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10.1371/journal.ppat.1007135 | Innate immune sensor LGP2 is cleaved by the Leader protease of foot-and-mouth disease virus | The RNA helicase LGP2 (Laboratory of Genetics and Physiology 2) is a non-signaling member of the retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), whose pivotal role on innate immune responses against RNA viruses is being increasingly uncovered. LGP2 is known to work in synergy with melanoma differentiation... | Foot-and-mouth disease virus (FMDV) is the causative agent of a devastating disease affecting livestock worldwide. FMDV is considered an extremely successful pathogen able to replicate and spread rapidly among its hosts. The induction of type-I interferon (IFN) response is a crucial event in mammalian cells against inf... | Antiviral response against RNA viruses greatly relies on detection of infection by cytoplasmic sensors. Among the different pattern-recognition receptors (PRRs) involved in antiviral immunity, the retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), recognize non-self RNA species derived from viral infection t... |
10.1371/journal.ppat.1005133 | Mitochondrial Activity and Cyr1 Are Key Regulators of Ras1 Activation of C. albicans Virulence Pathways | Candida albicans is both a major fungal pathogen and a member of the commensal human microflora. The morphological switch from yeast to hyphal growth is associated with disease and many environmental factors are known to influence the yeast-to-hyphae switch. The Ras1-Cyr1-PKA pathway is a major regulator of C. albicans... | Candida albicans is a successful fungal commensal and pathogen of humans. It is a polymorphic organism and the ability to switch from yeast to hyphal growth is associated with the commensal-to-pathogen switch. Previous research identified the Ras1-cAMP-protein kinase A pathway as a key regulator of hyphal growth. Here,... | Candida albicans, one of the most common human fungal pathogens, is an important cause of morbidity and mortality in immunocompromised individuals, particularly in patients with AIDS or those undergoing cancer chemotherapy or transplantation procedures [1]. The prolonged use of antifungal agents in such compromised pop... |
10.1371/journal.ppat.1007352 | Niche adaptation and viral transmission of human papillomaviruses from archaic hominins to modern humans | Recent discoveries on the origins of modern humans from multiple archaic hominin populations and the diversity of human papillomaviruses (HPVs) suggest a complex scenario of virus-host evolution. To evaluate the origin of HPV pathogenesis, we estimated the phylogeny, timing, and dispersal of HPV16 variants using a Baye... | Epidemiologic studies have demonstrated that persistent infection of select oncogenic human papillomaviruses (HPVs) is the main cause of cervix precancer and cancer. Nevertheless, our knowledge of the underlying evolutionary mechanisms driving the divergence and emergence of viral oncogenicity in specific types of HPVs... | Papillomaviruses (PVs) are ubiquitous, non-enveloped, small double-stranded circular DNA viruses that cause proliferation of epithelial cells in a wide range of vertebrate host species, from reptiles to mammals [1, 2]. Currently, over 200 PVs infecting primate hosts (human and non-human) have been characterized and sho... |
10.1371/journal.pbio.2005752 | Disruption of CTCF-YY1–dependent looping of the human papillomavirus genome activates differentiation-induced viral oncogene transcription | The complex life cycle of oncogenic human papillomavirus (HPV) initiates in undifferentiated basal epithelial keratinocytes where expression of the E6 and E7 oncogenes is restricted. Upon epithelial differentiation, E6/E7 transcription is increased through unknown mechanisms to drive cellular proliferation required to ... | Oncogenic human papillomavirus (HPV) infection causes cancers of the anogenital and oropharyngeal tracts. HPV infects undifferentiated basal cells of the epithelium at these body sites and expresses low levels of viral early genes, required for replication of the viral genome. In normal epithelia, cellular migration aw... | Human papillomaviruses (HPVs) are a family of small, double-stranded DNA viruses that infect epithelia at specific anatomical sites. Infection with any of the 12 mucosal oncogenic HPV types is a risk factor for the development of epithelial cancers such as cancer of the uterine cervix and oropharynx [1]. The majority o... |
10.1371/journal.pntd.0001350 | Re-Emergence of Crimean-Congo Hemorrhagic Fever Virus in Central Africa | Crimean-Congo hemorrhagic fever (CCHF) is a severe tick-borne disease well recognized through Europe and Asia where diagnostic tests and medical surveillance are available. However, it is largely neglected in Africa, especially in the tropical rainforest of Central Africa where only sporadic human cases have been repor... | Crimean-Congo hemorrhagic fever virus (CCHFV) is transmitted to humans through tick-bite or contact with infected blood or tissues from livestock, the main vertebrate hosts in a peri-domestic natural cycle. With numerous outbreaks, a high case fatality rate (3%–30%) and a high risk for nosocomial transmission, CCHFV be... | Crimean-Congo hemorrhagic fever virus (CCHFV, family Bunyaviridae, genus Nairovirus) is a tick-borne virus. It causes severe illness throughout Africa, Asia, Southeast Europe and the Middle East, with case fatality rates ranging from 3% to 30%. Its worldwide distribution closely matches that of its main arthropod vecto... |
10.1371/journal.ppat.1007154 | Mononuclear cell dynamics in M. tuberculosis infection provide opportunities for therapeutic intervention | Mycobacterium tuberculosis causes chronic infection of mononuclear phagocytes, especially resident (alveolar) macrophages, recruited macrophages, and dendritic cells. Despite the importance of these cells in tuberculosis (TB) pathogenesis and immunity, little is known about the population dynamics of these cells at the... | During certain chronic infections such as tuberculosis, inflammatory cells, including macrophages and dendritic cells, are recruited to infected tissues where they aggregate to form tissue lesions known as granulomas. Although granulomas can persist long term, the dynamics of the cell populations that comprise granulom... | Mononuclear phagocytes (MNP) harbor Mycobacterium tuberculosis in tissues of humans [1] and experimental animals [2–4]; and MNP are essential elements of granulomas, the characteristic tissue lesions in tuberculosis [5, 6]. Although macrophages have been characterized as prominent cellular hosts for M. tuberculosis in ... |
10.1371/journal.pgen.1002038 | Mouse Genome-Wide Association and Systems Genetics Identify Asxl2 As a Regulator of Bone Mineral Density and Osteoclastogenesis | Significant advances have been made in the discovery of genes affecting bone mineral density (BMD); however, our understanding of its genetic basis remains incomplete. In the current study, genome-wide association (GWA) and co-expression network analysis were used in the recently described Hybrid Mouse Diversity Panel ... | Osteoporosis is a disease of weak and fracture-prone bones. The characteristic of bone that is most predictive of fractures is low bone mineral density (BMD), a trait primarily controlled by genetics. In recent years, significant advances have been made in the discovery of genes affecting BMD; however, our understandin... | Osteoporosis is a common disease characterized by bone fragility and an increased risk of fracture [1]. One of strongest predictors of fracture is low bone mineral density (BMD) [2] and while BMD is influenced by both genetic and environmental factors, most (between 60% and 80%) of its variance is heritable [3]. Thus, ... |
10.1371/journal.ppat.1003635 | Human Cytomegalovirus Latency-Associated Proteins Elicit Immune-Suppressive IL-10 Producing CD4+ T Cells | Human cytomegalovirus (HCMV) is a widely prevalent human herpesvirus, which, after primary infection, persists in the host for life. In healthy individuals, the virus is well controlled by the HCMV-specific T cell response. A key feature of this persistence, in the face of a normally robust host immune response, is the... | Human cytomegalovirus (HCMV) is a widely prevalent virus, which is normally carried without clinical symptoms, but often causes severe clinical disease in individuals with compromised immune responses. In healthy HCMV carriers, the immune response to HCMV is robust and includes large numbers of virus-specific T-cells t... | Human cytomegalovirus (HCMV) is widely prevalent, with an estimated 50–60% of the world population being seropositive [1]. Primary infection in the immunocompetent host is usually asymptomatic and overt disease is seen almost exclusively in the immunocompromised and immuno-naive host. For example, placental transmissio... |
10.1371/journal.pgen.1005255 | Genetic Mechanism of Human Neutrophil Antigen 2 Deficiency and Expression Variations | Human neutrophil antigen 2 (HNA-2) deficiency is a common phenotype as 3–5% humans do not express HNA-2. HNA-2 is coded by CD177 gene that associates with human myeloproliferative disorders. HNA-2 deficient individuals are prone to produce HNA-2 alloantibodies that cause a number of disorders including transfusion-rela... | Human neutrophil antigen 2 (HNA-2) is coded by CD177 gene that involves in human myeloproliferative disorders. HNA-2 expression varies among humans and about 3–5% people lack HNA-2 expression. HNA-2 deficient people are susceptible to produce HNA-2 alloantibodies, which play a pathological role in various human disease... | Transfusion-related acute lung injury (TRALI) is associated with the transfusion of leukocyte alloantibodies from donors or associated with the presence of alloantibodies in recipients of blood [1,2]. Alloantibodies against human neutrophil alloantigenes (HNAs) are a very strong trigger for the development of TRALI [1,... |
10.1371/journal.pgen.1005674 | The Fanconi Anemia Pathway Protects Genome Integrity from R-loops | Co-transcriptional RNA-DNA hybrids (R loops) cause genome instability. To prevent harmful R loop accumulation, cells have evolved specific eukaryotic factors, one being the BRCA2 double-strand break repair protein. As BRCA2 also protects stalled replication forks and is the FANCD1 member of the Fanconi Anemia (FA) path... | R loops are co-transcriptional RNA-DNA hybrids that can have a physiological role in transcription and replication, but also may be a major threat to genome stability. To avoid the deleterious effects of R loops, specific factors prevent their formation or facilitate their removal. The double-strand break repair factor... | Genome instability is a cell pathology in which chromosomes undergo alterations in the form of DNA breaks, mutations, rearrangements and loss at a high rate. In many cases, the mechanism responsible for genome instability implies a DNA replication failure. For this reason, genome instability and replication stress are ... |
10.1371/journal.pgen.1003165 | MCM8 Is Required for a Pathway of Meiotic Double-Strand Break Repair Independent of DMC1 in Arabidopsis thaliana | Mini-chromosome maintenance (MCM) 2–9 proteins are related helicases. The first six, MCM2–7, are essential for DNA replication in all eukaryotes. In contrast, MCM8 is not always conserved in eukaryotes but is present in Arabidopsis thaliana. MCM8 is required for 95% of meiotic crossovers (COs) in Drosophila and is esse... | Species that reproduce sexually have two copies of each chromosome, inherited from their father and mother. During a special cell division called meiosis, these two chromosomes are mixed by homologous recombination to give genetically unique chromosomes that will be transmitted to the next generation. This recombinatio... | Meiosis is a process that occurs in the germlines of sexually reproducing organisms. Two successive rounds of chromosome segregation (meiosis I and II) follow a single round of DNA replication (S phase). The resulting four cells each contain half the genetic content of the pre-meiotic mother cell. The genetic complemen... |
10.1371/journal.pbio.1001489 | A Force-Activated Trip Switch Triggers Rapid Dissociation of a Colicin from Its Immunity Protein | Colicins are protein antibiotics synthesised by Escherichia coli strains to target and kill related bacteria. To prevent host suicide, colicins are inactivated by binding to immunity proteins. Despite their high avidity (Kd≈fM, lifetime ≈4 days), immunity protein release is a pre-requisite of colicin intoxication, whic... | Many proteins interact with other proteins as part of their function. One method of modulating the activity of protein complexes is to break them apart. Some complexes, however, are extremely kinetically stable and it is unclear how these can dissociate on a biologically relevant timescale. In this study we address thi... | Protein-protein interactions are integral to diverse cellular processes such as catalysis, transport, and signalling. For complexes of low affinity, changes in the relative concentrations of one (or more) binding partners, or alterations in the environment, are sufficient to trigger complex dissociation, allowing spati... |
10.1371/journal.pcbi.1003271 | Dynamic Change of Global and Local Information Processing in Propofol-Induced Loss and Recovery of Consciousness | Whether unique to humans or not, consciousness is a central aspect of our experience of the world. The neural fingerprint of this experience, however, remains one of the least understood aspects of the human brain. In this paper we employ graph-theoretic measures and support vector machine classification to assess, in ... | One of the most elusive aspects of the human brain is the neural fingerprint of the subjective feeling of consciousness. While a growing body of experimental evidence is starting to address this issue, to date we are still hard pressed to answer even basic questions concerning the nature of consciousness in humans as w... | Despite the centrality of consciousness to our experience, no agreement has yet emerged on which aspects of brain function underlie its presence, and what changes are connected to its disappearance in the healthy brain (e.g., during sleep) as well as in pathological conditions (e.g., coma). As a consequence, we are cur... |
10.1371/journal.pgen.1004512 | The Translational Regulators GCN-1 and ABCF-3 Act Together to Promote Apoptosis in C. elegans | The proper regulation of apoptosis requires precise spatial and temporal control of gene expression. While the transcriptional and translational activation of pro-apoptotic genes is known to be crucial to triggering apoptosis, how different mechanisms cooperate to drive apoptosis is largely unexplored. Here we report t... | Apoptosis, also referred to as programmed cell death, is a crucial cellular process that eliminates unwanted cells during animal development and tissue homeostasis. Abnormal regulation of apoptosis can cause developmental defects and a variety of other human disorders, including cancer, neurodegenerative diseases and a... | Apoptosis is a naturally occurring process that eliminates unwanted cells during development and maintains tissue homeostasis [1], [2]. For example, apoptosis removes most larval tissues of insects during metamorphosis, sculpts the future inner ear in chicks, eliminates the interdigital web in mammals and shapes the en... |
10.1371/journal.pgen.1002356 | SOX9 Governs Differentiation Stage-Specific Gene Expression in Growth Plate Chondrocytes via Direct Concomitant Transactivation and Repression | Cartilage and endochondral bone development require SOX9 activity to regulate chondrogenesis, chondrocyte proliferation, and transition to a non-mitotic hypertrophic state. The restricted and reciprocal expression of the collagen X gene, Col10a1, in hypertrophic chondrocytes and Sox9 in immature chondrocytes epitomise ... | Chondrogenic differentiation is a key process in the formation of endochondral bone. Despite the wealth of information about gene expression patterns and signaling pathways important for this process, it is not clear how differentiation state-specificity of transcription is controlled. The transcription factor SOX9 reg... | Chondrogenesis and the formation of bone by endochondral ossification depend on progressive steps of cell differentiation. Mesenchymal cells condense and differentiate into chondrocytes in a pattern that will define the eventual shape of the different skeletal elements. These chondrocytes proliferate, mature, exit the ... |
10.1371/journal.ppat.1004899 | A Ribonucleoprotein Complex Protects the Interleukin-6 mRNA from Degradation by Distinct Herpesviral Endonucleases | During lytic Kaposi’s sarcoma-associated herpesvirus (KSHV) infection, the viral endonuclease SOX promotes widespread degradation of cytoplasmic messenger RNA (mRNA). However, select mRNAs escape SOX-induced cleavage and remain robustly expressed. Prominent among these is interleukin-6 (IL-6), a growth factor important... | During replication of Kaposi’s sarcoma-associated herpesvirus (KSHV), the vast majority of mRNAs in the cytoplasm are cleaved and degraded by the viral nuclease SOX. However, some mRNAs escape this fate, including the transcript encoding the immunoregulatory cytokine IL-6. Here, we discover that this escape is mediated... | The posttranscriptional fate of mRNA, including translation, subcellular localization, and stability, is tightly controlled through complex networks of RNA-protein interactions. Many mRNA regulatory elements are located in the 3’ untranslated region (UTR), where they recruit factors that control the levels of the mRNA ... |
10.1371/journal.pgen.1004680 | The Chromosomal Association of the Smc5/6 Complex Depends on Cohesion and Predicts the Level of Sister Chromatid Entanglement | The cohesin complex, which is essential for sister chromatid cohesion and chromosome segregation, also inhibits resolution of sister chromatid intertwinings (SCIs) by the topoisomerase Top2. The cohesin-related Smc5/6 complex (Smc5/6) instead accumulates on chromosomes after Top2 inactivation, known to lead to a buildu... | When cells divide, sister chromatids have to be segregated away from each other for the daughter cells to obtain a correct set of chromosomes. Using yeast as model organism, we have analyzed the function of the cohesin and the Smc5/6 complexes, which are essential for chromosome segregation. Cohesin is known to hold si... | In order to maintain chromosome stability, cells need to overcome topological problems caused by the structure of the DNA molecule. One example of such topological problem is DNA supercoiling induced by replication or transcription. Another is sister chromatid intertwinings (SCIs), which is the wrapping of chromatids a... |
10.1371/journal.pgen.1000875 | Identification of the Regulatory Logic Controlling Salmonella Pathoadaptation by the SsrA-SsrB Two-Component System | Sequence data from the past decade has laid bare the significance of horizontal gene transfer in creating genetic diversity in the bacterial world. Regulatory evolution, in which non-coding DNA is mutated to create new regulatory nodes, also contributes to this diversity to allow niche adaptation and the evolution of p... | All organisms have a means to control gene expression ensuring correct spatiotemporal deployment of gene products. In bacteria, gene control presents a challenge because one species can reside in multiple niches, requiring them to coordinate gene expression with environmental sensing. Also, widespread acquisition of DN... | Precise gene regulation is crucial to the successful activation and execution of virulence programs for all pathogenic organisms. The acquisition of genes through horizontal gene transfer, a widespread means of bacterial evolution [1], requires a process to integrate new coding sequence into pre-existing regulatory cir... |
10.1371/journal.pcbi.1003102 | Models of Self-Peptide Sampling by Developing T Cells Identify Candidate Mechanisms of Thymic Selection | Conventional and regulatory T cells develop in the thymus where they are exposed to samples of self-peptide MHC (pMHC) ligands. This probabilistic process selects for cells within a range of responsiveness that allows the detection of foreign antigen without excessive responses to self. Regulatory T cells are thought t... | T cells develop in the thymus, where they are vetted – they must respond weakly to self-antigens, but not so strongly as to risk causing autoimmunity. This selection process involves developing T cells being exposed to a large sample of self-peptides presented on specialised cells in the thymus, and deciding to die or ... | Conventional T cells (T) and T regulatory cells (T) are essential components of the adaptive immune system. Conventional T cells develop effector function in response to foreign antigens, while natural T regulatory cells produced in the thymus play a key role in the maintenance of tolerance to self-antigens and preve... |
10.1371/journal.pntd.0006929 | Organization of oversight for integrated control of neglected tropical diseases within Ministries of Health | Neglected tropical diseases (NTDs) are communicable diseases that impact approximately 1 billion people, but receive relatively little research, funding, and attention. Many NTDs have similar treatments, epidemiology, and geographic distribution, and as a result, the integration of control efforts can improve accountab... | Neglected tropical diseases (NTDs) are communicable diseases that impact billions of people but receive disproportionately little attention from researchers and funders. Many of these diseases have similarities in their epidemiology and control measures, rendering the integration of control programs a practical option ... | Neglected tropical diseases (NTDs) are a collection of infectious diseases caused by parasites, viruses, and bacteria. These diseases affect approximately one billion of the world’s poorest people, and most often impact populations living in sub-tropical climates with inadequate access to health care, clean water, sani... |
10.1371/journal.pbio.1002072 | Effective Connectivity of Depth-Structure–Selective Patches in the Lateral Bank of the Macaque Intraparietal Sulcus | Extrastriate cortical areas are frequently composed of subpopulations of neurons encoding specific features or stimuli, such as color, disparity, or faces, and patches of neurons encoding similar stimulus properties are typically embedded in interconnected networks, such as the attention or face-processing network. The... | The cortex of primates consists of many areas that are highly interconnected, forming widespread functional networks engaged in specific tasks. Cortical areas frequently consist of submodules, columns, or patches of neurons that share functional properties. The neuronal characteristics of such clusters of neurons are d... | Extracellular recording studies have provided detailed information on the properties of individual neurons and neuronal populations during task performance, which can be correlated with [1,2], and even causally related to, behavior [3,4]. However in order to fully understand the function of neurons in any given brain a... |
10.1371/journal.pgen.1003869 | Dominant Mutations in S. cerevisiae PMS1 Identify the Mlh1-Pms1 Endonuclease Active Site and an Exonuclease 1-Independent Mismatch Repair Pathway | Lynch syndrome (hereditary nonpolypsis colorectal cancer or HNPCC) is a common cancer predisposition syndrome. Predisposition to cancer in this syndrome results from increased accumulation of mutations due to defective mismatch repair (MMR) caused by a mutation in one of the mismatch repair genes MLH1, MSH2, MSH6 or PM... | Lynch syndrome (hereditary nonpolypsis colorectal cancer or HNPCC) is a common cancer predisposition syndrome. Predisposition to cancer in this syndrome results from increased accumulation of mutations due to defective mismatch repair (MMR) caused by a mutation in one of the mismatch repair genes MLH1, MSH2, MSH6 or PM... | DNA mismatch repair (MMR) acts to repair the potentially mutagenic misincorporation errors that occur during normal DNA replication and the absence of MMR results in increased rates of accumulating mutations. Consequently, defects in human MMR genes cause the hereditary cancer susceptibility syndrome HNPCC (hereditary ... |
10.1371/journal.pgen.1007574 | Enhanced uptake of potassium or glycine betaine or export of cyclic-di-AMP restores osmoresistance in a high cyclic-di-AMP Lactococcus lactis mutant | The broadly conserved bacterial signalling molecule cyclic-di-adenosine monophosphate (c-di-AMP) controls osmoresistance via its regulation of potassium (K+) and compatible solute uptake. High levels of c-di-AMP resulting from inactivation of c-di-AMP phosphodiesterase activity leads to poor growth of bacteria under hi... | Second messengers relay signals received from the environment to intracellular targets that adjust cellular physiology. One widespread bacterial cyclic-dinucleotide signalling molecule, cyclic-di-AMP (c-di-AMP) has been shown to regulate a range of cellular processes via binding to protein and riboswitch targets, with ... | In order to survive and grow, bacteria must be able to sense and respond to a multitude of environmental conditions. Changes in external osmolarity can cause cellular water loss or gain due to uncontrolled osmotic movement across the semipermeable cytoplasmic membrane. Cells can adapt to these changes in order to maint... |
10.1371/journal.pntd.0002419 | Update on the Mapping of Prevalence and Intensity of Infection for Soil-Transmitted Helminth Infections in Latin America and the Caribbean: A Call for Action | It is estimated that in Latin America and the Caribbean (LAC) at least 13.9 million preschool age and 35.4 million school age children are at risk of infections by soil-transmitted helminths (STH): Ascaris lumbricoides, Trichuris trichiura and hookworms (Necator americanus and Ancylostoma duodenale). Although infection... | Soil-transmitted helminths (STH) are part of the group of neglected infectious diseases (NID) in Latin America and the Caribbean (LAC), and are associated with several adverse chronic effects on child health. Although control interventions such as periodic administration of anthelmintic drugs, health education, improve... | Helminth infections impose a great and often silent burden of morbidity and mortality on poor populations in developing countries. The most common helminth infections are caused by soil-transmitted helminths (STH): roundworms (Ascaris lumbricoides), whipworms (Trichuris trichiura), and hookworms (Necator americanus and... |
10.1371/journal.pbio.1002127 | Colour As a Signal for Entraining the Mammalian Circadian Clock | Twilight is characterised by changes in both quantity (“irradiance”) and quality (“colour”) of light. Animals use the variation in irradiance to adjust their internal circadian clocks, aligning their behaviour and physiology with the solar cycle. However, it is currently unknown whether changes in colour also contribut... | Animals use an internal brain clock to keep track of time and adjust their behaviour in anticipation of the coming day or night. To be useful, however, this clock must be synchronised to external time. Assessing external time is typically thought to rely on measuring large changes in ambient light intensity that occur ... | The ability to predict and adapt to recurring events in the environment is fundamental to survival. Organisms across the living world achieve this using endogenous circadian clocks [1–3]. However, if such clocks are to fulfil their ethological function they need to be regularly reset to local time. This is achieved by ... |
10.1371/journal.pgen.1005352 | Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND) | Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic contr... | Type 2 diabetes is the most common cause of severe kidney disease worldwide and diabetic kidney disease (DKD) associates with premature death. Individuals of non-European ancestry have the highest burden of type 2 DKD; hence understanding the causes of DKD remains critical to reducing health disparities. Family studies... | Diabetic kidney disease (DKD) is a devastating complication in patients with diabetes mellitus (DM) and is associated with high risk for cardiovascular disease and death.[1,2] DKD is the leading cause of end-stage kidney disease (ESKD) requiring renal replacement therapy in developed nations; these procedures incur hig... |
10.1371/journal.pntd.0002576 | Cholera Vaccination Campaign Contributes to Improved Knowledge Regarding Cholera and Improved Practice Relevant to Waterborne Disease in Rural Haiti | Haiti's cholera epidemic has been devastating partly due to underlying weak infrastructure and limited clean water and sanitation. A comprehensive approach to cholera control is crucial, yet some have argued that oral cholera vaccination (OCV) might result in reduced hygiene practice among recipients. We evaluated the ... | In October 2010, Haiti experienced a cholera outbreak that is now considered one of the largest cholera epidemics in recent history. A comprehensive approach is necessary to successfully fight the epidemic and proven methods for controlling cholera include improving access to clean water and sanitation as well as wides... | In October 2010, a cholera outbreak began in the Artibonite and Centre Departments of Haiti [1]. By December, cholera had been identified in all 10 departments of Haiti and has since reached neighboring countries [2], [3]. Cholera is an acute, watery diarrheal infection caused by the bacterium Vibrio cholerae of the O1... |
10.1371/journal.pbio.2003268 | A map of protein dynamics during cell-cycle progression and cell-cycle exit | The cell-cycle field has identified the core regulators that drive the cell cycle, but we do not have a clear map of the dynamics of these regulators during cell-cycle progression versus cell-cycle exit. Here we use single-cell time-lapse microscopy of Cyclin-Dependent Kinase 2 (CDK2) activity followed by endpoint immu... | The cell cycle is by nature highly dynamic, but we lack a standardized map of how core cell-cycle regulators change over time. In this study, we used time-lapse microscopy to track the dynamics of key cell-cycle proteins in individual human cells and found several unexpected patterns, even for well-studied proteins suc... | Cellular proliferation is driven by the mitotic cell cycle, a highly regulated process consisting of DNA synthesis (S phase) and mitosis (M phase), separated by gap phases (G1 and G2). Decades of cell-cycle research have led to in-depth understanding of the biochemical processes involved in cell-cycle progression, but ... |
10.1371/journal.pgen.1000553 | The Caenorhabditis elegans HNF4α Homolog, NHR-31, Mediates Excretory Tube Growth and Function through Coordinate Regulation of the Vacuolar ATPase | Nuclear receptors of the Hepatocyte Nuclear Factor-4 (HNF4) subtype have been linked to a host of developmental and metabolic functions in animals ranging from worms to humans; however, the full spectrum of physiological activities carried out by this nuclear receptor subfamily is far from established. We have found th... | The function of many important biological structures requires the construction of very complex cellular shapes. For example, mammalian kidneys or related renal systems in other animals rely on the formation of elongated tubes that maximize surface area to facilitate the exchange of ions between the body and excreted fl... | Nuclear receptors (NRs) comprise a large family of transcription factors distinguished by a highly conserved DNA binding domain and a structurally conserved ligand-binding domain. NRs are notable for their ability to interact with small molecule ligands, enabling these factors to respond to autocrine, paracrine, and en... |
10.1371/journal.pntd.0002307 | Cathelicidin-like Helminth Defence Molecules (HDMs): Absence of Cytotoxic, Anti-microbial and Anti-protozoan Activities Imply a Specific Adaptation to Immune Modulation | Host defence peptides (HDPs) are expressed throughout the animal and plant kingdoms. They have multifunctional roles in the defence against infectious agents of mammals, possessing both bactericidal and immune-modulatory activities. We have identified a novel family of molecules secreted by helminth parasites (helminth... | In mammals, secreted host defence peptides (HDPs) protect against a wide range of infectious pathogens. They also perform a range of immune modulatory functions which regulate the immune response to pathogens, ensuring that the protective inflammatory response is not exacerbated and that post-infection repair mechanism... | Host defence peptides (HDPs) are found in all living organisms and play a pivotal role as effector components of the innate immune system [1], [2]. They act as the first line of defence against pathogenic assaults from bacteria, fungi, eukaryotic parasites and viruses [3]–[5]. A range of HDPs with varied sequence lengt... |
10.1371/journal.pbio.1002224 | The Dynamics of Incomplete Lineage Sorting across the Ancient Adaptive Radiation of Neoavian Birds | The diversification of neoavian birds is one of the most rapid adaptive radiations of extant organisms. Recent whole-genome sequence analyses have much improved the resolution of the neoavian radiation and suggest concurrence with the Cretaceous-Paleogene (K-Pg) boundary, yet the causes of the remaining genome-level ir... | The rise of modern birds began after the mass extinction of nonavian dinosaurs and archaic birds at the Cretaceous-Paleogene (K-Pg) boundary, about 66 million years ago. This coincides with the super-rapid adaptive radiation of Neoaves (a group that contains most modern birds), which has been difficult to resolve even ... | The rich biodiversity of many organismal groups is the result of bursts of rapid species diversifications, with extreme examples in angiosperms [1] and vertebrates [2]. Among the latter, birds are one of the most speciose groups with a total of >10,500 recognized species that are proposed to be the result of mostly rec... |
10.1371/journal.pgen.1003882 | Correlated Occurrence and Bypass of Frame-Shifting Insertion-Deletions (InDels) to Give Functional Proteins | Short insertions and deletions (InDels) comprise an important part of the natural mutational repertoire. InDels are, however, highly deleterious, primarily because two-thirds result in frame-shifts. Bypass through slippage over homonucleotide repeats by transcriptional and/or translational infidelity is known to occur ... | Homonucleotide repeats are exceptionally prone to insertions and/or deletions of bases (InDels). However, unless they occur in a multiplicity of 3 bases, InDels disrupt the reading frame and are thus expected to be purged from coding regions. Homonucleotide repeats, however, are also vulnerable to slippage by RNA polym... | InDels occur in all kingdoms of life, and in some organisms they are as frequent as point mutations [1]. Short sequence repeats, and homonucleotide repeats in particular, are prone to InDels due to misalignment of the DNA strands during replication (polymerase slippage) [2]. In coding regions, at least 2/3 of InDels di... |
10.1371/journal.pgen.1004162 | Genomic Networks of Hybrid Sterility | Hybrid dysfunction, a common feature of reproductive barriers between species, is often caused by negative epistasis between loci (“Dobzhansky-Muller incompatibilities”). The nature and complexity of hybrid incompatibilities remain poorly understood because identifying interacting loci that affect complex phenotypes is... | New species are created when barriers to reproduction form between groups of organisms that formerly interbred freely. Reduced fertility or viability of hybrid offspring is a common form of reproductive isolation. Hybrid defects are caused by negative interactions between genes that have undergone evolutionary change w... | To understand patterns of biodiversity, it is essential to characterize the processes by which new species arise and are maintained in nature, including ecological specialization, population differentiation and reproductive isolation. Genetic dissection of reproductive isolation has proven to be an especially powerful ... |
10.1371/journal.pgen.1003349 | Human Spermatogenic Failure Purges Deleterious Mutation Load from the Autosomes and Both Sex Chromosomes, including the Gene DMRT1 | Gonadal failure, along with early pregnancy loss and perinatal death, may be an important filter that limits the propagation of harmful mutations in the human population. We hypothesized that men with spermatogenic impairment, a disease with unknown genetic architecture and a common cause of male infertility, are enric... | Infertility is a disease that prevents the transmission of DNA from one generation to the next, and consequently it has been difficult to study the genetics of infertility using classical human genetics methods. Now, new technologies for screening entire genomes for rare and patient-specific mutations are revolutionizi... | Male infertility is a multifaceted disorder affecting nearly 5% of men of reproductive age. In spite of its prevalence and a considerable research effort over the past several decades, the underlying cause of male infertility is uncharacterized in up to half of all cases [1]. Some degree of spermatogenic impairment is ... |
10.1371/journal.pcbi.1004018 | Protein-Protein Docking with Dynamic Residue Protonation States | Protein-protein interactions depend on a host of environmental factors. Local pH conditions influence the interactions through the protonation states of the ionizable residues that can change upon binding. In this work, we present a pH-sensitive docking approach, pHDock, that can sample side-chain protonation states of... | Protein-protein interactions are fundamental for biological function and are strongly influenced by their local environment. Cellular pH is tightly controlled and is one of the critical environmental factors that regulates protein-protein interactions. Three-dimensional structures of the protein complexes can help us u... | Through tightly controlled cellular pH, posttranslational modification by protons regulates biological function [1]. Cellular pH can vary from highly-acidic in the lysosomes (∼pH 5) to basic in the peroxisomes (∼pH 8) [2], profoundly influencing biomolecular folding and assembly processes [3], [4]. pH effects are espec... |
10.1371/journal.pcbi.1000316 | Intrinsic Disorder in Protein Interactions: Insights From a Comprehensive Structural Analysis | We perform a large-scale study of intrinsically disordered regions in proteins and protein complexes using a non-redundant set of hundreds of different protein complexes. In accordance with the conventional view that folding and binding are coupled, in many of our cases the disorder-to-order transition occurs upon comp... | Traditionally, protein structure is believed to determine function. Recently, it was observed that many proteins contain regions without well-defined structure (intrinsically disordered regions), including a large fraction of eukaryotic proteins. Intrinsic disorder has been associated with particular functions includin... | Many proteins and protein regions have been shown to be intrinsically disordered under native conditions; namely, they contain no or very little well-defined structure [1]–[6]. Intrinsically disordered proteins (IDPs) have been found in a wide scope of organisms and their disorder content was shown to increase with org... |
10.1371/journal.pcbi.1005848 | Choose, rate or squeeze: Comparison of economic value functions elicited by different behavioral tasks | A standard view in neuroeconomics is that to make a choice, an agent first assigns subjective values to available options, and then compares them to select the best. In choice tasks, these cardinal values are typically inferred from the preference expressed by subjects between options presented in pairs. Alternatively,... | In economic decision theory, value is a construct that provides a metric to compare options: agents are likely to select options leading to high-value outcomes. In neuroscience, different behavioral tasks have been used to elicit the subjective values of potential outcomes, notably rating tasks, which demand an explici... | Value (or utility) functions have been defined to account for preferences revealed in choice tasks [1]. One basic principle is that if an agent prefers A over B, then for this agent the value of A is higher than the value of B. Assuming basic axioms of expected utility theory, cardinal functions have been described, su... |
10.1371/journal.ppat.1005972 | NK-CD11c+ Cell Crosstalk in Diabetes Enhances IL-6-Mediated Inflammation during Mycobacterium tuberculosis Infection | In this study, we developed a mouse model of type 2 diabetes mellitus (T2DM) using streptozotocin and nicotinamide and identified factors that increase susceptibility of T2DM mice to infection by Mycobacterium tuberculosis (Mtb). All Mtb-infected T2DM mice and 40% of uninfected T2DM mice died within 10 months, whereas ... | In the current study, we employed an experimentally induced type 2 diabetes mellitus (T2DM) model in wild type C57BL/6 mice and investigated the immune response to Mycobacterium tuberculosis (Mtb) infection. We found that natural killer (NK) and CD11c+ cell interactions in Mtb-infected T2DM mice led to increased IL-6 p... | Mycobacterium tuberculosis (Mtb) infects one-third of the world’s population and causes almost 1.3 million deaths per year [1]. Approximately 90% of those infected have a latent tuberculosis infection and develop protective immunity to contain it; however, but 10% progressive to active tuberculosis (TB) disease months ... |
10.1371/journal.pgen.1001382 | ESR1 Is Co-Expressed with Closely Adjacent Uncharacterised Genes Spanning a Breast Cancer Susceptibility Locus at 6q25.1 | Approximately 80% of human breast carcinomas present as oestrogen receptor α-positive (ER+ve) disease, and ER status is a critical factor in treatment decision-making. Recently, single nucleotide polymorphisms (SNPs) in the region immediately upstream of the ER gene (ESR1) on 6q25.1 have been associated with breast can... | Recent genome-wide analysis has revealed that the way in which genes are arranged on chromosomes and the conformation of these chromosomes are crucial for the regulation of gene expression. Reflecting this arrangement, clusters of genes which are regulated together have been discovered. We have identified a previously ... | Breast cancer is the most common malignancy in women, accounting for more than 400,000 deaths per year worldwide [1]. Approximately 80% of human breast carcinomas present as oestrogen receptor α-positive (ER+ve) disease and ER status is arguably the most clinically important biological factor in all oncology [2]. The m... |
10.1371/journal.pntd.0007178 | Spontaneous healing of Mycobacterium ulcerans disease in Australian patients | Mycobacterium ulcerans causes necrotising infections of skin and soft tissue mediated by the polyketide exotoxin mycolactone that causes cell apoptosis and immune suppression. It has been postulated that infection can be eradicated before the development of clinical lesions but spontaneous resolution of clinical lesion... | Mycobacterium ulcerans causes a destructive infection of skin and soft tissue known as Buruli ulcer that when severe can lead to serious long-term deformity and disability. It is currently not well documented whether people with Mycobacterium ulcerans disease can cure themselves without treatment. In our study we descr... | Mycobacterium ulcerans causes a necrotising infection of skin and soft tissue known as Buruli ulcer (BU). If untreated it usually progresses, can result in major tissue destruction and be complicated by bone or joint infection.[1] In severe cases it may require plastic and reconstructive surgery and result in long-term... |
10.1371/journal.pcbi.0030108 | A Mass Conserved Reaction–Diffusion System Captures Properties of Cell Polarity | Cell polarity is a general cellular process that can be seen in various cell types such as migrating neutrophils and Dictyostelium cells. The Rho small GTP(guanosine 5′-tri phosphate)ases have been shown to regulate cell polarity; however, its mechanism of emergence has yet to be clarified. We first developed a reactio... | Eukaryotic cells such as neutrophils and Dictyostelium cells respond to temporal and spatial gradients of extracellular signals with directional movements. In a migrating cell, specific molecular events take place at the front and back edges. The spatially distinctive molecular accumulation inside cells is known as cel... | Eukaryotic cells such as neutrophils and Dictyostelium cells respond to temporal and spatial gradients of extracellular signals with directional movements [1–6]. This process, known as chemotaxis, is a fundamental cellular process [5,7–9]. In a migrating cell, specific molecular events take place at the front and back ... |
10.1371/journal.pntd.0004981 | Dengue Outbreak in Mombasa City, Kenya, 2013–2014: Entomologic Investigations | Dengue outbreaks were first reported in East Africa in the late 1970s to early 1980s including the 1982 outbreak on the Kenyan coast. In 2011, dengue outbreaks occurred in Mandera in northern Kenya and subsequently in Mombasa city along the Kenyan coast in 2013–2014. Following laboratory confirmation of dengue fever ca... | The first dengue outbreak in Kenya was reported in 1982 in the coastal region. This was followed almost 30 years later by the 2011 dengue outbreak in Mandera, northern Kenya and subsequently in Mombasa city in the coastal region (2013–2014). An entomologic investigation was conducted to establish the density of mosquit... | Dengue virus (DENV) is a member of the genus flavivirus (family Flaviviridae) that is transmitted principally by Aedes aegypti mosquitoes in an Ae. aegypti-human cycle [1], sometimes resulting in epidemics. Although the presence of other Stegomyia spp. including Ae. simpsoni complex, Ae. africanus and Ae. vittatus in d... |
10.1371/journal.ppat.1006256 | Integrated systems biology analysis of KSHV latent infection reveals viral induction and reliance on peroxisome mediated lipid metabolism | Kaposi’s Sarcoma associated Herpesvirus (KSHV), an oncogenic, human gamma-herpesvirus, is the etiological agent of Kaposi’s Sarcoma the most common tumor of AIDS patients world-wide. KSHV is predominantly latent in the main KS tumor cell, the spindle cell, a cell of endothelial origin. KSHV modulates numerous host cell... | Kaposi’s Sarcoma herpesvirus (KSHV) is the etiologic agent of Kaposi’s Sarcoma, the most common tumor of AIDS patients. KSHV modulates host cell signaling and metabolism to maintain a life-long latent infection. To unravel the underlying cellular mechanisms modulated by KSHV, we used multiple global systems biology pla... | Viruses have evolved functions to reprogram the proteomic landscape of their host and modulate cellular signaling pathways to adjust the regulation of cellular machinery. These cellular alterations support the survival of infected cells to allow replication and spread of the virus. Many viruses rewire host cell signali... |
10.1371/journal.pbio.1002082 | Estimating the Life Course of Influenza A(H3N2) Antibody Responses from Cross-Sectional Data | The immunity of a host population against specific influenza A strains can influence a number of important biological processes, from the emergence of new virus strains to the effectiveness of vaccination programmes. However, the development of an individual’s long-lived antibody response to influenza A over the course... | Host immunity against seasonal influenza viruses influences the emergence of new virus strains, the size and severity of “flu” epidemics, and the effectiveness of vaccination programmes. However, the specific factors that shape the immune response of a single human to a particular strain are little understood because i... | The immunity of a host population against specific influenza A strains can influence a number of important biological processes. It can affect the emergence of new virus strains, and hence shape the evolution of the disease [1,2]. It can also influence the size and severity of a pandemic [3–6], and the effectiveness of... |
10.1371/journal.pcbi.0030180 | What Are Lightness Illusions and Why Do We See Them? | Lightness illusions are fundamental to human perception, and yet why we see them is still the focus of much research. Here we address the question by modelling not human physiology or perception directly as is typically the case but our natural visual world and the need for robust behaviour. Artificial neural networks ... | Sometimes the best way to understand how the visual brain works is to understand why it sometimes does not. Thus, visual illusions have been central to the science and philosophy of human consciousness for decades. Here we explain the root cause of brightness illusions, not by modelling human perception or its assumed ... | Understanding how we generate accurate perceptions of surfaces is often best informed by understanding why we sometimes do not. Thus, illusions of lightness (and colour) are essential tools to vision research. In many natural environments, light levels vary across space and over time. It is important to be able to perc... |
10.1371/journal.ppat.1003478 | Negative Regulation of Type I IFN Expression by OASL1 Permits Chronic Viral Infection and CD8+ T-Cell Exhaustion | The type I interferons (IFN-Is) are critical not only in early viral control but also in prolonged T-cell immune responses. However, chronic viral infections such as those of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) in humans and lymphocytic choriomeningitis virus (LCMV) in mice overcome this earl... | Chronic viral infections, such as those of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) in humans, remain serious health problems worldwide, necessitating alternative targets/reagents for better treatment. Although the production of and/or response to type I interferon (IFN-I), a critical antiviral re... | Pattern-recognition receptors (PRRs) displayed on innate immune cells such as dendritic cells (DCs) and macrophages (Macs) sense pathogens by recognizing conserved pathogen-associated molecular patterns (PAMPs) [1], [2]. Major trans-membrane PRRs that sense viruses are the Toll-like receptors (TLRs) such as TLR3, TLR7,... |
10.1371/journal.pbio.1002427 | Excessive Osteocytic Fgf23 Secretion Contributes to Pyrophosphate Accumulation and Mineralization Defect in Hyp Mice | X-linked hypophosphatemia (XLH) is the most frequent form of inherited rickets in humans caused by mutations in the phosphate-regulating gene with homologies to endopeptidases on the X-chromosome (PHEX). Hyp mice, a murine homologue of XLH, are characterized by hypophosphatemia, inappropriately low serum vitamin D leve... | X-linked hypophosphatemia (XLH) is the most frequent form of inherited rickets in humans. A mouse model of XLH, known as Hyp, is characterized by exceptionally low serum phosphate and vitamin D levels, increased serum levels of the hormone fibroblast growth factor-23 (Fgf23), and impaired bone mineralization. Fgf23 is ... | X-linked hypophosphatemia (XLH) is the most frequent form of inherited rickets in humans. XLH is caused by inactivating mutations in the phosphate-regulating gene with homologies to endopeptidases on the X-chromosome (PHEX) [1–3]. Similarly, a loss-of-function deletion in Phex, the murine homologue of PHEX, leads to an... |
10.1371/journal.ppat.1004235 | cGMP and NHR Signaling Co-regulate Expression of Insulin-Like Peptides and Developmental Activation of Infective Larvae in Strongyloides stercoralis | The infectious form of the parasitic nematode Strongyloides stercoralis is a developmentally arrested third-stage larva (L3i), which is morphologically similar to the developmentally arrested dauer larva in the free-living nematode Caenorhabditis elegans. We hypothesize that the molecular pathways regulating C. elegans... | Human parasitic nematodes, including Strongyloides stercoralis, cause extensive morbidity in the developing world. The infectious form of S. stercoralis is a developmentally arrested third-stage larva (L3i), which resumes development into a parasitic adult upon entering a host. The molecular mechanisms controlling the ... | Parasitic nematodes infect approximately one in four persons globally, with the vast burden of disease concentrated in tropical and developing regions [1]. The parasitic nematode Strongyloides stercoralis infects an estimated 30–100 million people worldwide [2]; in corticosteroid-treated or human T-cell lymphotropic vi... |
10.1371/journal.pbio.1001243 | Sequential Analysis of Trans-SNARE Formation in Intracellular Membrane Fusion | SNARE complexes are required for membrane fusion in the endomembrane system. They contain coiled-coil bundles of four helices, three (Qa, Qb, and Qc) from target (t)-SNAREs and one (R) from the vesicular (v)-SNARE. NSF/Sec18 disrupts these cis-SNARE complexes, allowing reassembly of their subunits into trans-SNARE comp... | Cellular components often travel between organelles in vesicular entities. This intracellular traffic usually involves production of a vesicle containing cargo from one organelle membrane, movement of the vesicle to its destination, and then fusion of the vesicle with the target organelle. Thus, membrane fusion is a fu... | Cognate combinations of v- and t-SNAREs mediate membrane docking in every vesicular transport step in the endomembrane system. v- and t-SNAREs bind each other in coiled-coil complexes containing four helices [1]. Three of these helices (termed Qa, Qb, and Qc) are provided by t-SNAREs, while one (termed R) is provided b... |
10.1371/journal.ppat.1000291 | HCV Induces Oxidative and ER Stress, and Sensitizes Infected Cells to Apoptosis in SCID/Alb-uPA Mice | Hepatitis C virus (HCV) is a blood-borne pathogen and a major cause of liver disease worldwide. Gene expression profiling was used to characterize the transcriptional response to HCV H77c infection. Evidence is presented for activation of innate antiviral signaling pathways as well as induction of lipid metabolism gene... | Hepatitis C virus is a common cause of liver disease worldwide. The details of how HCV causes liver disease are not well understood. It has been thought that HCV infection does not kill liver cells directly, but indirectly by stimulating the immune system to kill HCV-infected liver cells. In this study we have used a m... | Hepatitis C virus (HCV) is a positive strand RNA virus that belongs to the family Flaviviradae. HCV is a blood borne pathogen which is a major cause of liver disease worldwide, with an estimated 200 million people infected. It is estimated that 30% of chronically infected patients eventually develop progressive liver d... |
10.1371/journal.pcbi.1000383 | A Structure-Based Approach for Detection of Thiol Oxidoreductases and
Their Catalytic Redox-Active Cysteine Residues | Cysteine (Cys) residues often play critical roles in proteins, for example, in
the formation of structural disulfide bonds, metal binding, targeting proteins
to the membranes, and various catalytic functions. However, the structural
determinants for various Cy... | Among the 20 amino acids commonly found in proteins, cysteine (Cys) is special in
that it is present more often than other residues in functionally important
locations within proteins. Some of these functions include metal binding,
catalysis, structural stabil... | Compared to other amino acids in proteins, cysteine (Cys) residues are less frequent,
yet often more conserved and found in functionally important locations.
Protein-based Cys thiols can be divided into several broad categories wherein these
residues (i) are engaged in st... |
10.1371/journal.pcbi.1006408 | The low spike density of HIV may have evolved because of the effects of T helper cell depletion on affinity maturation | The spikes on virus surfaces bind receptors on host cells to propagate infection. High spike densities (SDs) can promote infection, but spikes are also targets of antibody-mediated immune responses. Thus, diverse evolutionary pressures can influence virus SDs. HIV’s SD is about two orders of magnitude lower than that o... | The spike protein on the virus surface mediates its entry to the host cell and a high spike density promotes infection. HIV has a spike density that is almost two orders of magnitude lower than other viruses. This unique feature of HIV has defied explanation since it was first observed. By bringing together theory and ... | Viruses gain entry into their host cells by attaching to specific receptors on the host surface. The proteins that mediate entry comprise the viral spike. Since the host receptor does not mutate rapidly, spike proteins, while often being highly mutable, have conserved regions that bind to elements on the host receptor.... |
10.1371/journal.pgen.1003106 | The Tumor Suppressor Gene Retinoblastoma-1 Is Required for Retinotectal Development and Visual Function in Zebrafish | Mutations in the retinoblastoma tumor suppressor gene (rb1) cause both sporadic and familial forms of childhood retinoblastoma. Despite its clinical relevance, the roles of rb1 during normal retinotectal development and function are not well understood. We have identified mutations in the zebrafish space cadet locus th... | Before an organism can execute necessary behavioral responses to environmental stimuli, the underlying neural circuits that regulate these behaviors must be precisely wired during embryonic development. A properly wired neural circuit is the product of a sophisticated collaboration of multiple genetic pathways that orc... | Biallelic mutations in the retinoblastoma susceptibility gene rb1 are causal for intraocular childhood retinoblastomas. Rb1 is a member of a gene family that consists of three members, p105/Rb1, p107/Rb-like1, and p130/Rb-like2, collectively known as “pocket proteins” [1]. The activity of these proteins is controlled, ... |
10.1371/journal.pntd.0005165 | Comparison of the Estimated Incidence of Acute Leptospirosis in the Kilimanjaro Region of Tanzania between 2007–08 and 2012–14 | The sole report of annual leptospirosis incidence in continental Africa of 75–102 cases per 100,000 population is from a study performed in August 2007 through September 2008 in the Kilimanjaro Region of Tanzania. To evaluate the stability of this estimate over time, we estimated the incidence of acute leptospirosis in... | Leptospirosis is an infectious disease that causes a fever. It can be severe or fatal. Understanding how many people get leptospirosis helps to determine priorities in allocating resources for disease diagnosis, treatment, and prevention. There are few data about leptospirosis incidence in sub-Saharan African countries... | Leptospirosis is a major cause of illness worldwide with an estimated 1.03 million cases, 59,000 deaths, and 2.90 million disability adjusted life years lost annually [1, 2]. The burden of disease is thought to be greatest in tropical countries, although reported estimates of incidence in continental Africa are scarce ... |
10.1371/journal.pcbi.1004801 | Early Transcriptome Signatures from Immunized Mouse Dendritic Cells Predict Late Vaccine-Induced T-Cell Responses | Systems biology offers promising approaches for identifying response-specific signatures to vaccination and assessing their predictive value. Here, we designed a modelling strategy aiming to predict the quality of late T-cell responses after vaccination from early transcriptome analysis of dendritic cells. Using standa... | Vaccines are designed to elicit effective immune responses against antigens. The various vector platforms used in vaccine development are diverse and complex, rendering the selection of promising vaccines vector challenging. We have designed a modeling strategy that predicts the propensity of vaccine vectors to elicit ... | The development of vaccines against complex chronic diseases such as HIV or cancer has been largely unsuccessful so far. Novel vaccine technologies are rationally designed to generate appropriate protective immune responses [1], notably efficient T-cell responses. Such vaccine vectors include plasmid DNA, viral and bac... |
10.1371/journal.ppat.1000977 | Oxidation of Helix-3 Methionines Precedes the Formation of PK Resistant PrPSc | While elucidating the peculiar epitope of the α-PrP mAb IPC2, we found that PrPSc exhibits the sulfoxidation of residue M213 as a covalent signature. Subsequent computational analysis predicted that the presence of sulfoxide groups at both Met residues 206 and 213 destabilize the α-fold, suggesting oxidation may facili... | The protein only theory, a widely accepted model describing the prion agent, assumes that the mechanism underlying prion disease pathogenesis includes a conformational change of the α-helix rich, soluble and protease sensitive PrPC into an aggregated and protease resistant β-sheet rich PrPSc form. Until recently, no co... | Prions are infectious agents that cause neurodegenerative diseases, such as scrapie, bovine spongiform encephalopathy (BSE) and CJD. They are believed to be composed mainly of PrPSc, a misfolded form of the GPI-anchored glycoprotein termed PrPC[1]. While the function of PrPC has not been fully elucidated, it has been s... |
10.1371/journal.ppat.1005027 | Age-Dependent Cell Trafficking Defects in Draining Lymph Nodes Impair Adaptive Immunity and Control of West Nile Virus Infection | Impaired immune responses in the elderly lead to reduced vaccine efficacy and increased susceptibility to viral infections. Although several groups have documented age-dependent defects in adaptive immune priming, the deficits that occur prior to antigen encounter remain largely unexplored. Herein, we identify novel me... | While West Nile virus (WNV) infection preferentially causes severe neuroinvasive disease in elderly humans, the basis for this epidemiological linkage has remained uncertain. Here, we studied the impact of aging on WNV pathogenesis and immune responses using a mouse model of infection. Old mice showed increased lethali... | Aging is linked to a decline in immunity that causes increased susceptibility to infectious diseases and reduced vaccine efficacy in the elderly population. This process, termed immunosenescence, is the consequence of age-dependent changes to multiple components of the innate and adaptive immune responses. For example,... |
10.1371/journal.pntd.0002153 | Circulation of Japanese Encephalitis Virus in Pigs and Mosquito Vectors within Can Tho City, Vietnam | Japanese encephalitis virus (JEV) is a mosquito-borne, zoonotic flavivirus causing encephalitis in humans and reproductive disorder in pigs. JEV is present in large parts of Asia, where urbanization is high. Households within and outside Can Tho city, South Vietnam, were selected to monitor circulation of JEV. A nested... | Japanese encephalitis (JE) is a serious disease, especially in children, in large parts of Asia. It is transmitted by mosquitoes and mainly known as a disease in the rural, rice-producing areas in South and Southeast Asia. Here, the authors show that of 43 pigs sampled in Can Tho city, South Vietnam, all had antibodies... | Japanese encephalitis (JE) is a zoonotic disease spread over large parts of Asia. It is one of the most important arboviral encephalitis in humans, with an estimated 10 million cases over the last 60 years, with 30% case fatality [1]. Pigs and wading birds are amplifying hosts of the causative Japanese encephalitis vir... |
10.1371/journal.pgen.1005942 | The MRX Complex Ensures NHEJ Fidelity through Multiple Pathways Including Xrs2-FHA–Dependent Tel1 Activation | Because DNA double-strand breaks (DSBs) are one of the most cytotoxic DNA lesions and often cause genomic instability, precise repair of DSBs is vital for the maintenance of genomic stability. Xrs2/Nbs1 is a multi-functional regulatory subunit of the Mre11-Rad50-Xrs2/Nbs1 (MRX/N) complex, and its function is critical f... | Genomic DNA provides the essential blueprint for life, and therefore living organisms have several mechanisms for maintaining the stability of their own genomes. DNA double-strand breaks (DSBs) are one of the most severe forms of DNA damage, which, without precise repair, can provoke a loss of genetic information, lead... | The DNA double-strand break (DSB) is one of the most severe types of DNA damage and is most often repaired by homologous recombination (HR) or canonical non-homologous end joining (C-NHEJ) which is known as precise NHEJ. There are, however, several other minor pathways for DSB repair, some of which generate serious rea... |
10.1371/journal.pntd.0001575 | Ebola GP-Specific Monoclonal Antibodies Protect Mice and Guinea Pigs from Lethal Ebola Virus Infection | Ebola virus (EBOV) causes acute hemorrhagic fever in humans and non-human primates with mortality rates up to 90%. So far there are no effective treatments available. This study evaluates the protective efficacy of 8 monoclonal antibodies (MAbs) against Ebola glycoprotein in mice and guinea pigs. Immunocompetent mice o... | Ebola virus (EBOV) causes acute hemorrhagic fever in humans and non-human primates with mortality rates up to 90%. So far there are no effective treatments available. This study evaluates the protective efficacy of 8 monoclonal antibodies (MAbs) against the Ebola virus surface glycoprotein, in mice and guinea pigs. Var... | Ebola virus (EBOV) is a filovirus causing severe viral haemorrhagic fever in humans and non-human primates (NHPs) [1]. There are five species of EBOV: Zaire ebolavirus (ZEBOV), Sudan ebolavirus (SEBOV), Cote d'Ivoire ebolavirus (CIEBOV), Reston ebolavirus (REBOV), and Bundibugyo ebolavirus (BEBOV) [2]. ZEBOV has the hi... |
10.1371/journal.ppat.1004278 | A Tick Gut Protein with Fibronectin III Domains Aids Borrelia burgdorferi Congregation to the Gut during Transmission | Borrelia burgdorferi transmission to the vertebrate host commences with growth of the spirochete in the tick gut and migration from the gut to the salivary glands. This complex process, involving intimate interactions of the spirochete with the gut epithelium, is pivotal to transmission. We utilized a yeast surface dis... | Lyme borreliosis, the most common vector-borne illness in Northeastern parts of USA, is caused by Borrelia burgdorferi sensu lato spirochetes, and transmitted by the Ixodes scapularis ticks. Currently there is no vaccine available to prevent Lyme borreliosis. A better understanding of tick proteins that interact with B... | Ixodes scapularis is the predominant vector of several human pathogens including Borrelia burgdorferi, the agent of Lyme borreliosis in North America [1], [2]. There is currently no commercial vaccine to prevent Lyme borreliosis in humans [3], although recent efforts have been made in that direction [4]. An increased m... |
10.1371/journal.pbio.1001977 | A DNA Damage-Induced, SOS-Independent Checkpoint Regulates Cell Division in Caulobacter crescentus | Cells must coordinate DNA replication with cell division, especially during episodes of DNA damage. The paradigm for cell division control following DNA damage in bacteria involves the SOS response where cleavage of the transcriptional repressor LexA induces a division inhibitor. However, in Caulobacter crescentus, cel... | Cells have evolved sophisticated mechanisms for repairing their DNA and maintaining genome integrity. A critical aspect of the repair process is an arrest of cell cycle progression, thereby ensuring that cell division is not attempted before the genome has been repaired and fully duplicated. Our paper explores the mole... | Progress through the cell cycle requires the sequential execution of three fundamental processes: DNA replication, chromosome segregation, and cell division. Maintaining the precise order of these events is crucial to preserving genomic integrity, as any attempt to divide before completing DNA replication or chromosome... |
10.1371/journal.pgen.1004515 | A System for Genome-Wide Histone Variant Dynamics In ES Cells Reveals Dynamic MacroH2A2 Replacement at Promoters | Dynamic exchange of a subset of nucleosomes in vivo plays important roles in epigenetic inheritance of chromatin states, chromatin insulator function, chromosome folding, and the maintenance of the pluripotent state of embryonic stem cells. Here, we extend a pulse-chase strategy for carrying out genome-wide measurement... | The ability of cells to remember the correct cell fate is at least partly dependent on how the genome is packaged. Embryonic stem (ES) cells, which have the ability to become any cell type in the body, are a particularly well-studied system for understanding how the packaging of the genome – chromatin – controls cell s... | All genomic transactions in eukaryotes occur in the context of chromatin. While histones are generally among the most stably-associated DNA-binding proteins known [1], a subset of histones exhibit dynamic replication-independent exchange with the soluble pool of nucleoplasmic histones [2]–[4]. Dynamic histone exchange ... |
10.1371/journal.pcbi.0030162 | Inferring Function Using Patterns of Native Disorder in Proteins | Natively unstructured regions are a common feature of eukaryotic proteomes. Between 30% and 60% of proteins are predicted to contain long stretches of disordered residues, and not only have many of these regions been confirmed experimentally, but they have also been found to be essential for protein function. In this s... | As a result of high throughput sequencing technologies, there is a growing need to provide fast and accurate computational tools to predict the function of proteins from amino acid sequence. Most methods that attempt to do this rely on transferring function annotations between closely related proteins; however, a large... | One of the challenges of the post-genomic era is to predict the function of a protein given its amino acid sequence. Most automated function prediction methods rely upon identifying well-annotated sequence and structural homologues to transfer annotations to uncharacterised proteins (see [1,2] for a comprehensive revie... |
10.1371/journal.pntd.0004888 | Tourniquet Test for Dengue Diagnosis: Systematic Review and Meta-analysis of Diagnostic Test Accuracy | Dengue fever is a ubiquitous arboviral infection in tropical and sub-tropical regions, whose incidence has increased over recent decades. In the absence of a rapid point of care test, the clinical diagnosis of dengue is complex. The World Health Organisation has outlined diagnostic criteria for making the diagnosis of ... | Dengue is an infectious disease transmitted by mosquitoes in the Tropics. There are 2.5 billion people around the world at risk. Dengue presents as an acute febrile illness with symptoms including headache, bone or joint and muscular pains and rash. The objective of this study is to perform a diagnostic accuracy meta-a... | Dengue is an arboviral infection ubiquitous to tropical and sub-tropical regions,[1–3] where it is transmitted by domesticated day-biting mosquitoes including Aedes aegypti. After an incubation period of 4–10 days (mean, 7 days), illness onset is abrupt (with headache, fever, myalgia/arthralgia and rash) and can last u... |
10.1371/journal.pcbi.1002621 | Single Nucleotide Polymorphisms Can Create Alternative Polyadenylation Signals and Affect Gene Expression through Loss of MicroRNA-Regulation | Alternative polyadenylation (APA) can for example occur when a protein-coding gene has several polyadenylation (polyA) signals in its last exon, resulting in messenger RNAs (mRNAs) with different 3′ untranslated region (UTR) lengths. Different 3′UTR lengths can give different microRNA (miRNA) regulation such that short... | Variants in DNA that affect gene expression—so-called regulatory variants—are thought to play important roles in common complex diseases, such as cancer. In contrast to variants in protein-coding regions, regulatory variants do not affect protein sequence and function. Instead, regulatory variants affect the amount of ... | In protein-coding genes, the polyadenylation process consists of cleaving the end of the 3′ untranslated region (UTR) of precursor messenger RNA (pre-mRNA) and adding a polyadenylation (polyA) tail. Alternative polyadenylation (APA) can occur when several polyadenylation (polyA) signals lie in the last exon of a protei... |
10.1371/journal.pcbi.1000045 | The Dynamics of Human Body Weight Change | An imbalance between energy intake and energy expenditure will lead to a change in body weight (mass) and body composition (fat and lean masses). A quantitative understanding of the processes involved, which currently remains lacking, will be useful in determining the etiology and treatment of obesity and other conditi... | Understanding the dynamics of human body weight change has important consequences for conditions such as obesity, starvation, and wasting syndromes. Changes of body weight are known to result from imbalances between the energy derived from food and the energy expended to maintain life and perform physical work. However... | Obesity, anorexia nervosa, cachexia, and starvation are conditions that have a profound medical, social and economic impact on our lives. For example, the incidence of obesity and its co-morbidities has increased at a rapid rate over the past two decades [1],[2]. These conditions are characterized by changes in body we... |
10.1371/journal.pcbi.1006956 | Noise-precision tradeoff in predicting combinations of mutations and drugs | Many biological problems involve the response to multiple perturbations. Examples include response to combinations of many drugs, and the effects of combinations of many mutations. Such problems have an exponentially large space of combinations, which makes it infeasible to cover the entire space experimentally. To ove... | Sometimes a combination of drugs works much better than each drug alone. Finding such drug cocktails is a pressing challenge in order to combat drug resistance and to improve drug effects. However, it is impossible to test all combinations of multiple drug experimentally. Therefore, researchers are looking for computat... | Different fields of biology ask how multiple perturbations affect a biological system. For example, to understand the function of DNA sequences such as promoters or coding regions, or to design new ones, it is important to understand how mutations combine to affect function [1–4]. Another widely studied example is how ... |
10.1371/journal.pcbi.1002373 | Joint Analysis of Multiple Metagenomic Samples | The availability of metagenomic sequencing data, generated by sequencing DNA pooled from multiple microbes living jointly, has increased sharply in the last few years with developments in sequencing technology. Characterizing the contents of metagenomic samples is a challenging task, which has been extensively attempte... | Microorganisms are extremely abundant and diverse, and occupy almost every habitat on earth. Most of these habitats contain a complex mixture of many different microorganisms, and the characterization of these metagenomic mixtures, in terms of both taxonomy and function, is of great interest to science and medicine. Cu... | Metagenomic samples are pooled samples of the genomes of multiple microorganisms living in the same environment. They can be taken either from the outer environment or from microbial populations colonizing other living organisms. Metagenomic studies focus on the taxonomic and functional characterization of the microbia... |
10.1371/journal.pbio.1001306 | Hormonal Signal Amplification Mediates Environmental Conditions during Development and Controls an Irreversible Commitment to Adulthood | Many animals can choose between different developmental fates to maximize fitness. Despite the complexity of environmental cues and life history, different developmental fates are executed in a robust fashion. The nematode Caenorhabditis elegans serves as a powerful model to examine this phenomenon because it can adopt... | During development, many animals choose between mutually exclusive fates, such as workers, soldiers, or queens in bees or ants. The choice between states is uniform throughout the animal since mixtures of these fates are not observed in the wild. The nematode Caenorhabditis elegans larvae integrate environmental condit... | During development, organisms often face unpredictable and unfavorable environmental conditions that may decrease their fitness. In some cases, organisms of the same genotype develop into alternate phenotypes, each better adapted to a particular environment. Alternative phenotypes entail changes in metabolism, developm... |
10.1371/journal.pntd.0002888 | Strengths and Weaknesses of Global Positioning System (GPS) Data-Loggers and Semi-structured Interviews for Capturing Fine-scale Human Mobility: Findings from Iquitos, Peru | Quantifying human mobility has significant consequences for studying physical activity, exposure to pathogens, and generating more realistic infectious disease models. Location-aware technologies such as Global Positioning System (GPS)-enabled devices are used increasingly as a gold standard for mobility research. The ... | Being able to quantify human movement is important for studying activity patterns, exposure to pathogens and developing realistic infectious disease models. We compared fine-scale human mobility data obtained by Global Positioning System (GPS)-enabled devices and semi-structured interviews (SSI) from 160 individuals in... | Knowledge of daily and routine individual human mobility patterns within urban settings are important for urban planning [1]–[3], developing transportation models [3], promoting healthy lifestyles [4], and understanding infectious disease dynamics [5]–[13]. Measuring mobility at fine spatial and temporal scales through... |
10.1371/journal.pntd.0000507 | Importance of Coverage and Endemicity on the Return of Infectious Trachoma after a Single Mass Antibiotic Distribution | As part of the SAFE strategy, mass antibiotic treatments are useful in controlling the ocular strains of chlamydia that cause trachoma. The World Health Organization recommends treating at least 80% of individuals per community. However, the role of antibiotic coverage for trachoma control has been poorly characterized... | Trachoma, caused by ocular chlamydia infection, is the most common infectious cause of blindness in the world. The World Health Organization (WHO) recommends the SAFE strategy (eyelid surgery, antibiotics, facial hygiene, environmental improvements) for trachoma control. Oral antibiotics reduce the transmission of ocul... | The World Health Organization (WHO) recommends the SAFE strategy (eyelid surgery, mass antibiotics, facial hygiene promotion, and environmental improvement) for the control of trachoma, the world's leading infectious cause of blindness[1]. Mass antibiotic treatments target the ocular strains of chlamydia that cause tra... |
10.1371/journal.pbio.0050256 | Interlocking Transcriptional Feedback Loops Control White-Opaque Switching in Candida albicans | The human pathogen Candida albicans can assume either of two distinct cell types, designated “white” and “opaque.” Each cell type is maintained for many generations; switching between them is rare and stochastic, and occurs without any known changes in the nucleotide sequence of the genome. The two cell types differ dr... | The opportunistic fungal pathogen Candida albicans can switch between two heritable states—the “white” and “opaque” states. These two cell types differ in many characteristics, including cell structure, mating competence, and virulence. Recent studies of the molecular mechanism of regulating the white-opaque switch ide... | Transcriptional circuits are central to the regulation of many biological processes. Often the logic of the circuit, rather than the nature of its components, makes up its most critical feature. In this paper we describe an interlocking network of positive feedback loops that underlies white-opaque switching in the hum... |
10.1371/journal.pgen.1002464 | RIC-7 Promotes Neuropeptide Secretion | Secretion of neurotransmitters and neuropeptides is mediated by exocytosis of distinct secretory organelles, synaptic vesicles (SVs) and dense core vesicles (DCVs) respectively. Relatively little is known about factors that differentially regulate SV and DCV secretion. Here we identify a novel protein RIC-7 that is req... | Neuropeptides produce prolonged changes in circuit activity that are associated with changes in behavioral states (e.g. mood or appetite); consequently, there is great interest in identifying molecules that are required for neuropeptide secretion. Here we show that a novel neuronal protein RIC-7 promotes neuropeptide s... | Neurons secrete both neuropeptides and neurotransmitters. Neurotransmitters, such as acetylcholine (ACh), are secreted by exocytosis of small clear synaptic vesicles (SVs) whereas neuropeptide secretion is mediated by exocytosis of dense core vesicles (DCVs) [1], [2]. The mechanisms leading to DCV and SV exocytosis are... |
10.1371/journal.pntd.0006167 | Emerging trends of Zika apprehension in an epidemic setting | French Guiana is a territory that has a decades-long history of dengue outbreaks and more recently, in 2014, a chikungunya outbreak. Zika virus (ZIKV) emerged in late 2015 and subsequently led to an important outbreak.
A cross-sectional phone survey was conducted among the general population during the outbreak in June... | Although dengue fever has been a focus of many awareness campaigns in Latin America, very little information is available about beliefs, attitudes and behaviors regarding vector-borne diseases among the population of French Guiana. Following the end of the first chikungunya outbreak and at the initial onset of the firs... | Zika virus (ZIKV) is a Flavivirus transmitted by mosquitoes, primarily Aedes aegypti, the same vector that transmits dengue, chikungunya and yellow fever. During the next half century, ZIKV was considered as an emergent virus with few sporadic and imported cases reported in Africa and Asia until 2007, when a major epid... |
10.1371/journal.pcbi.1003023 | Evolutionary Capacitance and Control of Protein Stability in Protein-Protein Interaction Networks | In addition to their biological function, protein complexes reduce the exposure of the constituent proteins to the risk of undesired oligomerization by reducing the concentration of the free monomeric state. We interpret this reduced risk as a stabilization of the functional state of the protein. We estimate that prote... | The folded form of proteins is only marginally stable in vivo and constantly faces the risk of aggregation, unfolding/misfolding, and other aberrant interactions. For most proteins, the folded form is also the functionally relevant one and forces of natural selection strongly modulate its stability. In vivo, proteins i... | The toxicity due to protein misfolding and aggregation has a considerable effect on the viability of living organisms [1]–. Consequently, cells are under strong selection pressure to evolve thermodynamically stable [6] and aggregation-free protein sequences [7]. The internal region of stable proteins has a tightly pack... |
10.1371/journal.pcbi.1004977 | Machine Learning Meta-analysis of Large Metagenomic Datasets: Tools and Biological Insights | Shotgun metagenomic analysis of the human associated microbiome provides a rich set of microbial features for prediction and biomarker discovery in the context of human diseases and health conditions. However, the use of such high-resolution microbial features presents new challenges, and validated computational tools ... | The human microbiome–the entire set of microbial organisms associated with the human host–interacts closely with host immune and metabolic functions and is crucial for human health. Significant advances in the characterization of the microbiome associated with healthy and diseased individuals have been obtained through... | The human microbiome constitutes the whole set of microbial organisms associated with the human host. It has been shown to be crucial for human health and for the development and maintenance of the immune system and for several metabolic activities [1–3]. Significant effort has been devoted to its characterization in h... |
10.1371/journal.pntd.0005910 | Induction of allopurinol resistance in Leishmania infantum isolated from dogs | Resistance to allopurinol in zoonotic canine leishmaniasis has been recently shown to be associated with disease relapse in naturally-infected dogs. However, information regarding the formation of resistance and its dynamics is lacking. This study describes the successful in-vitro induction of allopurinol resistance in... | Visceral leishmaniasis caused by the parasite Leishmania infantum is a neglected tropical disease transmitted from animal hosts to humans by sand fly bites. This potentially fatal disease affects thousands of people annually and threatens millions who live in disease risk areas. Domestic dogs are considered as the main... | Visceral leishmaniasis caused by Leishmania infantum is a life threatening disease, affecting humans in Europe, Asia, North Africa and Latin America, as well as domestic dogs which are the main reservoir for this infection [1, 2]. We recently reported the detection of disease relapse in infected dogs associated with al... |
10.1371/journal.pgen.1002733 | Stimulation of Host Immune Defenses by a Small Molecule Protects C. elegans from Bacterial Infection | The nematode Caenorhabditis elegans offers currently untapped potential for carrying out high-throughput, live-animal screens of low molecular weight compound libraries to identify molecules that target a variety of cellular processes. We previously used a bacterial infection assay in C. elegans to identify 119 compoun... | Infections with antibiotic-resistant bacterial pathogens are increasing at an alarming rate, and there are very few new therapies currently being developed. We have identified a small molecule that protects the nematode C. elegans from bacterial infection by stimulating the host immune response, not by directly interfe... | Studies in the model nematode Caenorhabditis elegans have greatly expanded our understanding of development, neurobiology, host-pathogen interactions, and many other aspects of metazoan biology. Here we show that C. elegans-based assays enable the identification of immunostimulatory compounds, which can be employed tog... |
10.1371/journal.pcbi.1003171 | Task-Based Core-Periphery Organization of Human Brain Dynamics | As a person learns a new skill, distinct synapses, brain regions, and circuits are engaged and change over time. In this paper, we develop methods to examine patterns of correlated activity across a large set of brain regions. Our goal is to identify properties that enable robust learning of a motor skill. We measure b... | When someone learns a new skill, his/her brain dynamically alters individual synapses, regional activity, and larger-scale circuits. In this paper, we capture some of these dynamics by measuring and characterizing patterns of coherent brain activity during the learning of a motor skill. We extract time-evolving communi... | Cohesive structures have long been thought to play an important role in information processing in the human brain [1]. At the small scale of individual neurons, temporally coherent activity supports information transfer between cells [2]. At a much larger scale, simultaneously active cortical areas form functional syst... |
10.1371/journal.pgen.1006538 | Rfx2 Stabilizes Foxj1 Binding at Chromatin Loops to Enable Multiciliated Cell Gene Expression | Cooperative transcription factor binding at cis-regulatory sites in the genome drives robust eukaryotic gene expression, and many such sites must be coordinated to produce coherent transcriptional programs. The transcriptional program leading to motile cilia formation requires members of the DNA-binding forkhead (Fox) ... | The multiciliated cell extends hundreds of motile cilia to produce fluid flow in the airways and other organ systems. The formation of this specialized cell type requires the coordinated expression of hundreds of genes in order to produce all the protein parts motile cilia require. While a relatively small number of tr... | Animal gene expression is typically mediated by cell type specific transcription factors, acting through consensus binding sites present in distal enhancers and proximal promoters. Such factors act by opening chromatin,[1,2] by facilitating the deposition of histone modifications,[3] by employing local interactions wit... |
10.1371/journal.pgen.1007503 | No unexpected CRISPR-Cas9 off-target activity revealed by trio sequencing of gene-edited mice | CRISPR-Cas9 technologies have transformed genome-editing of experimental organisms and have immense therapeutic potential. Despite significant advances in our understanding of the CRISPR-Cas9 system, concerns remain over the potential for off-target effects. Recent studies have addressed these concerns using whole-geno... | The ability to precisely modify the genome has immense therapeutic potential and also represents a powerful tool to understand gene function. One of the key gene editing tools is CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats). Although CRISPR can be used to generate a range of genomic alterations or... | CRISPR-Cas9 technologies have transformed genome-editing of experimental organisms and have immense therapeutic potential. Despite significant advances in our understanding of the CRISPR-Cas9 system, concerns remain over the potential for off-target effects. Recent studies have addressed these concerns using whole-geno... |
10.1371/journal.ppat.1007174 | Alcohol enhances type 1 interferon-α production and mortality in young mice infected with Mycobacterium tuberculosis | In the current study, we used a mouse model and human blood samples to determine the effects of chronic alcohol consumption on immune responses during Mycobacterium tuberculosis (Mtb) infection. Alcohol increased the mortality of young mice but not old mice with Mtb infection. CD11b+Ly6G+ cells are the major source of ... | Chronic alcohol consumption modulates the host immune defense mechanism(s) and makes the host susceptible to various fungal, viral and bacterial infections, including Mycobacterium tuberculosis (Mtb). However, limited information is available about the mechanisms involved in alcohol-mediated host susceptibility to Mtb ... | It is estimated that more than two billion people worldwide are infected with Mycobacterium tuberculosis (Mtb), but only 5–10% of these individuals develop TB during their lifetime [1,2]. The geriatric population represents a large reservoir of latent tuberculosis infection (LTBI) [3]. It is difficult to diagnose and t... |
10.1371/journal.pntd.0003231 | Hepatotoxicity in Mice of a Novel Anti-parasite Drug Candidate Hydroxymethylnitrofurazone: A Comparison with Benznidazole | Treatment of Chagas disease, caused by Trypanosoma cruzi, relies on nifurtimox and benznidazole (BZL), which present side effects in adult patients, and natural resistance in some parasite strains. Hydroxymethylnitrofurazone (NFOH) is a new drug candidate with demonstrated trypanocidal activity; however, its safety is ... | Hydroxymethylnitrofurazone (NFOH) is a promising drug candidate with demonstrated trypanocidal activity in experimental models of Trypanosoma cruzi infection and chronic disease development. In this study, we monitored the safety of NFOH in established in vitro and in vivo models. Our data show that NFOH did not induce... | Chagas disease is endemic in 21 countries, and the World Health Organization estimates that approximately 9-million people are infected by Trypanosoma cruzi [1]. The acute phase lasts for ∼2-months, and is characterized by high parasitemia and fever. Chronic chagasic cardiomyopathy is the most severe clinical consequen... |
10.1371/journal.ppat.1005230 | Antigenic Characterization of the HCMV gH/gL/gO and Pentamer Cell Entry Complexes Reveals Binding Sites for Potently Neutralizing Human Antibodies | Human Cytomegalovirus (HCMV) is a major cause of morbidity and mortality in transplant patients and in fetuses following congenital infection. The glycoprotein complexes gH/gL/gO and gH/gL/UL128/UL130/UL131A (Pentamer) are required for HCMV entry in fibroblasts and endothelial/epithelial cells, respectively, and are ta... | Human Cytomegalovirus (HCMV) is a double stranded DNA, enveloped virus infecting >60% of the population worldwide. Typically asymptomatic in healthy adults, HCMV infection causes morbidity and mortality in immunocompromised patients and is the most common viral cause of birth defects in industrialized countries. Despit... | Human Cytomegalovirus (HCMV), a member of the Betaherpesvirinae sub-family of Herpesviridae, infects 40–60% of the human adult population [1]. Similar to other herpesviruses, after primary infection, HCMV becomes latent and persists for the host’s life span. Reactivation is generally asymptomatic in immune-competent in... |
10.1371/journal.pgen.1000399 | Destabilizing Protein Polymorphisms in the Genetic Background Direct Phenotypic Expression of Mutant SOD1 Toxicity | Genetic background exerts a strong modulatory effect on the toxicity of aggregation-prone proteins in conformational diseases. In addition to influencing the misfolding and aggregation behavior of the mutant proteins, polymorphisms in putative modifier genes may affect the molecular processes leading to the disease phe... | Correct folding and stability are essential for protein function. In cells, a network of molecular chaperones and degradative enzymes facilitate folding, prevent aggregation and ensure degradation of the misfolded proteins, thus maintaining protein homeostasis. In many diseases, including Amyotrophic Lateral Sclerosis ... | ALS (OMIM #105400 http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?cmd=entry&id=105400) is a progressive degenerative disorder affecting motor neurons in the brain stem and spinal cord. Up to 10% of cases have a dominant familial inheritance pattern with mutations in SOD1 (OMIM *14750 http://www.ncbi.nlm.nih.gov/entrez/... |
10.1371/journal.ppat.1004281 | Human APOBEC3 Induced Mutation of Human Immunodeficiency Virus Type-1 Contributes to Adaptation and Evolution in Natural Infection | Human APOBEC3 proteins are cytidine deaminases that contribute broadly to innate immunity through the control of exogenous retrovirus replication and endogenous retroelement retrotransposition. As an intrinsic antiretroviral defense mechanism, APOBEC3 proteins induce extensive guanosine-to-adenosine (G-to-A) mutagenesi... | Cytidine deaminases of the human APOBEC3 gene family act as an intrinsic defense mechanism against infection with HIV-1 and other viruses. The APOBEC3 proteins introduce mutations into the viral genome by inducing enzymatic modification of nucleotide sequences and inhibiting synthesis of cDNA strands from the viral RNA... | The pathogenesis of HIV-1 infection correlates with the level of active viral replication and relates to a variety of factors specific to the virus, the host, and its immune system. Mutations, insertions, deletions and recombinations that confer changes in the activity of virally encoded genes and gene products affect ... |
10.1371/journal.ppat.1003170 | Dynamic Epigenetic Regulation of Gene Expression during the Life Cycle of Malaria Parasite Plasmodium falciparum | Epigenetic mechanisms are emerging as one of the major factors of the dynamics of gene expression in the human malaria parasite, Plasmodium falciparum. To elucidate the role of chromatin remodeling in transcriptional regulation associated with the progression of the P. falciparum intraerythrocytic development cycle (ID... | Malaria is a devastating parasitic disease caused by the protozoan protist Plasmodium falciparum. The complex life cycle of P. falciparum comprises various morphological and functionally distinct forms and is completed in two different hosts. Various regulatory mechanisms are employed by these parasites to complete the... | In spite of worldwide efforts, malaria remains one of the most devastating illnesses with an estimated 216 million episodes leading to 655,000 deaths in 2010 [1]. The effectiveness of current treatment strategies is attenuated by increasing resistance of malaria parasites to the available chemotherapeutic drugs. The em... |
10.1371/journal.pgen.1001226 | LaeA Control of Velvet Family Regulatory Proteins for Light-Dependent Development and Fungal Cell-Type Specificity | VeA is the founding member of the velvet superfamily of fungal regulatory proteins. This protein is involved in light response and coordinates sexual reproduction and secondary metabolism in Aspergillus nidulans. In the dark, VeA bridges VelB and LaeA to form the VelB-VeA-LaeA (velvet) complex. The VeA-like protein Vel... | Numerous fungi have the potential to infect immunocompromised patients or to contaminate and spoil our nutrients. They represent an increasing danger that threatens public health and agriculture. This requires improved understanding of fungal growth, development, dissemination of spores, and mycotoxin production. We ha... | Multicellular organisms have developed a variety of different cell types, which become apparent during the ontogenesis of an organism to its adult form. Cell differentiation requires the coordinated interplay of key regulators, which respond to internal and external cues. Cell type specificity often requires specific p... |
10.1371/journal.ppat.1007574 | TDP-43 proteinopathy in Theiler’s murine encephalomyelitis virus infection | TDP-43, an RNA-binding protein that is primarily nuclear and important in splicing and RNA metabolism, is mislocalized from the nucleus to the cytoplasm of neural cells in amyotrophic lateral sclerosis (ALS), and contributes to disease. We sought to investigate whether TDP-43 is mislocalized in infections with the acut... | TDP-43 is a widely expressed nuclear protein that shuttles between the nucleus and cytoplasm, and regulates many aspects of RNA processing, such as splicing, trafficking, stabilization, and miRNA production. In almost all cases of ALS, neuronal and glial TDP-43 is phosphorylated, cleaved, and mislocalized to the cytopl... | Trans-activation response (TAR) DNA-binding protein of 43 kDa (TDP-43) is an RNA-binding protein (as well as DNA-binding protein) primarily present in the nucleus and important in RNA processing, mRNA transport/stability, and mRNA translation [2–4]. A variety of cellular stresses normally triggers TDP-43 to transiently... |
10.1371/journal.pgen.1007838 | Evolution of maternal and zygotic mRNA complements in the early Drosophila embryo | The earliest stages of animal development are controlled by maternally deposited mRNA transcripts and proteins. Once the zygote is able to transcribe its own genome, maternal transcripts are degraded, in a tightly regulated process known as the maternal to zygotic transition (MZT). While this process has been well-stud... | Genetic control of embryonic development in all animals requires precise coordination between mother and zygote. The mother provides gene products to the egg to drive the earliest stages of development, until the zygote is able to transcribe its own genome. Many processes of early development are highly conserved over ... | Most early developmental processes, such as rapid cleavage cycles and the establishment of body axes, are shared across multicellular animals, but the extent to which the mechanisms and the genes involved are also shared remains an open question.
Throughout the animal kingdom, the first stages of development are contr... |
10.1371/journal.pgen.1004470 | Regulation of Feto-Maternal Barrier by Matriptase- and PAR-2-Mediated Signaling Is Required for Placental Morphogenesis and Mouse Embryonic Survival | The development of eutherian mammalian embryos is critically dependent on the selective bi-directional transport of molecules across the placenta. Here, we uncover two independent and partially redundant protease signaling pathways that include the membrane-anchored serine proteases, matriptase and prostasin, and the G... | Development of mammalian embryos is dependent on an efficient exchange of nutrients, oxygen, and waste products between the mother and the embryo. The interface between the two systems is provided by the placenta in a form of a specialized epithelium that both facilitates the transport of molecules between the mother a... | The development of eutherian mammals requires an efficient exchange of nutrients, oxygen, ions, hormones, and waste products between the maternal and fetal blood. In humans and mice, a functional feto-maternal interface is established in the placenta by the formation of a complex embryonic vascular tree that is submerg... |
10.1371/journal.pntd.0001349 | Factors Affecting Infestation by Triatoma infestans in a Rural Area of the Humid Chaco in Argentina: A Multi-Model Inference Approach | Transmission of Trypanosoma cruzi by Triatoma infestans remains a major public health problem in the Gran Chaco ecoregion, where understanding of the determinants of house infestation is limited. We conducted a cross-sectional study to model factors affecting bug presence and abundance at sites within house compounds i... | Vector-borne transmission of Chagas disease remains a major public health problem in parts of Latin America. Triatoma infestans is the main vector in the countries located in the South American Cone, particularly in the Gran Chaco ecoregion where residual insecticide control has achieved only a moderate, irregular impa... | The transmission of Trypanosoma cruzi, the etiologic agent of Chagas disease, by hematophagous triatomine bugs remains a major public health problem in many rural and some periurban communities in Latin America [1]. For decades vector control actions have relied mostly on residual insecticide spraying; implementation h... |
10.1371/journal.ppat.1002661 | AMP-Activated Kinase Restricts Rift Valley Fever Virus Infection by Inhibiting Fatty Acid Synthesis | The cell intrinsic innate immune responses provide a first line of defense against viral infection, and often function by targeting cellular pathways usurped by the virus during infection. In particular, many viruses manipulate cellular lipids to form complex structures required for viral replication, many of which are... | RNA viruses represent an important worldwide source of infection and disease in both humans and animals. While individual viruses have unique characteristics, some stages of infection are conserved and must be completed in order to successfully infect and grow. Viruses must undergo genome replication, protein synthesis... | Emerging and re-emerging arthropod-borne viral pathogens have lead to significant world-wide morbidity and mortality in humans and domestic animals, and are of medical and agricultural concern. Bunyaviruses are an important group of insect-borne RNA viruses that include disease causing members such as Sin Nombre, Hanta... |
10.1371/journal.pntd.0003338 | Influence of Household Rat Infestation on Leptospira Transmission in the Urban Slum Environment | The Norway rat (Rattus norvegicus) is the principal reservoir for leptospirosis in many urban settings. Few studies have identified markers for rat infestation in slum environments while none have evaluated the association between household rat infestation and Leptospira infection in humans or the use of infestation ma... | The Norway rat is an important reservoir for urban leptospirosis, a life-threatening zoonotic disease. In urban settings, leptospirosis transmission occurs primarily in the peri-domiciliary environment of the slums. Rodent control is one of the most frequent strategies to prevent leptospirosis, but the identification o... | In developing countries, leptospirosis is an emerging health problem affecting urban slum communities [1]–[4]. Annual epidemics of the disease typically occur during periods of seasonal rainfall [1], [5]–[8]. Lack of sanitation infrastructure such as open sewage systems and poor refuse collection services provide condi... |
10.1371/journal.ppat.1000484 | Vector Transmission of Leishmania Abrogates Vaccine-Induced Protective Immunity | Numerous experimental vaccines have been developed to protect against the cutaneous and visceral forms of leishmaniasis caused by infection with the obligate intracellular protozoan Leishmania, but a human vaccine still does not exist. Remarkably, the efficacy of anti-Leishmania vaccines has never been fully evaluated ... | The generation of vaccines that protect against intracellular pathogens such as malaria, human immunodeficiency virus and leishmaniasis have met with limited success. A perplexing aspect of this failure as it relates to leishmaniasis is the knowledge that individuals typically get the disease only once, and that indivi... | Leishmania are obligate-intracellular protozoan parasites that establish infection in mammalian hosts following transmission to the skin by the bite of an infected Phlebotomine sand fly [1]. Different Leishmania species are associated with a spectrum of clinical outcomes in humans, including fatal, disseminated infecti... |
10.1371/journal.ppat.1003946 | Identification of Host-Targeted Small Molecules That Restrict Intracellular Mycobacterium tuberculosis Growth | Mycobacterium tuberculosis remains a significant threat to global health. Macrophages are the host cell for M. tuberculosis infection, and although bacteria are able to replicate intracellularly under certain conditions, it is also clear that macrophages are capable of killing M. tuberculosis if appropriately activated... | Infection with the bacterial pathogen Mycobacterium tuberculosis causes the disease tuberculosis (TB) that imposes significant worldwide morbidity and mortality. Approximately 2 billion people are infected with M. tuberculosis, and almost 1.5 million people die annually from TB. With increasing drug resistance and few ... | Tuberculosis continues to be a cause of significant morbidity and mortality world-wide due to numerous factors, including the rise of drug resistance and the absence of an effective vaccine. The challenge of adherence to long treatment regimens and the limited number of effective therapeutics drive the need for innovat... |
10.1371/journal.pgen.1005539 | Dynamic Contacts of U2, RES, Cwc25, Prp8 and Prp45 Proteins with the Pre-mRNA Branch-Site and 3' Splice Site during Catalytic Activation and Step 1 Catalysis in Yeast Spliceosomes | Little is known about contacts in the spliceosome between proteins and intron nucleotides surrounding the pre-mRNA branch-site and their dynamics during splicing. We investigated protein-pre-mRNA interactions by UV-induced crosslinking of purified yeast Bact spliceosomes formed on site-specifically labeled pre-mRNA, an... | The spliceosome is a highly dynamic RNP machine that during the catalytic cycle undergoes many changes in composition and conformation. The pre-catalytic Bact spliceosome contains the U2, U6 and U5 snRNAs and ~40 proteins, which are evolutionarily conserved between budding yeast and metazoans. The Bact spliceosome is c... | The removal of introns from nuclear pre-mRNAs proceeds by way of two phosphoester transfer reactions and is catalyzed by the spliceosome, a large ribonucleoprotein (RNP) complex composed of the snRNPs U1, U2, U4/U6 and U5 and several proteins [1]. The spliceosome is a highly dynamic RNP machine that undergoes many chan... |
10.1371/journal.pcbi.1005444 | redGEM: Systematic reduction and analysis of genome-scale metabolic reconstructions for development of consistent core metabolic models | Genome-scale metabolic reconstructions have proven to be valuable resources in enhancing our understanding of metabolic networks as they encapsulate all known metabolic capabilities of the organisms from genes to proteins to their functions. However the complexity of these large metabolic networks often hinders their u... | Reduced models are used commonly to understand the metabolism of organisms and to integrate experimental data for many different studies such as physiology, fluxomics and metabolomics. Without consistent or clear criteria on how these reduced models are actually developed, it is difficult to ensure that they reflect th... | Stoichiometric models have been used to study the physiology of organisms since 1980s [1–3], and with the accumulation of knowledge, and progressing techniques for genome annotation, these models have evolved into Genome Scale Metabolic Reconstructions (GEMs), which encapsulate all known biochemistry that takes place i... |
10.1371/journal.ppat.0030073 | Crystal Structure of the P Pilus Rod Subunit PapA | P pili are important adhesive fibres involved in kidney infection by uropathogenic Escherichia coli strains. P pili are assembled by the conserved chaperone–usher pathway, which involves the PapD chaperone and the PapC usher. During pilus assembly, subunits are incorporated into the growing fiber via the donor–strand e... | Bacterial adhesion to a host is a crucial step that determines the onset of bacterial infection. It is mediated through recognition of a receptor on the host cell surface by a protein called an adhesin displayed on the surface of the bacterium. Many adhesins are displayed at the tip of specialized organelles called pil... | Urinary tract infections, which include infections of the bladder (cystitis) and kidney (pyelonephritis), are some of the most common bacterial infections. These infections are caused mainly by uropathogenic Escherichia coli [1]. Once uropathogenic E. coli is introduced, survival and persistence of these bacteria in th... |
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