Drosophila) which antagonize the activity of BM... |
10.1371/journal.pbio.0050223 | Conserving Biodiversity Efficiently: What to Do, Where, and When | Conservation priority-setting schemes have not yet combined geographic priorities with a framework that can guide the allocation of funds among alternate conservation actions that address specific threats. We develop such a framework, and apply it to 17 of the world's 39 Mediterranean ecoregions. This framework offers ... | Given limited funds for biodiversity conservation, we need to carefully prioritise where funds are spent. Various schemes have been developed to set priorities for conservation spending among different countries and regions. However, there is no framework for guiding the allocation of funds among alternative conservati... | Many sophisticated approaches exist for identifying priority areas for conservation at a global scale. These “biodiversity hotspots” or “crisis ecoregions” are typically identified using data on endemic species richness, total biodiversity, and past habitat conversion [1–3]. With few exceptions, these approaches neglec... |
10.1371/journal.pbio.1002449 | Structural and Molecular Mechanism of CdpR Involved in Quorum-Sensing and Bacterial Virulence in Pseudomonas aeruginosa | Although quorum-sensing (QS) systems are important regulators of virulence gene expression in the opportunistic human pathogen Pseudomonas aeruginosa, their detailed regulatory mechanisms have not been fully characterized. Here, we show that deletion of PA2588 resulted in increased production of pyocyanin and biofilm, ... | Although many transcriptional regulators tune P. aeruginosa virulence factor expression and secretion, the molecular mechanisms of the underlying regulatory network are still elusive. Quorum sensing, the ability of bacteria to communicate and detect cell density to determine the most advantageous time to orchestrate co... | P. aeruginosa is one of the most common nosocomial pathogens associated with fatal lung disease in cystic fibrosis patients [1]. This bacterium synthesizes a group of virulence factors consisting of pyocyanin, rhamnolipids, proteases, and biofilms that are regulated by a cell density-dependent quorum-sensing (QS) syste... |
10.1371/journal.ppat.1000386 | High Throughput Functional Assays of the Variant Antigen PfEMP1 Reveal a Single Domain in the 3D7 Plasmodium falciparum Genome that Binds ICAM1 with High Affinity and Is Targeted by Naturally Acquired Neutralizing Antibodies | Plasmodium falciparum–infected erythrocytes bind endothelial receptors to sequester in vascular beds, and binding to ICAM1 has been implicated in cerebral malaria. Binding to ICAM1 may be mediated by the variant surface antigen family PfEMP1: for example, 6 of 21 DBLβC2 domains from the IT4 strain PfEMP1 repertoire wer... | Plasmodium falciparum exports the protein PfEMP1 to the surface of parasitized erythrocytes for roles in immunoevasion and adhesion. The size and structural complexity of this diverse protein family have limited earlier studies of PfEMP1 biology to low throughput and semi-quantitative approaches. We developed a high th... | The variant surface antigen Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a virulence factor of the human malaria parasite P. falciparum. PfEMP1 variants are encoded by about 60 var genes per parasite, and have been implicated in the cytoadhesion of P. falciparum-infected erythrocytes (PE) to vascula... |
10.1371/journal.pgen.1007691 | Amn1 governs post-mitotic cell separation in Saccharomyces cerevisiae | Post-mitotic cell separation is one of the most prominent events in the life cycle of eukaryotic cells, but the molecular underpinning of this fundamental biological process is far from being concluded and fully characterized. We use budding yeast Saccharomyces cerevisiae as a model and demonstrate AMN1 as a major gene... | Separation of mother and daughter cells after mitosis in eukaryotes enacts various functional and/or developmental needs and has significant medical and industrial implications. How this cellular behaviour is regulated is far from being concluded. We report here a novel Amn1 mediated post-mitotic cell separation in a b... | The switch between effective and inhibited separation of mother and daughter cells in eukaryotic mitosis represents a fundamental process for understanding the evolution of organizational and functional complexity of organisms, and also has significant medical and industrial value [1–3]. It has been well documented tha... |
10.1371/journal.ppat.1004498 | A Gatekeeper Chaperone Complex Directs Translocator Secretion during Type Three Secretion | Many Gram-negative bacteria use Type Three Secretion Systems (T3SS) to deliver effector proteins into host cells. These protein delivery machines are composed of cytosolic components that recognize substrates and generate the force needed for translocation, the secretion conduit, formed by a needle complex and associat... | Type Three Secretion Systems (T3SS) are essential virulence factors found in many pathogenic Gram-negative bacteria. These machines aid infection by delivering bacterial proteins into host cells where these proteins modulate host processes and help establish a niche for the bacteria. Protein delivery occurs in a highly... | Type Three Secretion Systems (T3SS) are conserved bacterial protein delivery machines used by many pathogenic Gram-negative bacteria to deliver a diverse group of protein molecules, termed effectors, into cells [1]–[4]. The type three secretion (T3S) apparatus is a conserved molecular machine that forms a protein-condu... |
10.1371/journal.pntd.0004467 | IL-33-Dependent Endothelial Activation Contributes to Apoptosis and Renal Injury in Orientia tsutsugamushi-Infected Mice | Endothelial cells (EC) are the main target for Orientia tsutsugamushi infection and EC dysfunction is a hallmark of severe scrub typhus in patients. However, the molecular basis of EC dysfunction and its impact on infection outcome are poorly understood. We found that C57BL/6 mice that received a lethal dose of O. tsut... | Scrub typhus is a life-threatening disease, caused by infection with O. tsutsugamushi, a Gram-negative bacterium that preferentially infects and replicates in the endothelium. Every year, approximately one million people are infected globally, especially in the Asia-Pacific region. However, the molecular mechanism(s) o... | Orientia tsutsugamushi is an obligately intracellular bacterium and the etiological agent of scrub typhus with a geographical distribution that encompasses much of the Asia-Pacific region [1]. Scrub typhus is a neglected but important tropical disease, which puts one-third of the world’s population at risk. The disease... |
10.1371/journal.pgen.1002794 | Gene Expression Profiles in Parkinson Disease Prefrontal Cortex Implicate FOXO1 and Genes under Its Transcriptional Regulation | Parkinson disease (PD) is a complex neurodegenerative disorder with largely unknown genetic mechanisms. While the degeneration of dopaminergic neurons in PD mainly takes place in the substantia nigra pars compacta (SN) region, other brain areas, including the prefrontal cortex, develop Lewy bodies, the neuropathologica... | Parkinson disease (PD) is a neurodegenerative disease, which impairs the motor and cognitive abilities of affected individuals. Although the involvement of specific genes in the disease process has been recognized, the underlying genetic mechanisms are not yet understood. One common investigation approach for PD has be... | Parkinson disease (PD, OMIM #168600) is a neurodegenerative disorder, which affects primarily motor function (difficulty in movement initiation, tremor, slowness of movement), and secondarily cognitive capabilities of affected individuals. The lifetime risk for the disease is 1.5%, with a median age at onset of 60 and ... |
10.1371/journal.ppat.1003046 | Intracellular Vesicle Acidification Promotes Maturation of Infectious Poliovirus Particles | The autophagic pathway acts as part of the immune response against a variety of pathogens. However, several pathogens subvert autophagic signaling to promote their own replication. In many cases it has been demonstrated that these pathogens inhibit or delay the degradative aspect of autophagy. Here, using poliovirus as... | The autophagic degradation pathway is a well-known agent of innate immunity. Several pathogens, including poliovirus (PV), a model for several medically important RNA viruses, subvert this pathway for their own benefit. In doing so, pathogens often inhibit the degradative portion of the pathway, presumably to prevent t... | The Picornaviridae, a family of non-enveloped viruses with a small positive strand RNA genome, includes numerous known and emerging pathogens of medical, veterinary and agricultural importance [1]. Poliovirus (PV) is the most extensively studied virus in this family in terms of our collective understanding of its molec... |
10.1371/journal.ppat.1002927 | Kaposi's Sarcoma Herpesvirus K15 Protein Contributes to Virus-Induced Angiogenesis by Recruiting PLCγ1 and Activating NFAT1-dependent RCAN1 Expression | Kaposi's Sarcoma (KS), caused by Kaposi's Sarcoma Herpesvirus (KSHV), is a highly vascularised angiogenic tumor of endothelial cells, characterized by latently KSHV-infected spindle cells and a pronounced inflammatory infiltrate. Several KSHV proteins, including LANA-1 (ORF73), vCyclin (ORF72), vGPCR (ORF74), vIL6 (ORF... | Kaposi's Sarcoma Herpesvirus (KSHV) causes a multifocal angio-proliferative neoplasm, Kaposi's Sarcoma (KS), whose development involves angiogenic growth factors and cytokines. The K15 protein of KSHV upregulates the host factor RCAN1/DSCR1. RCAN1/DSCR1 has been implicated in angiogenesis but its role in KS has never b... | Kaposi's Sarcoma Herpesvirus (KSHV) or Human Herpesvirus 8 (HHV8) is a gammaherpesvirus first identified in Kaposi's Sarcoma (KS) biopsies [1]. Apart from being the etiological agent of the classic, AIDS-associated, endemic (African) and iatrogenic forms of Kaposi's sarcoma, it is also associated with two lymphoprolife... |
10.1371/journal.pbio.0050246 | Chromatin Structure Regulates Gene Conversion | Homology-directed repair is a powerful mechanism for maintaining and altering genomic structure. We asked how chromatin structure contributes to the use of homologous sequences as donors for repair using the chicken B cell line DT40 as a model. In DT40, immunoglobulin genes undergo regulated sequence diversification by... | Homologous recombination promotes genetic exchange between regions containing identical or highly related sequences. This is useful in repairing damaged DNA, or in reassorting genes in meiosis, but uncontrolled homologous recombination can create genomic instability. Chromosomes are made up of a complex of DNA and prot... | Homologous recombination provides a pathway for restoring or altering DNA sequence and structure [1–7]. Homologous recombination can recreate the original DNA sequence at a DNA break, and predominates in S/G2 phases of cell cycle, when sister chromatids can serve as donors for faithful repair [8,9]. Homologous recombin... |
10.1371/journal.pmed.1002581 | Geographic and sociodemographic variation of cardiovascular disease risk in India: A cross-sectional study of 797,540 adults | Cardiovascular disease (CVD) is the leading cause of mortality in India. Yet, evidence on the CVD risk of India’s population is limited. To inform health system planning and effective targeting of interventions, this study aimed to determine how CVD risk—and the factors that determine risk—varies among states in India,... | Cardiovascular disease (CVD) is thought to cause a large and increasing health and economic burden in India.
Understanding how CVD risk varies among India’s population groups could inform health system planning and the targeting of CVD programs to those most in need.
Yet, to date, there has not, to our knowledge, been ... | Cardiovascular disease (CVD) is the leading cause of mortality worldwide, including in low- and middle-income countries [1]. While the Global Burden of Disease project has recently highlighted the limited data availability for India [2], it nonetheless estimated that the country contributed almost one-fifth (18.6%) of ... |
10.1371/journal.ppat.1001246 | Critical Role of IRF-5 in the Development of T helper 1 responses to Leishmania donovani infection | The transcription factor Interferon Regulatory Factor 5 (IRF-5) has been shown to be involved in the induction of proinflammatory cytokines in response to viral infections and TLR activation and to play an essential role in the innate inflammatory response. In this study, we used the experimental model of visceral leis... | Leishmania donovani is a parasite that currently infects 12 million people around the world. In order to better understand why this parasite causes incurable disease we chose to investigate how the immune system sees L. donovani. The immune system sees infecting organisms by the recognition of molecules that are specif... | The protozoan parasite Leishmania donovani is the causative agent of visceral leishmaniasis (VL), a chronic life threatening disease if untreated. In the experimental model of VL, the two main target organs are the liver and the spleen [1]. While the spleen stays chronically infected, infection in the liver is self-res... |
10.1371/journal.pcbi.1002552 | Simple Epidemiological Dynamics Explain Phylogenetic Clustering of HIV from Patients with Recent Infection | Phylogenies of highly genetically variable viruses such as HIV-1 are potentially informative of epidemiological dynamics. Several studies have demonstrated the presence of clusters of highly related HIV-1 sequences, particularly among recently HIV-infected individuals, which have been used to argue for a high transmiss... | Diversity of viral genetic sequences depends on epidemiological mechanisms and dynamics, however the exact mechanisms responsible for patterns observed in phylogenies of HIV remain poorly understood. We observe that virus taken from patients with early/acute HIV infection are more likely to be closely related. By devel... | Phylogenetic clusters of closely related virus such as HIV arise from the epidemiological dynamics and transmission by infected hosts. If virus is phylogenetically clustered, it is an indication that the hosts are connected by a short chain of transmissions [1].
If super-infection is rare, and assuming an extrem... |
10.1371/journal.pcbi.1002429 | Beyond the Binding Site: The Role of the β2 – β3 Loop and Extra-Domain Structures in PDZ Domains | A general paradigm to understand protein function is to look at properties of isolated well conserved domains, such as SH3 or PDZ domains. While common features of domain families are well understood, the role of subtle differences among members of these families is less clear. Here, molecular dynamics simulations indi... | Protein interactions play crucial roles in all biological processes. A common way of studying them is to focus on sub-parts of proteins, called domains, that mediate specific types of interactions. For instance, it is known that most PDZ domains mediate protein interactions by binding to the C-terminus of other protein... | PDZ domains are modular protein interaction domains specialized in binding short linear motifs at the C-terminus of their cognate protein partners [1], [2]. In human, they are found in hundreds of different proteins and are mostly involved in cell-cell adhesion and epithelial junctions [3]. PDZ domains are often classi... |
10.1371/journal.ppat.1002203 | Complex Recombination Patterns Arising during Geminivirus Coinfections Preserve and Demarcate Biologically Important Intra-Genome Interaction Networks | Genetic recombination is an important process during the evolution of many virus species and occurs particularly frequently amongst begomoviruses in the single stranded DNA virus family, Geminiviridae. As in many other recombining viruses it is apparent that non-random recombination breakpoint distributions observable ... | Genetic recombination between viruses is a form of parasexual reproduction during which two parental viruses each contribute genetic information to an offspring, or recombinant, virus. Unlike with sexual reproduction, however, recombination in viruses can even involve the transfer of sequences between the members of di... | Although variations in the basal mechanistic predispositions of different regions of nucleic acid molecules to recombine is certainly a primary determinant of recombination patterns detectable within some viral genomes [1]–[5], it is becoming increasingly apparent that an important secondary determinant is natural sele... |
10.1371/journal.pgen.1008164 | Genome-wide association study of multisite chronic pain in UK Biobank | Chronic pain is highly prevalent worldwide and represents a significant socioeconomic and public health burden. Several aspects of chronic pain, for example back pain and a severity-related phenotype ‘chronic pain grade’, have been shown previously to be complex heritable traits with a polygenic component. Additional p... | Chronic pain is common worldwide and imposes a significant burden from a public health and socioeconomic perspective. The reasons why some individuals develop chronic pain and others do not are not fully understood. In this study we searched for genetic variants associated with chronic pain in a large general-populatio... | Chronic pain, conventionally defined as pain lasting longer than 3 months, has high global prevalence (~30%; [1]), imposes a significant socioeconomic burden, and contributes to excess mortality [2,3]. It is often associated with both specific and non-specific medical conditions such as cancers, HIV/AIDS, fibromyalgia ... |
10.1371/journal.pcbi.1003366 | Designing Molecular Dynamics Simulations to Shift Populations of the Conformational States of Calmodulin | We elucidate the mechanisms that lead to population shifts in the conformational states of calcium-loaded calmodulin (Ca2+-CaM). We design extensive molecular dynamics simulations to classify the effects that are responsible for adopting occupied conformations available in the ensemble of NMR structures. Electrostatic ... | Calmodulin (CaM) is involved in calcium signaling pathways in eukaryotic cells as an intracellular Ca2+ receptor. Exploiting pH differences in the cell, CaM performs a variety of functions by conveniently adopting different conformational states. We aim to reveal pH and ionic strength (IS) dependent shifts in the popul... | Protein behavior in solution may be manipulated and controlled through tailored structural perturbations [1] and rational control of the solution conditions [2] http://www.pnas.org/content/109/50/E3454.full.pdfhtml. In the living cell, proteins adapt to particular subcellular compartments which pose different environme... |
10.1371/journal.pcbi.1002899 | Significantly Improved HIV Inhibitor Efficacy Prediction Employing Proteochemometric Models Generated From Antivirogram Data | Infection with HIV cannot currently be cured; however it can be controlled by combination treatment with multiple anti-retroviral drugs. Given different viral genotypes for virtually each individual patient, the question now arises which drug combination to use to achieve effective treatment. With the availability of v... | Infection with the human immunodeficiency virus (HIV) currently cannot be cured. It can however be contained through treatment with a combination of several anti-viral drugs. Yet, during treatment resistance can occur which leads to drugs becoming ineffective. Through a combination of drugs, this resistance can be defe... | The Human Immunodeficiency Virus (HIV) was discovered and isolated as the cause of ‘Acquired Immuno Deficiency Syndrome’ (AIDS) in 1983. [1], [2] Over the following three decades HIV has turned into a global epidemic, the number of people living with HIV in 2010 being estimated at 34 million according to the World Heal... |
10.1371/journal.pgen.1003796 | Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations | Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigate... | Calcium is vital to many biological processes and its serum concentration is tightly regulated. Family studies have shown that serum calcium is under strong genetic control. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 indiv... | Normal calcium homeostasis is regulated by three major hormones acting on their corresponding receptors in gut, kidney, and bone: parathyroid hormone (PTH) release governed by the calcium-sensing receptor (CASR), calcitonin, and the active metabolite of vitamin D, 1,25(OH)2-D. Despite heritability estimates of 33–78%, ... |
10.1371/journal.pntd.0004303 | Genetic Diversity and Population Structure of Leishmania infantum from Southeastern France: Evaluation Using Multi-Locus Microsatellite Typing | In the south of France, Leishmania infantum is responsible for numerous cases of canine leishmaniasis (CanL), sporadic cases of human visceral leishmaniasis (VL) and rare cases of cutaneous and muco-cutaneous leishmaniasis (CL and MCL, respectively). Several endemic areas have been clearly identified in the south of Fr... | In the south of France, the parasite Leishmania infantum is responsible for diseases that primarily affect dogs but can also impact humans. Several endemic areas have been clearly identified in the south of France including the Pyrénées-Orientales, Cévennes (CE), Provence (P), Alpes-Maritimes (AM) and Corsica (CO). In ... | Leishmaniases are a group of diseases caused by obligatory intracellular protozoan parasites of the genus Leishmania. Among the species of Leishmania, Leishmania infantum is mostly responsible for canine leishmaniasis (CanL), although it also causes sporadic cases of human visceral leishmaniasis (VL), and rare cases of... |
10.1371/journal.pbio.3000106 | A census-based estimate of Earth's bacterial and archaeal diversity | The global diversity of Bacteria and Archaea, the most ancient and most widespread forms of life on Earth, is a subject of intense controversy. This controversy stems largely from the fact that existing estimates are entirely based on theoretical models or extrapolations from small and biased data sets. Here, in an att... | The global diversity of Bacteria and Archaea ("prokaryotes"), the most ancient and most widespread forms of life on Earth, is subject to high uncertainty. Here, to estimate the global diversity of prokaryotes, we analyzed a large number of 16S ribosomal RNA gene sequences, found in all prokaryotes and commonly used to ... | Microorganisms are the most ancient and the most widespread form of life on Earth, inhabiting virtually every ecosystem and driving the bulk of global biogeochemical cycles. Culture-independent methods such as amplicon sequencing of 16S ribosomal RNA genes revealed the existence of a potentially vast undescribed microb... |
10.1371/journal.pgen.1003102 | Selective Pressure Causes an RNA Virus to Trade Reproductive Fitness for Increased Structural and Thermal Stability of a Viral Enzyme | The modulation of fitness by single mutational substitutions during environmental change is the most fundamental consequence of natural selection. The antagonistic tradeoffs of pleiotropic mutations that can be selected under changing environments therefore lie at the foundation of evolutionary biology. However, the mo... | The most fundamental mechanism of natural selection in a changing environment is the modulation of fitness by mutations. It is the tradeoffs offered by these mutations that drive evolution. However, fitness tradeoffs are rarely understood at the molecular level, in terms of how the selected mutations affect protein str... | The ability of a single mutational substitution to modulate fitness across environments is the most important consequence of natural selection under environmental change. Understanding the antagonistic tradeoffs of pleiotropic mutations that promote survival in changing environments is therefore essential for a complet... |
10.1371/journal.pcbi.1005683 | Towards a category theory approach to analogy: Analyzing re-representation and acquisition of numerical knowledge | Category Theory, a branch of mathematics, has shown promise as a modeling framework for higher-level cognition. We introduce an algebraic model for analogy that uses the language of category theory to explore analogy-related cognitive phenomena. To illustrate the potential of this approach, we use this model to explore... | Analogy is claimed to be the core of human cognition due to its pervasive involvement in phenomena such as language, reasoning and learning. However, this phenomenon has mainly been studied in isolation through computational methods, which has made it difficult to appreciate its different roles in diverse cognitive phe... | More than five decades ago, a formal notion of “isomorphism” was used to define “representations” that sustained measurement theory and models of cognitive systems [1, 2]. Afterwards, it was proposed to describe how certain processes in a cognitive symbol system are able to reflect corresponding processes in an environ... |
10.1371/journal.pgen.1001215 | RACK-1 Acts with Rac GTPase Signaling and UNC-115/abLIM in Caenorhabditis elegans Axon Pathfinding and Cell Migration | Migrating cells and growth cones extend lamellipodial and filopodial protrusions that are required for outgrowth and guidance. The mechanisms of cytoskeletal regulation that underlie cell and growth cone migration are of much interest to developmental biologists. Previous studies have shown that the Arp2/3 complex and ... | In the developing nervous system, the growth cone guides axons of neurons to their correct targets in the organism. The growth cone is a highly dynamic specialization at the tip of the axon that senses cues and responds by crawling toward its target, leaving the axon behind. Key to growth cone motility are dynamic cell... | The actin cytoskeleton is necessary for the formation of cellular protrusions, lamellipodia and filopodia, that underlie morphogenetic events such as cell migration and axon pathfinding [1]–[4]. Unraveling the complex molecular events that regulate actin structure and dynamics in migrating cells and growth cones will b... |
10.1371/journal.pcbi.1002219 | Receptive Field Inference with Localized Priors | The linear receptive field describes a mapping from sensory stimuli to a one-dimensional variable governing a neuron's spike response. However, traditional receptive field estimators such as the spike-triggered average converge slowly and often require large amounts of data. Bayesian methods seek to overcome this probl... | A central problem in systems neuroscience is to understand how sensory neurons convert environmental stimuli into spike trains. The receptive field (RF) provides a simple model for the first stage in this encoding process: it is a linear filter that describes how the neuron integrates the stimulus over time and space. ... | A fundamental problem in systems neuroscience is to determine how sensory stimuli are functionally related to a neuron's response. A popular mathematical description of this encoding relationship is the “cascade” model, which consists of a linear filter followed by a noisy nonlinear spiking process. The linear stage in... |
10.1371/journal.pcbi.0030052 | Positive and Negative Design in Stability and Thermal Adaptation of Natural Proteins | The aim of this work is to elucidate how physical principles of protein design are reflected in natural sequences that evolved in response to the thermal conditions of the environment. Using an exactly solvable lattice model, we design sequences with selected thermal properties. Compositional analysis of designed model... | What mechanisms does Nature use in her quest for thermophilic proteins? It is known that stability of a protein is mainly determined by the energy gap, or the difference in energy, between native state and a set of incorrectly folded (misfolded) conformations. Here we show that Nature makes thermophilic proteins by wid... | Despite recent advances in computational protein design [1], there is no complete understanding of basic principles that govern design and selection of naturally occurring proteins [2]. In particular, the physical basis for the ability of proteins to achieve an adaptation to a wide variety of external conditions is sti... |
10.1371/journal.pntd.0001943 | Calodium hepaticum: Household Clustering Transmission and the Finding of a Source of Human Spurious Infection in a Community of the Amazon Region | Background: Calodium hepaticum (syn. Capillaria hepatica) is a worldwide helminth parasite of which several aspects of transmission still remain unclear. In the Amazon region, the mechanism of transmission based on the ingestion of eggs present in the liver of wild mammals has been suggested as the cause of the spuriou... | The zoonotic parasite Calodium hepaticum is the causative agent of rarely reported liver disease (hepatic calodiasis) and spurious infections in humans. In spurious infections eggs of this parasite are excreted in the stools without causing disease. It has been suggested that the cause of this type of infection in Amaz... | Calodium hepaticum (syn. Capillaria hepatica) is a zoonotic nematode of the Trichinellidae family found worldwide. This helminth infects the hepatic parenchyma of rodents (principle hosts) and various other mammals (e.g. carnivores, humans) of different families [1]. In humans infection may cause hepatic calodiasis (sy... |
10.1371/journal.pmed.1002418 | Comparison of two cash transfer strategies to prevent catastrophic costs for poor tuberculosis-affected households in low- and middle-income countries: An economic modelling study | Illness-related costs for patients with tuberculosis (TB) ≥20% of pre-illness annual household income predict adverse treatment outcomes and have been termed “catastrophic.” Social protection initiatives, including cash transfers, are endorsed to help prevent catastrophic costs. With this aim, cash transfers may either... | Household costs related to active drug-susceptible (DS) or drug-resistant (DR) tuberculosis (TB) disease include costs for consultations, transport to and from clinics, increased food needs and lost income. If these costs are greater than or equal to one-fifth (20%) of the household’s annual income, then the patient is... | Tuberculosis (TB) disproportionately affects poor households in low- and middle-income countries that are least able to afford the burden that TB-related costs represent relative to their income [1–6]. Even when diagnosis and treatment is available free of direct charges, TB-affected households are known to incur hidde... |
10.1371/journal.pntd.0005671 | Minimal genetic change in Vibrio cholerae in Mozambique over time: Multilocus variable number tandem repeat analysis and whole genome sequencing | Although cholera is a major public health concern in Mozambique, its transmission patterns remain unknown. We surveyed the genetic relatedness of 75 Vibrio cholerae isolates from patients at Manhiça District Hospital between 2002–2012 and 3 isolates from river using multilocus variable-number tandem-repeat analysis (ML... | Cholera is a deadly disease caused by the bacterium Vibrio cholerae. The ancestral home of cholera is around the Bay of Bengal, but recently cholera has moved to Africa. In Africa, cholera occurs in sporadic outbreaks. In order prevent cases of cholera, we want to understand the transmission of cholera in Africa, does ... | Cholera remains a public health concern in developing countries with an estimated burden of 1.2–4.3 million cases and 28,000–142,000 deaths per year, worldwide [1]. South Asia and sub-Saharan Africa account with the majority of cases and deaths. Between 01 January and 03 June 2013, a total of 25,762 cholera cases and 4... |
10.1371/journal.ppat.1005090 | AAV-Delivered Antibody Mediates Significant Protective Effects against SIVmac239 Challenge in the Absence of Neutralizing Activity | Long-term delivery of potent broadly-neutralizing antibodies is a promising approach for the prevention of HIV-1 infection. We used AAV vector intramuscularly to deliver anti-SIV monoclonal antibodies (mAbs) in IgG1 form to rhesus monkeys. Persisting levels of delivered mAb as high as 270 μg/ml were achieved. However, ... | AAV-mediated antibody delivery represents a promising alternative to classical vaccine approaches for the prevention of HIV/AIDS in humans. We used recombinant adeno-associated viral vectors (rAAV) as gene carrier to deliver anti-SIV (simian immunodeficiency virus) antibodies to monkeys. This non-classical immunization... | There are good reasons for believing that development of an effective preventive vaccine against HIV-1 is going to be a very difficult task. HIV-1 has evolved a variety of immune evasion strategies that allow continuous virus replication in the face of apparently strong host immune responses, both cellular and humoral ... |
10.1371/journal.pntd.0004347 | Dynamics of Vector-Host Interactions in Avian Communities in Four Eastern Equine Encephalitis Virus Foci in the Northeastern U.S. | Eastern equine encephalitis (EEE) virus (Togaviridae, Alphavirus) is a highly pathogenic mosquito-borne zoonosis that is responsible for occasional outbreaks of severe disease in humans and equines, resulting in high mortality and neurological impairment in most survivors. In the past, human disease outbreaks in the no... | Eastern equine encephalitis (EEE) is a highly pathogenic mosquito-borne virus responsible for outbreaks of severe disease in humans and equines, causing high mortality and neurological impairment in most survivors. In the past, human disease outbreaks in the northeastern U.S. occurred sporadically with no apparent patt... | Eastern equine encephalitis (EEE) virus (Togaviridae, Alphavirus) is responsible for outbreaks of severe disease in humans and equines, causing high mortality and neurological sequelae in most survivors [1,2]. EEE virus is maintained in an enzootic transmission cycle involving ornithophagic mosquitoes, specifically Cul... |
10.1371/journal.pcbi.1006100 | The AmP project: Comparing species on the basis of dynamic energy budget parameters | We developed new methods for parameter estimation-in-context and, with the help of 125 authors, built the AmP (Add-my-Pet) database of Dynamic Energy Budget (DEB) models, parameters and referenced underlying data for animals, where each species constitutes one database entry. The combination of DEB parameters covers al... | We discovered that parameters of Dynamic Energy Budget (DEB) models can be estimated from a set of simple data on animal life history aspects, growth and reproduction, if treated in combination. Apart from goodness-of-fit as an estimation criterion, relations with parameter values of other species are important, since ... | The role of biodiversity in ecosystem structure and functioning is central for conservation and environmental quality management, as well as biospherics and earth system studies. Biodiversity is not only about the number of species present, but also the number and nature of the different characteristics and functions w... |
10.1371/journal.pcbi.1000962 | Evolution of a Signaling Nexus Constrained by Protein Interfaces and Conformational States | Heterotrimeric G proteins act as the physical nexus between numerous receptors that respond to extracellular signals and proteins that drive the cytoplasmic response. The Gα subunit of the G protein, in particular, is highly constrained due to its many interactions with proteins that control or react to its conformatio... | Proteins evolve new protein-protein interactions through changes to their residues. Many residue changes are harmful because they disrupt important existing interactions and functions. The more interactions a protein participates in, the more difficult it is to make changes that are not harmful to the protein. And yet,... | How is functional novelty generated when a protein is highly constrained by its many interactions with other proteins and by its critical role in the cell? In these proteins, new mutations are likely to have deleterious consequences by disrupting some important function within the cell due to the high probability that ... |
10.1371/journal.pgen.1001042 | The Fitness Landscapes of cis-Acting Binding Sites in Different Promoter and Environmental Contexts | The biophysical nature of the interaction between a transcription factor and its target sequences in vitro is sufficiently well understood to allow for the effects of DNA sequence alterations on affinity to be predicted. But even in relatively simple in vivo systems, the complexities of promoter organization and activi... | A major challenge in molecular genetics has been to understand how cis-regulatory information is integrated to determine the amount of transcript generated. The difficulty has been that there are a large number of variables (known and unknown) that combine through an extensive array of possible mechanisms. Differences ... | While we have a reasonable understanding of the biophysical forces that determine the affinity of a transcription factor to its target sequences [1]–[4], we still have a poor understanding of how the affinity of a factor for a site affects the output of the promoter in which it sits. The major challenge is that these r... |
10.1371/journal.pgen.1003579 | Evidence for Two Different Regulatory Mechanisms Linking Replication and Segregation of Vibrio cholerae Chromosome II | Understanding the mechanisms that coordinate replication initiation with subsequent segregation of chromosomes is an important biological problem. Here we report two replication-control mechanisms mediated by a chromosome segregation protein, ParB2, encoded by chromosome II of the model multichromosome bacterium, Vibri... | Replication and segregation are the two main processes that maintain chromosomes in growing cells. In eukaryotes, the two processes are restricted to distinct phases of the cell cycle. In bacteria, segregation follows replication initiation with a modest lag. Influences of one process on the other have been postulated.... | Studies in bacteria as well as in eukaryotes have shown that processes that maintain chromosomes, such as replication, recombination and repair, although able to occur independently of each other, often influence each other. Chromosome segregation is a major maintenance process but our knowledge of it in bacteria is re... |
10.1371/journal.pcbi.1006867 | Increasing consensus of context-specific metabolic models by integrating data-inferred cell functions | Genome-scale metabolic models provide a valuable context for analyzing data from diverse high-throughput experimental techniques. Models can quantify the activities of diverse pathways and cellular functions. Since some metabolic reactions are only catalyzed in specific environments, several algorithms exist that build... | Genome-scale models of human metabolism have facilitated numerous exciting discoveries regarding human physiology and therapeutics. The accuracy of results from such studies requires that models capture the tissue or cell-type specific metabolism. In hopes to obtain accurate models, several algorithms have been develop... | Genome-scale metabolic models (GeMs) have been widely used for model-guided analysis of large omics datasets, since they provide cellular context to these data by establishing a mechanistic link from genotype to phenotype. GeMs include all reactions in an organism. Since not all enzymes are active in each cell type or ... |
10.1371/journal.ppat.1002462 | CNS Recruitment of CD8+ T Lymphocytes Specific for a Peripheral Virus Infection Triggers Neuropathogenesis during Polymicrobial Challenge | Although viruses have been implicated in central nervous system (CNS) diseases of unknown etiology, including multiple sclerosis and amyotrophic lateral sclerosis, the reproducible identification of viral triggers in such diseases has been largely unsuccessful. Here, we explore the hypothesis that viruses need not repl... | There are many CNS diseases, including multiple sclerosis and amyotrophic lateral sclerosis, which have an inflammatory component, though no direct link has been established between incidence and a CNS-resident infectious agent. We reasoned that peripheral immunogens could play a role in CNS disease by inducing an immu... | Despite the exquisitely specific activation of the adaptive immune response following antigenic encounter, recruitment of immune cells to the affected site is governed by relatively nonspecific factors, including chemokine gradients and adhesion molecule induction on barrier endothelia [1]–[3]. Indeed, some studies hav... |
10.1371/journal.pntd.0001698 | Footprint of Positive Selection in Treponema pallidum subsp. pallidum Genome Sequences Suggests Adaptive Microevolution of the Syphilis Pathogen | In the rabbit model of syphilis, infection phenotypes associated with the Nichols and Chicago strains of Treponema pallidum (T. pallidum), though similar, are not identical. Between these strains, significant differences are found in expression of, and antibody responses to some candidate virulence factors, suggesting ... | During infection, the agent of syphilis, Treponema pallidum subsp. pallidum (T. pallidum), successfully evades the host immune defenses and establishes a persistent infection that can cause blindness, paralysis, or even death in some individuals that progress to the tertiary stage of the disease. The study of the Nicho... | Syphilis continues to be a common and serious disease, affecting at least 25 million persons worldwide [1]. It is a recognized cofactor in the transmission and acquisition of HIV [2], [3], and is a major cause of stillbirth and perinatal morbidity particularly in the developing world [4], [5]. The peculiar biology of t... |
10.1371/journal.pcbi.1004313 | Detailed Per-residue Energetic Analysis Explains the Driving Force for Microtubule Disassembly | Microtubules are long filamentous hollow cylinders whose surfaces form lattice structures of αβ-tubulin heterodimers. They perform multiple physiological roles in eukaryotic cells and are targets for therapeutic interventions. In our study, we carried out all-atom molecular dynamics simulations for arbitrarily long mic... | The molecular machinery of chromosome segregation during cell division is one of the most sophisticated molecular biology mechanisms employing the interplay of different proteins and forces. The long filamentous tube-shaped microtubule structure is a central player in chromosome segregation and cell division, making it... | Microtubules (MTs) are cellular organelles that participate in major cellular processes such as mitosis, cell shape maintenance, cell motility and motor protein transport and constitute a major target for a wide range of drugs, most notably anti-mitotic chemotherapy agents such as paclitaxel. Due to their importance in... |
10.1371/journal.ppat.1004835 | Conserved Streptococcus pneumoniae Spirosomes Suggest a Single Type of Transformation Pilus in Competence | The success of S. pneumoniae as a major human pathogen is largely due to its remarkable genomic plasticity, allowing efficient escape from antimicrobials action and host immune response. Natural transformation, or the active uptake and chromosomal integration of exogenous DNA during the transitory differentiated state ... | Streptococcus pneumoniae often escapes prevention and treatment through rapid horizontal gene transfer via natural transformation. Uptake of exogenous DNA requires expression of a transformation pilus but two markedly different models for pilus assembly and function have been proposed. We previously reported a long, Ty... | Despite medical advances and vaccination campaigns, respiratory tract invasion by Streptococcus pneumoniae remains a leading mortality cause worldwide [1–3]. A particular challenge in the prevention and treatment of pneumococcal infections lies in the bacterium’s striking genomic plasticity, as it allows for efficient ... |
10.1371/journal.pgen.1003437 | Extensive Natural Epigenetic Variation at a De Novo Originated Gene | Epigenetic variation, such as heritable changes of DNA methylation, can affect gene expression and thus phenotypes, but examples of natural epimutations are few and little is known about their stability and frequency in nature. Here, we report that the gene Qua-Quine Starch (QQS) of Arabidopsis thaliana, which is invol... | Epigenetics is defined as the study of heritable changes in gene expression that are not linked to changes in the DNA sequence. In plants, these heritable variations are often associated with differences in DNA methylation. So far, very little is known about the extent and stability of epigenetic variation in nature. I... | DNA mutations are the main known source of heritable phenotypic variation, but epimutations, such as heritable changes of gene expression associated with gain or loss of DNA methylation, are also a source of phenotypic variability. Indeed, several stable DNA methylation variants affecting a wide range of characters hav... |
10.1371/journal.ppat.1000066 | The Uptake of Apoptotic Cells Drives Coxiella burnetii Replication and Macrophage Polarization: A Model for Q Fever Endocarditis | Patients with valvulopathy have the highest risk to develop infective endocarditis (IE), although the relationship between valvulopathy and IE is not clearly understood. Q fever endocarditis, an IE due to Coxiella burnetii, is accompanied by immune impairment. Patients with valvulopathy exhibited increased levels of ci... | Infective endocarditis (IE) is a problem of public health that still causes high mortality despite antibiotic treatments. Most of the patients who develop an IE have pre-existing cardiac lesions, although the relationship between IE and valvulopathy is not clearly understood. We showed here that patients with valvulopa... | Infective endocarditis (IE) has long been recognized as a fatal disease. Despite the availability of antimicrobial agents and cardiac surgery, IE still causes high morbidity and mortality. About 75% of patients with IE have pre-existing cardiac diseases [1], including congenital cardiac malformations, acquired valvular... |
10.1371/journal.pgen.1008139 | Functional robustness of adult spermatogonial stem cells after induction of hyperactive Hras | Accumulating evidence indicates that paternal age correlates with disease risk in children. De novo gain-of-function mutations in the FGF-RAS-MAPK signaling pathway are known to cause a subset of genetic diseases associated with advanced paternal age, such as Apert syndrome, achondroplasia, Noonan syndrome, and Costell... | Recent research has found that advanced paternal age is associated with increased risk in children to develop a subset of congenital anomalies, such as Apert syndrome, achondroplasia, Noonan syndrome, and Costello syndrome. The causative genetic errors (mutations) in these disorders have been identified to originate fr... | In order to propagate genetic information to the next generation with high fidelity, germline cells must maintain a low mutation rate. Nevertheless, maternal germline cells (human oocytes) are well known to transmit abnormal chromosomes to offspring, especially in advanced maternal age (reviewed in [1]). Surprisingly, ... |
10.1371/journal.ppat.1003055 | The Calmodulin-like Calcium Binding Protein EhCaBP3 of Entamoeba histolytica Regulates Phagocytosis and Is Involved in Actin Dynamics | Phagocytosis is required for proliferation and pathogenesis of Entamoeba histolytica and erythrophagocytosis is considered to be a marker of invasive amoebiasis. Ca2+ has been found to play a central role in the process of phagocytosis. However, the molecular mechanisms and the signalling mediated by Ca2+ still remain ... | Entamoeba histolytica is one of the major causes of morbidity and mortality in developing countries. Phagocytosis plays an important role in both survival and virulence and has been used as a virulence marker. Inhibition of phagocytosis leads to a defect in cellular proliferation. Therefore, the molecules that particip... | A variety of cell types, such as macrophages and neutrophils and many unicellular eukaryotes have the ability to engulf particles of size greater than 0.5 µm through a process called phagocytosis. In the former this process has evolved as one of the critical elements of host defence, while in the latter it serves as a ... |
10.1371/journal.pbio.1000615 | A Quantitative Test of Hamilton's Rule for the Evolution of Altruism | The evolution of altruism is a fundamental and enduring puzzle in biology. In a seminal paper Hamilton showed that altruism can be selected for when rb − c>0, where c is the fitness cost to the altruist, b is the fitness benefit to the beneficiary, and r is their genetic relatedness. While many studies have provided qu... | One of the enduring puzzles in biology and the social sciences is the origin and persistence of altruism, whereby a behavior benefiting another individual incurs a direct cost for the individual performing the altruistic action. This apparent paradox was resolved by Hamilton's theory, known as kin selection, which stat... | One of the enduring puzzles in biology and the social sciences is the origin and persistence of altruism, whereby a behavior benefiting another individual incurs a direct cost for the individual performing the altruistic action. A solution to this apparent paradox was first provided by Hamilton [1], who showed that a b... |
10.1371/journal.ppat.1004659 | Viral and Cellular Proteins Containing FGDF Motifs Bind G3BP to Block Stress Granule Formation | The Ras-GAP SH3 domain–binding proteins (G3BP) are essential regulators of the formation of stress granules (SG), cytosolic aggregates of proteins and RNA that are induced upon cellular stress, such as virus infection. Many viruses, including Semliki Forest virus (SFV), block SG induction by targeting G3BP. In this wor... | Stress granules (SGs) are dynamic aggregates of proteins and translationally silenced mRNA that are formed in cells upon various stress conditions, such as virus infection. SGs are thought to be antiviral, and many viruses have hence evolved countermeasures to prevent their formation, often targeting the essential SG p... | The Ras-GAP SH3 domain–binding proteins (G3BP) are multifunctional RNA-binding proteins, present in two forms, G3BP-1 and G3BP-2 (here collectively referred to as G3BP). They have a well-described importance in mediating the formation of RNA stress granules (SG), both in cells exposed to environmental stress and viral ... |
10.1371/journal.pcbi.1001061 | PhylOTU: A High-Throughput Procedure Quantifies Microbial Community Diversity and Resolves Novel Taxa from Metagenomic Data | Microbial diversity is typically characterized by clustering ribosomal RNA (SSU-rRNA) sequences into operational taxonomic units (OTUs). Targeted sequencing of environmental SSU-rRNA markers via PCR may fail to detect OTUs due to biases in priming and amplification. Analysis of shotgun sequenced environmental DNA, know... | Microorganisms comprise the majority of the biodiversity on the planet. Because the overwhelming majority of microbes are not readily cultured in the laboratory, researchers often rely on PCR-based investigations of genomic sequence to characterize microbial diversity. These analyses have dramatically expanded our unde... | A central goal of ecology and evolution is to understand the forces that shape biodiversity - the variety of life on Earth. It is becoming increasingly clear that global biodiversity is mostly microbial. It is estimated that there are millions of microbial species on the planet, relatively few of which have been isolat... |
10.1371/journal.pbio.0060255 | Diverse RNA-Binding Proteins Interact with Functionally Related Sets of RNAs, Suggesting an Extensive Regulatory System | RNA-binding proteins (RBPs) have roles in the regulation of many post-transcriptional steps in gene expression, but relatively few RBPs have been systematically studied. We searched for the RNA targets of 40 proteins in the yeast Saccharomyces cerevisiae: a selective sample of the approximately 600 annotated and predic... | Regulation of gene transcription has been extensively studied, but much less is known about how the fates of the resulting mRNA transcripts are regulated. We were intrigued by the fact that while most eukaryotic genomes encode hundreds of RNA-binding proteins (RBPs), the targets and regulatory roles of only a small fra... | Much of the regulation of eukaryotic gene expression programs is still unaccounted for. Although these programs are subject to regulation at many steps, most investigation has focused on regulation of transcription. There are clues, however, that a significant portion of undiscovered regulation might be post-transcript... |
10.1371/journal.pbio.2006062 | Repeated translocation of a gene cassette drives sex-chromosome turnover in strawberries | Turnovers of sex-determining systems represent important diversifying forces across eukaryotes. Shifts in sex chromosomes—but conservation of the master sex-determining genes—characterize distantly related animal lineages. Yet in plants, in which separate sexes have evolved repeatedly and sex chromosomes are typically ... | Sex chromosomes frequently restructure themselves during organismal evolution, often becoming highly differentiated. This dynamic process is poorly understood for most taxa, especially during the early stages typical of many dioecious flowering plants. We show that in wild strawberries, a female-specific region of DNA ... | Sex chromosomes can be a strikingly diverse and evolutionarily labile component of eukaryotic genomes [1]. The defining feature of a sex chromosome, the sex-determining region (SDR), has experienced similar restructuring in multiple independent instances of autosomes evolving into heteromorphic sex chromosomes [2]. Spe... |
10.1371/journal.pgen.1002982 | Proteome-Wide Analysis of Disease-Associated SNPs That Show Allele-Specific Transcription Factor Binding | A causative role for single nucleotide polymorphisms (SNPs) in many genetic disorders has become evident through numerous genome-wide association studies. However, identification of these common causal variants and the molecular mechanisms underlying these associations remains a major challenge. Differential transcript... | Genome-wide association studies (GWAS) are a powerful approach to identifying genes contributing to risk of disease. However, individual mapped single nucleotide polymorphisms (SNPs) may not map close to a gene, and it can be difficult to distinguish marker SNPs from causal SNPs. Furthermore, the molecular mechanism re... | Genome-wide association studies (GWAS) of common diseases typically result in the identification of genomic susceptibility loci, in which several single nucleotide polymorphisms (SNPs) showing strong inter-marker linkage disequilibrium (LD) are equally associated with disease predisposition. Further fine-mapping and re... |
10.1371/journal.pgen.1006469 | Whole-Organism Developmental Expression Profiling Identifies RAB-28 as a Novel Ciliary GTPase Associated with the BBSome and Intraflagellar Transport | Primary cilia are specialised sensory and developmental signalling devices extending from the surface of most eukaryotic cells. Defects in these organelles cause inherited human disorders (ciliopathies) such as retinitis pigmentosa and Bardet-Biedl syndrome (BBS), frequently affecting many physiological and development... | Ciliopathies are genetic disorders that arise from loss or mutation of genes that encode proteins which play roles in the biology of cilia, organelles found on most of the cells in the human body. Ciliopathy-associated ailments include–but are not limited to–kidney dysfunction, blindness, skeletal abnormalities, as wel... | The cilium is a conserved organelle, inferred to have existed in the last eukaryotic common ancestor (LECA) and now present in most extant protists, as well as all multicellular animals. Motile cilia generate cell movement or fluid flow, whereas non-motile (primary) cilia have evolved as specialised ‘antennae’ that cap... |
10.1371/journal.pgen.1008093 | Destabilization of chromosome structure by histone H3 lysine 27 methylation | Chromosome and genome stability are important for normal cell function as instability often correlates with disease and dysfunction of DNA repair mechanisms. Many organisms maintain supernumerary or accessory chromosomes that deviate from standard chromosomes. The pathogenic fungus Zymoseptoria tritici has as many as e... | Genome and chromosome stability are essential to maintain normal cell function and viability. However, differences in genome and chromosome structure are frequently found in organisms that undergo rapid adaptation to changing environmental conditions, and in humans are often found in cancer cells. We study genome insta... | Chromatin structure plays an important role in genome organization and gene expression [1–3]. A well-studied hallmark of epigenetic regulation is the reversible modification of histone tails, which can alter chromatin structure [4]. Chromatin structure determines accessibility of the underlying DNA to regulatory elemen... |
10.1371/journal.pntd.0005057 | Osteopontin Is Upregulated in Human and Murine Acute Schistosomiasis Mansoni | Symptomatic acute schistosomiasis mansoni is a systemic hypersensitivity reaction against the migrating schistosomula and mature eggs after a primary infection. The mechanisms involved in the pathogenesis of acute schistosomiasis are not fully elucidated. Osteopontin has been implicated in granulomatous reactions and i... | Schistosomiasis is a major health problem that affects over 200 million people. Symptomatic acute schistosomiasis is a systemic reaction to the worms and eggs in individuals from non-endemic areas after a primary infection. Tourists, military personnel and people who practice water sports are at risk. Although most cas... | Schistosomiasis is a severe tropical disease caused by Schistosoma spp. flatworms that affects over 200 million of people from 76 countries and territories [1]. S. mansoni is the only species in the Americas and Brazil holds the majority of infected individuals with 25 million living in endemic areas and 4–6 million in... |
10.1371/journal.pcbi.1000931 | Role of Hsp70 ATPase Domain Intrinsic Dynamics and Sequence Evolution in Enabling its Functional Interactions with NEFs | Catalysis of ADP-ATP exchange by nucleotide exchange factors (NEFs) is central to the activity of Hsp70 molecular chaperones. Yet, the mechanism of interaction of this family of chaperones with NEFs is not well understood in the context of the sequence evolution and structural dynamics of Hsp70 ATPase domains. We studi... | The heat shock protein 70 (Hsp70) serves as a housekeeper in the cell, assisting in the correct folding, trafficking, and degradation of many proteins. The ATPase domain is the control unit of this molecular machine and its efficient functioning requires interactions with co-chaperones, including, in particular, the nu... | Many proteins are molecular machines. They function because their three-dimensional structure allows them to undergo cooperative changes in conformation that maintain the native fold while enabling their biological functions. The changes have been pointed out to be structure-encoded, intrinsically accessible to protein... |
10.1371/journal.pcbi.1000190 | Organization of Excitable Dynamics in Hierarchical Biological Networks | This study investigates the contributions of network topology features to the dynamic behavior of hierarchically organized excitable networks. Representatives of different types of hierarchical networks as well as two biological neural networks are explored with a three-state model of node activation for systematically... | Many complex biological networks are characterized by the coexistence of topological features such as modules and central hub nodes. What are the relative contributions of these structural features to the networks' dynamic behavior? We used a computational model to simulate the general activation and inactivation behav... | The analysis of biological networks presents an intriguing challenge, due to the complex, non-random organization of these systems and the diverse dynamic behaviors that they express. The topology of several biological networks has been shown to be based on a scale-free degree distribution, which implies the existence ... |
10.1371/journal.pgen.1000199 | Deletion of the Pluripotency-Associated Tex19.1 Gene Causes Activation of Endogenous Retroviruses and Defective Spermatogenesis in Mice | As genetic information is transmitted through successive generations, it passes between pluripotent cells in the early embryo and germ cells in the developing foetus and adult animal. Tex19.1 encodes a protein of unknown function, whose expression is restricted to germ cells and pluripotent cells. During male spermatog... | The germ cells—eggs in females and sperm in males—are responsible for passing genetic information from one generation to the next. As any genetic changes that arise in the germ cells can be transmitted to the next generation, germ cells are a prime target for the activity of mobile genetic elements. Mobile genetic elem... | The germ cells of sexually reproducing organisms have a unique role in generating genetic diversity and transmitting genetic information from one generation to the next. Establishment of the germline in mammals involves the induction of germ cells from pluripotent epiblast cells through the action of extra-embryonic ec... |
10.1371/journal.pcbi.1006652 | Multiscale computational model of Achilles tendon wound healing: Untangling the effects of repair and loading | Mechanical stimulation of the healing tendon is thought to regulate scar anisotropy and strength and is relatively easy to modulate through physical therapy. However, in vivo studies of various loading protocols in animal models have produced mixed results. To integrate and better understand the available data, we deve... | Tendons and ligaments transmit force between muscles and bones throughout the body and are comprised of highly aligned collagen fibers that help bear high loads. The Achilles tendon is exposed to exceptionally high loads and is prone to rupture. When damaged Achilles tendons heal, they typically have reduced strength a... | Many mechanically loaded tissues including skin, tendon, ligament, and heart respond to injury by forming a collagen-rich scar. Normally, tendons are comprised of highly aligned collagen fibers that help transmit forces between muscles and bones throughout the body and bear high loads. The Achilles tendon in particular... |
10.1371/journal.pgen.1008084 | Meiotic gatekeeper STRA8 suppresses autophagy by repressing Nr1d1 expression during spermatogenesis in mice | The transition from mitotic to meiotic cell cycles is essential for haploid gamete formation and fertility. Stimulated by retinoic acid gene 8 (Stra8) is an essential gatekeeper of meiotic initiation in vertebrates; yet, the molecular role of STRA8 remains principally unknown. Here we demonstrate that STRA8 functions a... | Meiotic initiation is a key feature of sexual reproduction that launches an intricate chromosomal program involving DNA double strand breaks (DSBs), homolog pairing, cohesion, synapsis, and recombination. Vertebrate gene Stra8 is an essential gatekeeper of meiotic initiation. However, the molecular role of STRA8 and it... | Meiosis is a fundamental process in sexual reproduction during which diploid cells halve their chromosome number by two rounds of cell divisions to generate haploid cells or gametes. In mammals, temporal regulation of meiosis in germ cells is sex-specific: meiosis in females begins during embryogenesis, whereas meiosis... |
10.1371/journal.pgen.1002289 | Bmp and Nodal Independently Regulate lefty1 Expression to Maintain Unilateral Nodal Activity during Left-Right Axis Specification in Zebrafish | In vertebrates, left-right (LR) axis specification is determined by a ciliated structure in the posterior region of the embryo. Fluid flow in this ciliated structure is responsible for the induction of unilateral left-sided Nodal activity in the lateral plate mesoderm, which in turn regulates organ laterality. Bmp sign... | Although vertebrates are bilaterally symmetric when observed from the outside, inside the body cavity the organs are positioned asymmetrically with respect to the left and right sides. Cases where all the organs are mirror imaged, known as situs inversus, are not associated with any medical defects. Severe medical prob... | In vertebrates the internal organs are positioned asymmetrically along the left-right (LR) axis. For example, in humans, the heart is positioned on the left side, as is the stomach whilst the liver is positioned on the right side. Within organs LR asymmetry also exists. For example, the two lungs appear identical howev... |
10.1371/journal.pntd.0007363 | Development and validation of a multiplexed-tandem qPCR tool for diagnostics of human soil-transmitted helminth infections | Soil-transmitted helminths (STH) are a major cause of morbidity in tropical developing countries with a global infection prevalence of more than one billion people and disease burden of around 3.4 million disability adjusted life years. Infection prevalence directly correlates to inadequate sanitation, impoverished con... | Soil-transmitted helminthiases are among the most prevalent and damaging neglected tropical diseases and have a significant global health impact. Accurate identification and quantitation of STH infection is a cornerstone of effective control. Direct observation and counting of eggs in faeces is the current gold-standar... | Soil-transmitted helminths (STH), including roundworms (Ascaris lumbricoides), whipworms (Trichuris trichiura) and hookworms (Necator americanus, Ancylostoma duodenale, Ancylostoma ceylanicum) represent a major cause of morbidity in tropical to sub-tropical developing and low-income countries [1]. In 2016, the Global B... |
10.1371/journal.pgen.1003252 | Antagonism Versus Cooperativity with TALE Cofactors at the Base of the Functional Diversification of Hox Protein Function | Extradenticle (Exd) and Homothorax (Hth) function as positive transcriptional cofactors of Hox proteins, helping them to bind specifically their direct targets. The posterior Hox protein Abdominal-B (Abd-B) does not require Exd/Hth to bind DNA; and, during embryogenesis, Abd-B represses hth and exd transcription. Here ... | Hox genes encode transcription factors necessary to achieve the morphological differences between anterior and posterior regions of the body. These genes have been functionally conserved during animal evolution, and similar classes can be recognized in vertebrates and invertebrates. To bind DNA and regulate many of the... | In segmented animals the differential anterior-posterior morphology is achieved during development under the control of the Hox genes [1]. Hox genes encode a conserved family of transcription factors organized in clusters in most animals. Hox clusters originated before the divergence of protostomes and deuterostomes an... |
10.1371/journal.ppat.1005211 | Fundamental Roles of the Golgi-Associated Toxoplasma Aspartyl Protease, ASP5, at the Host-Parasite Interface | Toxoplasma gondii possesses sets of dense granule proteins (GRAs) that either assemble at, or cross the parasitophorous vacuole membrane (PVM) and exhibit motifs resembling the HT/PEXEL previously identified in a repertoire of exported Plasmodium proteins. Within Plasmodium spp., cleavage of the HT/PEXEL motif by the e... | The opportunistic pathogen Toxoplasma gondii infects a large range of nucleated cells where it replicates intracellularly within a parasitophorous vacuole (PV) surrounded by a membrane (PVM). Parasites constitutively secrete dense-granule proteins (GRAs) both into and beyond the PV which participate in remodelling of t... | The phylum Apicomplexa groups obligate protozoan parasites that are the causative agents of severe diseases in humans and animals such as malaria, toxoplasmosis, babesiosis and coccidiosis. The key process of invasion and subsequent multiplication within their host cells is maintained via secretion from three distinct ... |
10.1371/journal.pcbi.1000401 | SpaK/SpaR Two-component System Characterized by a Structure-driven
Domain-fusion Method and in Vitro Phosphorylation Studies | Here we introduce a quantitative structure-driven computational domain-fusion
method, which we used to predict the structures of proteins believed to be
involved in regulation of the subtilin pathway in Bacillus
subtilis, and used to predict a protein-protein ... | Because proteins so frequently function in coordination with other proteins,
identification and characterization of the interactions among proteins are
essential for understanding how proteins work. Computational methods for
identification of protein-protein i... | Because proteins so frequently function in coordination with other proteins,
identification and characterization of protein-protein complexes are essential
aspects of protein sequence annotation and function determination [1]. A
variety of empirical [2]–[4] and computatio... |
10.1371/journal.pgen.1001378 | GWAS of Follicular Lymphoma Reveals Allelic Heterogeneity at 6p21.32
and Suggests Shared Genetic Susceptibility with Diffuse Large B-cell
Lymphoma | Non-Hodgkin lymphoma (NHL) represents a diverse group of hematological
malignancies, of which follicular lymphoma (FL) is a prevalent subtype. A
previous genome-wide association study has established a marker, rs10484561 in
the human leukocyte antigen (HLA) cl... | Earlier studies have established a marker rs10484561, in the HLA class II region
on 6p21.32, associated with increased follicular lymphoma (FL) risk. Here, in a
three-stage genome-wide association study of 1,428 FL cases and 6,581 controls,
we identified a sec... | Non-Hodgkin lymphoma (NHL) represents a diverse group of B- and T-cell malignancies
of lymphatic origin. The most common subtypes are of B-cell origin and are further
classified on the basis of their resemblance to normal stages of B-cell
differentiation [1]. Epidemiologi... |
10.1371/journal.pbio.0050150 | Setting the Tempo in Development: An Investigation of the Zebrafish Somite Clock Mechanism | The somites of the vertebrate embryo are clocked out sequentially from the presomitic mesoderm (PSM) at the tail end of the embryo. Formation of each somite corresponds to one cycle of oscillation of the somite segmentation clock—a system of genes whose expression switches on and off periodically in the cells of the PS... | Somites—the embryonic segments of the vertebrate body—are formed sequentially, with a spacing determined by a gene expression oscillator, the segmentation clock, operating in the cells at the tail end of the embryo. This system provides a rare opportunity to analyse how the timing of at least one set of developmental e... | How do genes set the tempo of embryonic development? This basic question is still largely unanswered. We lack quantitative information about the dynamics of gene expression in the embryo, and in most cases, we do not even know which genes govern timing, let alone how they do so. In this paper, we focus on one particula... |
10.1371/journal.ppat.1000116 | Histidine-Rich Glycoprotein Protects from Systemic Candida Infection | Fungi, such as Candida spp., are commonly found on the skin and at mucosal surfaces. Yet, they rarely cause invasive infections in immunocompetent individuals, an observation reflecting the ability of our innate immune system to control potentially invasive microbes found at biological boundaries. Antimicrobial protein... | It has been estimated that humans contain about 1 kg of microbes, an observation that reflects our coexistence with colonizing microbes such as bacteria and fungi. The fungal species Candida is present as a commensal at mucosal surfaces and on skin. Although it may cause life-threatening infections, such as sepsis, par... | The innate immune system, based on antimicrobial peptides (AMP) and proteins, provides a first line of defence against invading microbes [1]–[3]. At present, over 880 different AMPs have been identified in eukaryotes (www.bbcm.univ.trieste.it/tossi/pag5.htm). During recent years it has become increasingly evident that ... |
10.1371/journal.pcbi.1000053 | Efficient Olfactory Coding in the Pheromone Receptor Neuron of a Moth | The concept of coding efficiency holds that sensory neurons are adapted, through both evolutionary and developmental processes, to the statistical characteristics of their natural stimulus. Encouraged by the successful invocation of this principle to predict how neurons encode natural auditory and visual stimuli, we at... | Efficient coding is an overarching principle, well tested in visual and auditory neurobiology, which states that sensory neurons are adapted to the statistical characteristics of their natural stimulus - in brief, neurons best process those stimuli that occur most frequently. To assess its validity in olfaction, we exa... | According to the ‘efficient-coding hypothesis’ [1], the sensory neurons are adapted to the statistical properties of the signals to which they are exposed. Because not all signals are equally likely, sensory systems should best encode those signals that occur most frequently. This idea was first tested by Laughlin [2] ... |
10.1371/journal.pcbi.1004615 | How Obstacles Perturb Population Fronts and Alter Their Genetic Structure | As populations spread into new territory, environmental heterogeneities can shape the population front and genetic composition. We focus here on the effects of an important building block of heterogeneous environments, isolated obstacles. With a combination of experiments, theory, and simulation, we show how isolated o... | Geographical structure influences the dynamics of the expansion of populations into new habitats and the relative importance of the evolutionary forces of mutation, selection, genetic drift, and gene flow. While populations often spread and evolve in highly complex environments, simplified scenarios allow one to uncove... | Populations expand into new territory on all length and time scales. Examples include the migration of humans out of Africa [1], the recent invasion of cane toads in Australia [2], and the growth of colonies of microbes. Although populations often persist long after invading [3], events during their spread can have lon... |
10.1371/journal.pcbi.1005915 | MPLasso: Inferring microbial association networks using prior microbial knowledge | Due to the recent advances in high-throughput sequencing technologies, it becomes possible to directly analyze microbial communities in human body and environment. To understand how microbial communities adapt, develop, and interact with the human body and the surrounding environment, one of the fundamental challenges ... | Microbial communities exhibit rich dynamics including the way they adapt, develop, and interact with the human body and the surrounding environment. The associations among microbes can provide a solid foundation to model the interplay between the (host) human body and the microbial populations. However, due to the uniq... | Microbes play an important role both in environment and human life. However, the way microbes affect the human health remains largely unknown. Knowledge of the microbial interactions can provide a solid foundation to model the interplay between the (host) human body and the microbial populations; this can serve as a ke... |
10.1371/journal.ppat.1006178 | A single mutation in the envelope protein modulates flavivirus antigenicity, stability, and pathogenesis | The structural flexibility or ‘breathing’ of the envelope (E) protein of flaviviruses allows virions to sample an ensemble of conformations at equilibrium. The molecular basis and functional consequences of virus conformational dynamics are poorly understood. Here, we identified a single mutation at residue 198 (T198F)... | Flaviviruses include emerging pathogens such as WNV, DENV, and ZIKV that threaten global health. Despite causing significant morbidity, effective vaccines or therapeutic agents to protect humans against many flaviviruses are lacking. Because of the importance of antibodies in flavivirus immunity and vaccine protection,... | Flaviviruses are enveloped, positive-stranded RNA viruses typically transmitted to humans via infected ticks or mosquitoes. As many members of the flavivirus genus are emerging, they constitute a significant threat to global health. For example, approximately 390 million humans worldwide are infected annually with one ... |
10.1371/journal.pgen.1007696 | Functional equivalence of germ plasm organizers | The proteins Oskar (Osk) in Drosophila and Bucky ball (Buc) in zebrafish act as germ plasm organizers. Both proteins recapitulate germ plasm activities but seem to be unique to their animal groups. Here, we discover that Osk and Buc show similar activities during germ cell specification. Drosophila Osk induces addition... | Multicellular organisms use gametes for their propagation. Gametes are formed from germ cells, which are specified during embryogenesis in some animals by the inheritance of RNP granules known as germ plasm. Transplantation of germ plasm induces extra germ cells, whereas germ plasm ablation leads to the loss of gametes... | Living systems have the unique ability to reproduce copies of themselves. In animals, the reproductive cells or their precursors, the primordial germ cells (PGCs) are specified by two different modes during embryogenesis [reviewed in 1]. In the inductive mode, the embryo generates signals, which specify a subset of cel... |
10.1371/journal.pntd.0004605 | Neutropenic Mice Provide Insight into the Role of Skin-Infiltrating Neutrophils in the Host Protective Immunity against Filarial Infective Larvae | Our knowledge and control of the pathogenesis induced by the filariae remain limited due to experimental obstacles presented by parasitic nematode biology and the lack of selective prophylactic or curative drugs. Here we thought to investigate the role of neutrophils in the host innate immune response to the infection ... | Filariases are chronic debilitating diseases caused by parasitic nematodes affecting more than 150 million people worldwide. None of the current drugs are selective, neither able to eliminate the parasites nor to prevent new infections once the drug pressure has waned. Therefore, blocking the entry and the migration of... | Filarial nematodes constitute a large group of human pathogens (i.e. Onchocerca volvulus, Brugia malayi, Brugia timori, Wuchereria bancrofti, Loa loa, Mansonella spp.) infecting around 150 million people throughout the tropics with more than 1.5 billion at risk of infection. Filariases remain a health issue, as no sele... |
10.1371/journal.ppat.1006419 | Competition between influenza A virus subtypes through heterosubtypic immunity modulates re-infection and antibody dynamics in the mallard duck | Our overall hypothesis is that host population immunity directed at multiple antigens will influence the prevalence, diversity and evolution of influenza A virus (IAV) in avian populations where the vast subtype diversity is maintained. To investigate how initial infection influences the outcome of later infections wit... | Many features of pathogen diversification remain poorly explored although host immunity is recognized as a major driver of pathogen evolution. Influenza A viruses (IAVs) can infect many avian and mammalian hosts, but while few IAV subtypes circulate in human populations, subtype diversity is extensive in wild bird popu... | Diversification is a common feature in pathogen populations and this often involves the evolution of antigenic variants [1]. Examples of this exist in various pathogen systems: viruses (influenza A virus, Dengue virus, Bluetongue virus, and rotaviruses), bacteria (Borrelia spp, Neisseria meningitis, and Pneumococcus) a... |
10.1371/journal.ppat.1003852 | The CD8-Derived Chemokine XCL1/Lymphotactin Is a Conformation-Dependent, Broad-Spectrum Inhibitor of HIV-1 | CD8+ T cells play a key role in the in vivo control of HIV-1 replication via their cytolytic activity as well as their ability to secrete non-lytic soluble suppressive factors. Although the chemokines that naturally bind CCR5 (CCL3/MIP-1α, CCL4/MIP- 1β, CCL5/RANTES) are major components of the CD8-derived anti-HIV acti... | Although HIV, the causative agent of AIDS, establishes a lifelong infection that cannot be eradicated even with effective treatment, the host immune system has the ability to contain its replication for many years in which the disease remains asymptomatic. Key players in HIV control are CD8+ T cells, specialized immune... | The replication of HIV-1 is regulated in vivo by a complex network of cytokines and chemokines expressed by immune and inflammatory cells. Key players in the mechanisms of HIV-1 control are CD8+ T cells, which, in addition to their cytolytic activity, secrete soluble factors that suppress HIV-1 in a non-lytic fashion [... |
10.1371/journal.pcbi.1003515 | Viral Quasispecies Assembly via Maximal Clique Enumeration | Virus populations can display high genetic diversity within individual hosts. The intra-host collection of viral haplotypes, called viral quasispecies, is an important determinant of virulence, pathogenesis, and treatment outcome. We present HaploClique, a computational approach to reconstruct the structure of a viral ... | Humans infected with a virus, such as the human immunodeficiency virus (HIV-1) or hepatitis C virus (HCV), host a population of billions of virus particles. Among these, there is an unknown number of genetically different strains, some of which can harbor drug resistance and immune escape mutations. It is of clinical i... | Genetic diversity is an important characteristic of evolving populations and it affects the chances of survival in changing environments. Assessing the genetic diversity of a population experimentally is generally labor-intensive and difficult. Populations of individual cells or viruses, however, can be analyzed effici... |
10.1371/journal.pgen.1006714 | Microhomology-mediated end joining induces hypermutagenesis at breakpoint junctions | Microhomology (MH) flanking a DNA double-strand break (DSB) drives chromosomal rearrangements but its role in mutagenesis has not yet been analyzed. Here we determined the mutation frequency of a URA3 reporter gene placed at multiple locations distal to a DSB, which is flanked by different sizes (15-, 18-, or 203-bp) o... | Recurrent chromosome translocations juxtapose chromosomal fragments and alter expression of tumor suppressors or oncogenes at or near breakpoint junctions to develop distinct types of leukemias and childhood sarcomas. The prevalence of 2–20 bp of imperfect overlapping sequences (a.k.a. microhomology [MH]) at the breakp... | The presence of short stretches of overlapping sequence (microhomology, MH) is a frequent feature of pathogenic chromosomal translocation breakpoints in human cells and has been implicated in juxtaposing two DNA ends for the error-prone repair of DNA breaks in both yeast and vertebrates [1–3]. This so-called microhomol... |
10.1371/journal.pcbi.1002745 | Emergence of the Mitochondrial Reticulum from Fission and Fusion Dynamics | Mitochondria form a dynamic tubular reticulum within eukaryotic cells. Currently, quantitative understanding of its morphological characteristics is largely absent, despite major progress in deciphering the molecular fission and fusion machineries shaping its structure. Here we address the principles of formation and t... | Mitochondria control energy production, initiation of cell death and several other critical cellular processes. Most often, they form a constantly reshaping tubular reticulum spread over the cytosol. Despite extensive knowledge of mitochondrial physiology, accurate description of their large-scale architecture is missi... | Whereas experimental biology provides important insights into numerous characteristics and protein complexes responsible for cellular physiology, understanding the functional properties of many organelles can best be achieved when cell-wide structural complexity is included. This is provided by mathematical models able... |
10.1371/journal.pntd.0005815 | Increased level and interferon-γ production of circulating natural killer cells in patients with scrub typhus | Natural killer (NK) cells are essential immune cells against several pathogens. Not much is known regarding the roll of NK cells in Orientia tsutsugamushi infection. Thus, this study aims to determine the level, function, and clinical relevance of NK cells in patients with scrub typhus.
This study enrolled fifty-six sc... | Orientia tsutsugamushi is an obligate intracellular bacterium. It primarily invades endothelial cells, macrophages, monocytes, and dendritic cells. Plasma concentrations of interferon (IFN)-γ, several cytokines and chemokines, which are known to recruit natural killer (NK) cells and T cells, were found to be increased ... | Orientia tsutsugamushi is an obligate intracellular bacterium that causes scrub typhus in humans. It is a mite-borne, endothelium-targeting intracellular bacterium. Scrub typhus is prevalent in Asia, Northern Australia, and the Indian subcontinent. Most patients may recover from scrub typhus without complications if pr... |
10.1371/journal.ppat.1004332 | Primary Seronegative but Molecularly Evident Hepadnaviral Infection Engages Liver and Induces Hepatocarcinoma in the Woodchuck Model of Hepatitis B | Hepadnavirus at very low doses establishes in woodchucks asymptomatic, serologically undetectable but molecularly evident persistent infection. This primary occult infection (POI) preferentially engages the immune system and initiates virus-specific T cell response in the absence of antiviral antibody induction. The cu... | Introduction of highly sensitive molecular assays for detection of hepatitis B virus (HBV) identified the existence of persistent occult HBV infection years after recovery from an episode of hepatitis B and in individuals exposed to HBV but without symptoms and classical markers of infection. Because HBV integrates int... | It is estimated that 370 million people have serologically evident chronic hepatitis B virus (HBV) infection and over 2 billion have been exposed to this virus [1]. Chronic hepatitis B (CHB) frequently (20–25%) advances to cirrhosis and liver failure, while hepatocellular carcinoma (HCC) develops in approximately 5% of... |
10.1371/journal.pcbi.1003386 | Electrodiffusive Model for Astrocytic and Neuronal Ion Concentration Dynamics | The cable equation is a proper framework for modeling electrical neural signalling that takes place at a timescale at which the ionic concentrations vary little. However, in neural tissue there are also key dynamic processes that occur at longer timescales. For example, endured periods of intense neural signaling may c... | When neurons generate electrical signals they release potassium ions (K+) into the extracellular space. During periods of intense neural activity, the local extracellular K+ may increase drastically. If it becomes too high, it can lead to neural dysfunction. Astrocytes (a kind of glial cells) are involved in preventing... | The interaction between neurons and glial cells has been the topic of many recent studies within the field of neuroscience (see reviews in [1]–[3]). Astrocytes (a species of glial cells) play an important role in modulating excitatory and inhibitory synapses by removal, metabolism, and release of neurotransmitters [4],... |
10.1371/journal.ppat.1000669 | A Novel System of Cytoskeletal Elements in the Human Pathogen Helicobacter pylori | Pathogenicity of the human pathogen Helicobacter pylori relies upon its capacity to adapt to a hostile environment and to escape from the host response. Therefore, cell shape, motility, and pH homeostasis of these bacteria are specifically adapted to the gastric mucus. We have found that the helical shape of H. pylori ... | The human pathogen Helicobacter pylori lives in the hostile environment of the human stomach. H. pylori possesses a spiral shape and high motility that enable the bacterium to swim through the stomach lumen and to come into close contact with epithelial cells. High urease activity in the bacterium counterbalances the l... | Helicobacter pylori is a Gram negative, highly motile, microaerophilic, spiral-shaped organism, which colonizes the stomachs of at least half of the world's population [1]. Infection of humans results in persistent gastritis, which can develop into peptic ulcer disease and adenocarcinoma [2],[3]. Motility is a key fact... |
10.1371/journal.pgen.1005428 | Variability of Gene Expression Identifies Transcriptional Regulators of Early Human Embryonic Development | An analysis of gene expression variability can provide an insightful window into how regulatory control is distributed across the transcriptome. In a single cell analysis, the inter-cellular variability of gene expression measures the consistency of transcript copy numbers observed between cells in the same population.... | In order to function properly, cells express specific sets of genes that are regulated via complex transcriptional programs. During early stages of development, when an embryo consists of only a handful of cells, it is vital that these cells work together so that the embryo can develop into a healthy baby. Single cell ... | The regulatory program that ensures that a human embryo can develop successfully starting from a single cell zygote is one of the most fascinating examples of systems-level genetic control. During development, individual cells must quickly respond to internal and external signals while the number of cells that make up ... |
10.1371/journal.pbio.1000612 | Mechanism of Neuroprotective Mitochondrial Remodeling by
PKA/AKAP1 | Mitochondrial shape is determined by fission and fusion reactions catalyzed by
large GTPases of the dynamin family, mutation of which can cause neurological
dysfunction. While fission-inducing protein phosphatases have been identified,
the identity of opposing... | Mitochondria, the cellular powerhouse, are highly dynamic organelles shaped by
opposing fission and fusion events. Research over the past decade has identified
many components of the mitochondrial fission/fusion machinery and led to the
discovery that mutation... | Opposing fission and fusion events determine the shape and interconnectivity of
mitochondria to regulate various aspects of their function, including ATP
production, Ca++ buffering, free radical homeostasis,
mitochondrial DNA inheritance, and organelle quality control. In... |
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