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10.1371/journal.pntd.0002994 | Characterization of Aedes aegypti Innate-Immune Pathways that Limit Chikungunya Virus Replication | Replication of arboviruses in their arthropod vectors is controlled by innate immune responses. The RNA sequence-specific break down mechanism, RNA interference (RNAi), has been shown to be an important innate antiviral response in mosquitoes. In addition, immune signaling pathways have been reported to mediate arbovir... | Chikungunya virus (CHIKV) is a mosquito-borne human-pathogenic arbovirus of the Togaviridae family, genus Alphavirus. Arbovirus replication in vectors, such as mosquitoes, is not passively tolerated but leads to immune responses, that control virus infection. These responses therefore represent interesting targets for ... | Arthropod-borne viruses (arboviruses) replicate in both their vertebrate host and arthropod vector. This poses a unique problem for arboviruses as they are exposed to both the vertebrate and invertebrate immune systems. Arthropod vectors of arboviruses, such as mosquitoes, do not have the combination of innate and adap... |
10.1371/journal.ppat.1004256 | Novel Drosophila Viruses Encode Host-Specific Suppressors of RNAi | The ongoing conflict between viruses and their hosts can drive the co-evolution between host immune genes and viral suppressors of immunity. It has been suggested that an evolutionary ‘arms race’ may occur between rapidly evolving components of the antiviral RNAi pathway of Drosophila and viral genes that antagonize it... | Viruses and their hosts can engage in an evolutionary arms race. Viruses may select for hosts with more effective immune responses, whereas the immune response of the host may select for viruses that evade the immune system. These viral counter-defenses may in turn drive adaptations in host immune genes. A potential ou... | As obligate intracellular parasites, viruses modulate and exploit the host cellular environment for their replication. The host antiviral defense system restricts virus infections, and in turn, viruses dedicate a significant fraction of their coding capacity to produce factors that antagonize the antiviral immune respo... |
10.1371/journal.ppat.1006708 | Selection for avian leukosis virus integration sites determines the clonal progression of B-cell lymphomas | Avian leukosis virus (ALV) is a simple retrovirus that causes a wide range of tumors in chickens, the most common of which are B-cell lymphomas. The viral genome integrates into the host genome and uses its strong promoter and enhancer sequences to alter the expression of nearby genes, frequently inducing tumors. In th... | The Avian Leukosis Virus (ALV) is a simple retrovirus that causes cancer in chickens. The virus integrates its genome into the host genome and induces changes in expression of nearby genes. Here, we determine the sites of viral integrations and their role in the progression of tumors. We report pathways and novel gene ... | Avian leukosis virus (ALV) is a simple retrovirus that causes cancer, primarily B-cell lymphomas in chickens [1–3]. The ALV genome does not contain a viral oncogene and induces aberrant host gene expression via use of strong viral enhancer and promoter elements. Relative to other well studied retroviruses like HIV-1 an... |
10.1371/journal.ppat.1003747 | A Novel Membrane Sensor Controls the Localization and ArfGEF Activity of Bacterial RalF | The intracellular bacterial pathogen Legionella pneumophila (Lp) evades destruction in macrophages by camouflaging in a specialized organelle, the Legionella-containing vacuole (LCV), where it replicates. The LCV maturates by incorporating ER vesicles, which are diverted by effectors that Lp injects to take control of ... | The intracellular pathogens Legionella pneumophila (Lp) and Rickettsia prowazekii (Rp) inject an effector (RalF) that diverts the host trafficking small GTPase Arf1. In the case of Lp, LpRalF recruits Arf1 to the Legionella-containing vacuole (LCV), where the pathogen replicates. RalF proteins are related to eukaryotic... | A number of intracellular pathogenic bacteria can bypass regulatory networks used to control trafficking and cytoskeletal pathways of the infected cell by delivering bacterial effector proteins into the host cytosol that function as illegitimate regulators of small GTPases (reviewed in [1], [2]). One of them, Legionell... |
10.1371/journal.ppat.1003715 | Bacterial Effector Activates Jasmonate Signaling by Directly Targeting JAZ Transcriptional Repressors | Gram-negative bacterial pathogens deliver a variety of virulence proteins through the type III secretion system (T3SS) directly into the host cytoplasm. These type III secreted effectors (T3SEs) play an essential role in bacterial infection, mainly by targeting host immunity. However, the molecular basis of their funct... | Many Gram-negative bacterial pathogens rely on the type III secretion system, which is a specialized protein secretion apparatus, to inject virulence proteins, called effectors, into the host cells. The type III secreted effectors (T3SEs) directly target host substrates in order to promote bacterial colonization and di... | A prevailing concept for plant-pathogen interactions highlights the continuing battles between the activation of plant immune responses upon pathogen perception and the subversion of host immunity by virulence factors produced by successful pathogens. One branch of the plant immunity system is based on the recognition ... |
10.1371/journal.ppat.1005052 | Latent KSHV Infected Endothelial Cells Are Glutamine Addicted and Require Glutaminolysis for Survival | Kaposi’s Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of Kaposi’s Sarcoma (KS). KSHV establishes a predominantly latent infection in the main KS tumor cell type, the spindle cell, which is of endothelial cell origin. KSHV requires the induction of multiple metabolic pathways, including glycolysis and fa... | KSHV is the etiologic agent of KS, the most common tumor of AIDS patients worldwide. Currently, there are no therapeutics available to directly treat latent KSHV infection. This study reveals that latent KSHV infection induces endothelial cells to become glutamine addicted, similarly to cancer cells. Extracellular glut... | Kaposi’s Sarcoma-associated Herpesvirus (KSHV) is a human γ-herpesvirus and the etiologic agent of several malignancies, including two B-cell lymphomas, primary effusion lymphoma (PEL) and Multicentric Castleman’s Disease (MCD), as well as Kaposi’s Sarcoma (KS), an angioproliferative tumor[1, 2]. KS is the most common ... |
10.1371/journal.ppat.1005155 | The NLRP3 Inflammasome and IL-1β Accelerate Immunologically Mediated Pathology in Experimental Viral Fulminant Hepatitis | Viral fulminant hepatitis (FH) is a severe disease with high mortality resulting from excessive inflammation in the infected liver. Clinical interventions have been inefficient due to the lack of knowledge for inflammatory pathogenesis in the virus-infected liver. We show that wild-type mice infected with murine hepati... | The NLRP3 inflammasome and IL-1β play essential roles in mediating the primary inflammatory responses against pathogen invasions in the host. Hyperactivation of this signaling pathway can lead to life-threatening diseases under certain circumstances. However, it is not clear if NLRP3 inflammasome activation participate... | Viral fulminant hepatitis (FH) is a clinical syndrome characterized by massive necrosis of hepatocytes along with hepatic encephalopathy during the infections [1]. Despite advances in the development of antiviral drugs, a poor understanding of the immune mechanisms underlying viral FH has largely stalled the identifica... |
10.1371/journal.pgen.1006528 | Genome-wide physical activity interactions in adiposity ― A meta-analysis of 200,452 adults | Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 18... | Decline in daily physical activity is thought to be a key contributor to the global obesity epidemic. However, the impact of sedentariness on adiposity may be in part determined by a person’s genetic constitution. The specific genetic variants that are sensitive to physical activity and regulate adiposity remain largel... | In recent decades, we have witnessed a global obesity epidemic that may be driven by changes in lifestyle such as easier access to energy-dense foods and decreased physical activity (PA) [1]. However, not everyone becomes obese in obesogenic environments. Twin studies suggest that changes in body weight in response to ... |
10.1371/journal.pcbi.1000423 | Drug Discovery Using Chemical Systems Biology: Repositioning the Safe Medicine Comtan to Treat Multi-Drug and Extensively Drug Resistant Tuberculosis | The rise of multi-drug resistant (MDR) and extensively drug resistant (XDR) tuberculosis around the world, including in industrialized nations, poses a great threat to human health and defines a need to develop new, effective and inexpensive anti-tubercular agents. Previously we developed a chemical systems biology app... | The rise of multi-drug resistant (MDR) and extensively drug resistant (XDR) tuberculosis around the world, including in industrialized nations, poses a great threat to human health. This resistance highlights the need to develop new, effective and inexpensive anti-tubercular agents. Unfortunately, conventional approach... | Tuberculosis, which is caused by the bacterial pathogen Mycobacterium tuberculosis (M.tuberculosis), is a leading cause of mortality among infectious diseases. It has been estimated by the World Health Organization (WHO) that almost one-third of the world's population, around 2 billion people, is infected with the dise... |
10.1371/journal.ppat.1008009 | A robust human norovirus replication model in zebrafish larvae | Human noroviruses (HuNoVs) are the most common cause of foodborne illness, with a societal cost of $60 billion and 219,000 deaths/year. The lack of robust small animal models has significantly hindered the understanding of norovirus biology and the development of effective therapeutics. Here we report that HuNoV GI and... | Human norovirus (HuNoV) is the number one agent of viral gastroenteritis worldwide. It can infect people of all age groups, resulting in 700 million infections and 219,000 deaths each year. Outbreaks of acute HuNoV gastroenteritis occur often, but chronic infections also happen in people with immune deficiencies. Despi... | Human noroviruses (HuNoVs) are an important cause of epidemic and sporadic acute gastroenteritis worldwide; annually about 700 million people develop a HuNoV infection resulting in ~219,000 deaths and a societal cost estimated at 60 billion US dollars [1]. Large outbreaks of norovirus gastroenteritis are frequent and h... |
10.1371/journal.pcbi.1000676 | Adaptable Functionality of Transcriptional Feedback in Bacterial Two-Component Systems | A widespread mechanism of bacterial signaling occurs through two-component systems, comprised of a sensor histidine kinase (SHK) and a transcriptional response regulator (RR). The SHK activates RR by phosphorylation. The most common two-component system structure involves expression from a single operon, the transcript... | Bacteria have evolved various mechanisms for surviving unpredictable changes and stresses in the environment, such as nutrient limitation. One common survival mechanism is the two-component system, where a sensor protein responds to a particular type of stress by activating a regulator in the cell. These regulators can... | Unpredictably changing environments necessitate appropriate responses for successful survival by bacteria. Bacterial two-component system (TCS) signaling shifts transcriptional programs in response to a variety of external cues affecting bacterial growth such as nutrient availability, osmolarity, redox state, temperatu... |
10.1371/journal.pgen.1001221 | Essential Functions of the Histone Demethylase Lid | Drosophila Little imaginal discs (Lid) is a recently described member of the JmjC domain class of histone demethylases that specifically targets trimethylated histone H3 lysine 4 (H3K4me3). To understand its biological function, we have utilized a series of Lid deletions and point mutations to assess the role that each... | Correct spatial and temporal control of gene expression is essential for development. One of the many ways that gene expression is regulated is by the addition, recognition, and removal of methyl groups from the histone proteins around which DNA is wrapped within the nucleus. Here we describe a systematic analysis of L... | The Drosophila lid gene is essential for development and encodes a protein with multiple domains implicated in chromatin-mediated regulation of transcription, including the recently described lysine demethylase domain, Jumonji C (JmjC). Six lysine residues of histones H3 and H4 can be mono, di or trimethylated, and eac... |
10.1371/journal.ppat.1004314 | Strain-Specific Properties and T Cells Regulate the Susceptibility to Papilloma Induction by Mus musculus Papillomavirus 1 | The immunocytes that regulate papillomavirus infection and lesion development in humans and animals remain largely undefined. We found that immunocompetent mice with varying H-2 haplotypes displayed asymptomatic skin infection that produced L1 when challenged with 6×1010 MusPV1 virions, the recently identified domestic... | Infection with papillomaviruses can cause benign warts (papillomas) on skin and mucosae of humans and animals but also malignancies, especially anogenital carcinomas and, in genetically predisposed or immunocompromised individuals, cutaneous squamous cell cancers. Control and clearance of these viruses are thought to b... | Papillomaviruses (PV) are DNA tumor viruses that infect stratified squamous epithelia of the skin and mucous membranes of humans and many other vertebrate species [1]. PV infections are species-restricted and region-restricted, in that only part of the skin and mucous membranes of the host species of a given PV is perm... |
10.1371/journal.pcbi.1000254 | Game Theory of Mind | This paper introduces a model of ‘theory of mind’, namely, how we represent the intentions and goals of others to optimise our mutual interactions. We draw on ideas from optimum control and game theory to provide a ‘game theory of mind’. First, we consider the representations of goals in terms of value functions that a... | The ability to work out what other people are thinking is essential for effective social interactions, be they cooperative or competitive. A widely used example is cooperative hunting: large prey is difficult to catch alone, but we can circumvent this by cooperating with others. However, hunting can pit private goals t... | This paper is concerned with modelling the intentions and goals of others in the context of social interactions; in other words, how do we represent the behaviour of others in order to optimise our own behaviour? Its aim is to elaborate a simple model of ‘theory of mind’ [1],[2] that can be inverted to make inferences ... |
10.1371/journal.pntd.0006494 | Molecular, immunological and neurophysiological evaluations for early diagnosis of neural impairment in seropositive leprosy household contacts | Household contacts constitute the highest risk group for leprosy development, and despite significant progress in the disease control, early diagnosis remains the primary goals for leprosy management programs.
We have recruited 175 seropositive and 35 seronegative household contacts from 2014 to 2016, who were subjecte... | Despite the apparent progress observed in recent years in leprosy control, early identification of cases remains one of the primary objectives of control programs. In addition, the failure of the current therapeutic scheme on the incidence of leprosy demonstrates that the disease elimination as a public health program ... | Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae), an obligate intracellular parasite with a predilection for infecting peripheral nerves and skin. Leprosy is a current and challenging disease, because it still represents a problem for public health in developing countries such as Brazi... |
10.1371/journal.ppat.1006500 | An essential EBV latent antigen 3C binds Bcl6 for targeted degradation and cell proliferation | The latent EBV nuclear antigen 3C (EBNA3C) is required for transformation of primary human B lymphocytes. Most mature B-cell malignancies originate from malignant transformation of germinal center (GC) B-cells. The GC reaction appears to have a role in malignant transformation, in which a major player of the GC reactio... | Epstein-Barr virus (EBV) is the first characterized human tumor virus, which is associated with a broad range of human cancers. One of the latent proteins, EBV encoded nuclear antigen 3C (EBNA3C) plays a critical role in EBV-mediated B-cell transformation. Bcl6 is a master regulator required in mature B-cells during ge... | B-cell development through the germinal center (GC) is controlled strictly by sequential activation or repression of crucial transcription factors, executing the pre- and post-GC B-cell differentiation [1]. The deregulation of induced GC reactions during B-cell development is associated with malignant transformation gi... |
10.1371/journal.pgen.1001140 | dMyc Functions Downstream of Yorkie to Promote the Supercompetitive Behavior of Hippo Pathway Mutant Cells | Genetic analyses in Drosophila epithelia have suggested that the phenomenon of “cell competition” could participate in organ homeostasis. It has been speculated that competition between different cell populations within a growing organ might play a role as either tumor promoter or tumor suppressor, depending on the cel... | One of the major challenges of developmental biology and cancer research is to get a better understanding of how different signals regulate proper organ growth and prevent tumor formation. Even though there is a strong correlation between tumor progression and Myc family misexpression or Hippo signaling pathway malfunc... | Growth regulation requires the fine tuning between the rate of cell death and cell proliferation in developing organs. Studies in Drosophila have revealed that somatic cells within a growing epithelium compete with one another for contribution to the adult organ and this phenomenon, known as “cell competition” [1], is ... |
10.1371/journal.pntd.0000547 | Molecular Characterization of the Schistosoma mansoni Zinc Finger Protein SmZF1 as a Transcription Factor | During its development, the parasite Schistosoma mansoni is exposed to different environments and undergoes many morphological and physiological transformations as a result of profound changes in gene expression. Characterization of proteins involved in the regulation of these processes is of importance for the underst... | Schistosomes are parasites that exhibit a complex life cycle during which they progress through many morphological and physiological transformations. These transformations are likely accompanied by alterations in gene expression, making genetic regulation important for parasite development. Here we describe a Schistoso... | Schistosomiasis is a disease caused by trematode worms, mainly Schistosoma mansoni, S. haematobium and S.japonicum. According to World Health Organization, this parasitic disease affects 200 million people throughout the world [1]. Although the level of schistosome-associated morbidity is unclear, some recent studies h... |
10.1371/journal.pbio.1001988 | Protection of Armadillo/β-Catenin by Armless, a Novel Positive Regulator of Wingless Signaling | The Wingless (Wg/Wnt) signaling pathway is essential for metazoan development, where it is central to tissue growth and cellular differentiation. Deregulated Wg pathway activation underlies severe developmental abnormalities, as well as carcinogenesis. Armadillo/β-Catenin plays a key role in the Wg transduction cascade... | The Wg/Wnt signaling pathway, found in most animals, is essential for regulating tissue growth and the formation of different cell types during development. Defects in the Wg/Wnt signaling relay can have serious consequences, ranging from aberrant organ patterning to malignant tumor formation. A pivotal step in the tra... | The wingless (wg) gene was found nearly forty years ago with the characterization of a Drosophila mutant without wings [1]. The gene encodes a secreted glycoprotein, the founding member of the Wnt family of signaling proteins [2]. In the decades following its discovery, Wg/Wnt signaling has been shown to be essential d... |
10.1371/journal.pmed.1002200 | IL-7 Receptor Mutations and Steroid Resistance in Pediatric T cell Acute Lymphoblastic Leukemia: A Genome Sequencing Study | Pediatric acute lymphoblastic leukemia (ALL) is the most common childhood cancer and the leading cause of cancer-related mortality in children. T cell ALL (T-ALL) represents about 15% of pediatric ALL cases and is considered a high-risk disease. T-ALL is often associated with resistance to treatment, including steroids... | Although modern treatment protocols have drastically increased the cure rate among patients with T cell acute lymphoblastic leukemia (T-ALL), nearly 40% of patients require the most aggressive treatment regimen, significantly increasing the risk of harmful treatment effects later in life. These detrimental effects can ... | In children with acute lymphoblastic leukemia (ALL), response to therapy, including in vitro or in vivo steroid response, is a strong predictor of survival and cure [1–3]. ALL can be classified as T cell ALL (T-ALL) or B cell precursor ALL (BCP-ALL): T-ALL, particularly, has a high risk of relapse and is refractory to ... |
10.1371/journal.pgen.1003987 | Expanding the Marine Virosphere Using Metagenomics | Viruses infecting prokaryotic cells (phages) are the most abundant entities of the biosphere and contain a largely uncharted wealth of genomic diversity. They play a critical role in the biology of their hosts and in ecosystem functioning at large. The classical approaches studying phages require isolation from a pure ... | Prokaryotic species contain extremely large gene pools (pan-genome) the study of which has been constrained by the difficulties in getting enough cultivated representatives of most of them. The situation of their viruses, also known as phages, that provide part of this genomic diversity and preserve it, is even worse. ... | Prokaryotic viruses, often referred to as phages, are one of the largest reservoirs of underexplored genetic diversity on Earth. They are more numerous than any other biological form on the planet, and the astronomical values put forward for their numbers are to the tune of 1030, difficult to comprehend even by metapho... |
10.1371/journal.ppat.1006778 | Prohibitin plays a critical role in Enterovirus 71 neuropathogenesis | A close relative of poliovirus, enterovirus 71 (EV71) is regarded as an important neurotropic virus of serious public health concern. EV71 causes Hand, Foot and Mouth Disease and has been associated with neurological complications in young children. Our limited understanding of the mechanisms involved in its neuropatho... | A close relative of poliovirus, Enterovirus 71 (EV71) causes Hand, Foot and Mouth Disease and has been associated with neurological complications in young children. The lack of effective therapeutics is largely due to our limited understanding of the mechanisms involved in EV71 neuropathogenesis. Here, using a proteomi... | Enterovirus 71 (EV71) is a non-enveloped, positive-sense, single-stranded RNA virus, and causes hand, foot and mouth disease (HFMD) in humans. Being a close relative of poliovirus, EV71 is deemed as an important neurotropic virus worldwide [1]. Since its first isolation in California in 1969, several major outbreaks ha... |
10.1371/journal.pgen.1000348 | Heterochromatic Threads Connect Oscillating Chromosomes during Prometaphase I in Drosophila Oocytes | In Drosophila oocytes achiasmate homologs are faithfully segregated to opposite poles at meiosis I via a process referred to as achiasmate homologous segregation. We observed that achiasmate homologs display dynamic movements on the meiotic spindle during mid-prometaphase. An analysis of living prometaphase oocytes rev... | Proper chromosome segregation is essential during the production of eggs and sperm. Chromosome missegregation during meiosis results in the lethality of the offspring or in children carrying extra copies of a given chromosome (for example, Down syndrome). Recombination results in homologous chromosomes becoming physica... | The accurate segregation of homologs during meiosis is essential for the propagation of virtually all eukaryotes. In many organisms proper chromosome segregation is ensured by recombination and the formation of chiasmata. Chiasmata lock homologs together and constrain the centromeres to orient towards opposite poles of... |
10.1371/journal.ppat.1002900 | Telomere Length Affects the Frequency and Mechanism of Antigenic Variation in Trypanosoma brucei | Trypanosoma brucei is a master of antigenic variation and immune response evasion. Utilizing a genomic repertoire of more than 1000 Variant Surface Glycoprotein-encoding genes (VSGs), T. brucei can change its protein coat by “switching” from the expression of one VSG to another. Each active VSG is monoallelically expre... | A broad array of human pathogens (including bacteria, fungi and parasites) vary the proteins on their cell surface to escape the immune response of their hosts. This process, called antigenic variation, relies on a repertoire of variant protein encoding genes in the genome and the organism's ability to accurately switc... | Trypanosoma brucei is an extracellular human pathogen with an unparalleled capacity to evade host humoral immunity. The causative agent of African sleeping sickness in humans and nagana in cattle, T. brucei is transmitted into the bloodstream of its host by a tsetse vector and can grow to densities as high as 109 cells... |
10.1371/journal.pgen.1001199 | Localization of a Guanylyl Cyclase to Chemosensory Cilia Requires the Novel Ciliary MYND Domain Protein DAF-25 | In harsh conditions, Caenorhabditis elegans arrests development to enter a non-aging, resistant diapause state called the dauer larva. Olfactory sensation modulates the TGF-β and insulin signaling pathways to control this developmental decision. Four mutant alleles of daf-25 (abnormal DAuer Formation) were isolated fro... | C. elegans mutants that either fail to form or arrest development as dauer larvae, a stress-resistant lifestage, usually have defects in genes involved in evolutionarily conserved signaling pathways. In this study, we identified the gene mutated in daf-25 mutant strains, which inappropriately arrest as dauer larvae and... | The dauer larva of Caenorhabditis elegans is an alternate third larval stage where a stress resistant, non-aging life plan is adopted in harsh environmental conditions [1]. Dauer larvae disperse and will resume development when conditions improve. The study of dauer formation has elucidated a complex gene network used ... |
10.1371/journal.pgen.1002070 | Finished Genome of the Fungal Wheat Pathogen Mycosphaerella graminicola Reveals Dispensome Structure, Chromosome Plasticity, and Stealth Pathogenesis | The plant-pathogenic fungus Mycosphaerella graminicola (asexual stage: Septoria tritici) causes septoria tritici blotch, a disease that greatly reduces the yield and quality of wheat. This disease is economically important in most wheat-growing areas worldwide and threatens global food production. Control of the diseas... | The plant-pathogenic fungus Mycosphaerella graminicola causes septoria tritici blotch, one of the most economically important diseases of wheat worldwide and a potential threat to global food production. Unlike most other plant pathogens, M. graminicola has a long latent period during which it seems able to evade host ... | The ascomycete fungus Mycosphaerella graminicola (Figure S1) causes septoria tritici blotch (STB), a foliar disease of wheat that poses a significant threat to global food production. Losses to STB can reduce yields of wheat by 30 to 50% with a huge economic impact [1]; global expenditures for fungicides to manage STB ... |
10.1371/journal.pgen.1005756 | Exonic Splicing Mutations Are More Prevalent than Currently Estimated and Can Be Predicted by Using In Silico Tools | The identification of a causal mutation is essential for molecular diagnosis and clinical management of many genetic disorders. However, even if next-generation exome sequencing has greatly improved the detection of nucleotide changes, the biological interpretation of most exonic variants remains challenging. Moreover,... | The biological interpretation of most disease-associated variants has become a real challenge, especially with the implementation of next-generation sequencing. Particular attention is typically given to protein-coding changes often neglecting the potential impact of exonic variants on RNA splicing. Here, we used the e... | Tremendous progress has been made in recent years in high-throughput technologies enabling fast and affordable massive parallel DNA sequencing. These methods are now being implemented both in molecular diagnostic settings and in basic research laboratories and hold great promise for discovering the genetic bases of rar... |
10.1371/journal.pgen.1003005 | Mining the Unknown: A Systems Approach to Metabolite Identification Combining Genetic and Metabolic Information | Recent genome-wide association studies (GWAS) with metabolomics data linked genetic variation in the human genome to differences in individual metabolite levels. A strong relevance of this metabolic individuality for biomedical and pharmaceutical research has been reported. However, a considerable amount of the molecul... | Genome-wide association studies on metabolomics data have demonstrated that genetic variation in metabolic enzymes and transporters leads to concentration changes in the respective metabolite levels. The conventional goal of these studies is the detection of novel interactions between the genome and the metabolic syste... | Recently, genome-wide association studies (GWAS) on metabolic quantitative traits have proven valuable tools to uncover the genetically determined metabolic individuality in the general population [1]–[5]. Interestingly, a great portion of the genetic loci that were found to significantly associate with levels of speci... |
10.1371/journal.pntd.0002282 | Mapping the Genes for Susceptibility and Response to Leishmania tropica in Mouse | L. tropica can cause both cutaneous and visceral leishmaniasis in humans. Although the L. tropica-induced cutaneous disease has been long known, its potential to visceralize in humans was recognized only recently. As nothing is known about the genetics of host responses to this infection and their clinical impact, we d... | Leishmaniasis, a disease caused by Leishmania ssp. is among the most neglected infectious diseases. In humans, L. tropica causes cutaneous form of leishmaniasis, but can damage internal organs too. The reasons for this variability are not known, and its genetic basis was never investigated. Therefore, analysis of genes... | Leishmaniasis is endemic in 98 countries on 5 continents, causing 20,000 to 40,000 deaths per year [1]. In the past decade the number of endemic regions have expanded, prevalence has increased and the number of unrecorded cases must have been substantial, because notification has been compulsory in only 32 of the 98 co... |
10.1371/journal.ppat.1004610 | Protective Efficacy of Centralized and Polyvalent Envelope Immunogens in an Attenuated Equine Lentivirus Vaccine | Lentiviral Envelope (Env) antigenic variation and related immune evasion present major hurdles to effective vaccine development. Centralized Env immunogens that minimize the genetic distance between vaccine proteins and circulating viral isolates are an area of increasing study in HIV vaccinology. To date, the efficacy... | Our best effort for containment of the global HIV epidemic is the development of a broadly protective vaccine. Current research has focused on vaccines that can generate a protective immune response against numerous strains of the virus. For this reason, vaccines with centralized HIV genes as immunogens, which merge HI... | The scientific community has aggressively sought after the development of a universal HIV vaccine that can prevail over the extraordinary levels of antigenic diversity in the fight against HIV and AIDS. The considerable extent of genomic variation found between isolates and within clades, and to a larger extent within ... |
10.1371/journal.pcbi.1005800 | Bayesian refinement of protein structures and ensembles against SAXS data using molecular dynamics | Small-angle X-ray scattering is an increasingly popular technique used to detect protein structures and ensembles in solution. However, the refinement of structures and ensembles against SAXS data is often ambiguous due to the low information content of SAXS data, unknown systematic errors, and unknown scattering contr... | In solution, many proteins adopt ensembles of multiple distinct states. The relative concentrations of the states are tightly controlled by factors such as pH, phosphorylation, or ligand binding, and a misbalance between the states underlies diseases such as cancer or neurodegeneration. However, detecting protein ensem... | Proteins are dynamic nanomachines that often populate heterogeneous ensembles of multiple distinct structural states. Controlling the relative population of such states is pivotal for the correct functioning of biological cells, and any misbalance between states may lead to severe conditions such as cancer or neurodege... |
10.1371/journal.pbio.2005853 | Mice learn to avoid regret | Regret can be defined as the subjective experience of recognizing that one has made a mistake and that a better alternative could have been selected. The experience of regret is thought to carry negative utility. This typically takes two distinct forms: augmenting immediate postregret valuations to make up for losses, ... | Regret describes a unique postdecision phenomenon in which losses are realized as a fault of one’s own actions. Regret is often hypothesized to have an inherent negative utility, and humans will often incur costs so as to avoid the risk of future regret. However, current models of nonhuman decision-making are based on ... | Regretful experiences comprise those in which an individual recognizes a better decision could have been made in the past. Humans assert a strong desire to avoid feeling regret [1]. Regret can have an immediate impact on influencing subsequent valuations, but it can also motivate individuals to learn to avoid future re... |
10.1371/journal.pmed.1002250 | Early diagnosis of mild cognitive impairment and mild dementia through basic and instrumental activities of daily living: Development of a new evaluation tool | Assessment of activities of daily living (ADL) is paramount to determine impairment in everyday functioning and to ensure accurate early diagnosis of neurocognitive disorders. Unfortunately, most common ADL tools are limited in their use in a diagnostic process. This study developed a new evaluation by adopting the ite... | Mild cognitive impairment (MCI) is seen as a transitional zone between normal aging and dementia.
Assessment of activities of daily living (ADL) is paramount to underpin accurate diagnostic classification in MCI and dementia.
Unfortunately, most common report-based ADL tools have limitations for diagnostic purposes.
We... | Health services are dealing with an increasing number of older patients. Although most seniors are in reasonably good health and living an active life, a considerable number of them are at risk of developing major chronic conditions and mental disorders such as dementia. Worldwide, it is estimated that dementia affects... |
10.1371/journal.pntd.0006181 | Household expenditure on leprosy outpatient services in the Indian health system: A comparative study | Leprosy is a major public health problem in many low and middle income countries, especially in India, and contributes considerably to the global burden of the disease. Leprosy and poverty are closely associated, and therefore the economic burden of leprosy is a concern. However, evidence on patient’s expenditure is sc... | Leprosy leads to low quality of life even after cure. The anaesthetic hands and feet leading to ulcers and deformities, stigma and poor mental health are just a few challenges. After declaration of leprosy elimination at global level, the research activities reduced significantly, and the health economics aspect was no... | Leprosy is caused by Mycobacterium leprae, affecting the peripheral skin, nerve and nasal mucosa [1]. The adverse impact of leprosy on human lives is serious due to nerve function impairment and disabilities. Moreover, the early manifestation of disability in the form of sensory loss of hands or feet, often fails to se... |
10.1371/journal.pcbi.1003569 | A Coarse-Grained Elastic Network Atom Contact Model and Its Use in the Simulation of Protein Dynamics and the Prediction of the Effect of Mutations | Normal mode analysis (NMA) methods are widely used to study dynamic aspects of protein structures. Two critical components of NMA methods are coarse-graining in the level of simplification used to represent protein structures and the choice of potential energy functional form. There is a trade-off between speed and acc... | Normal mode analysis (NMA) methods can be used to explore potential movements around an equilibrium conformation by mean of calculating the eigenvectors and eigenvalues associated to different normal modes. Each normal mode represents a global collective, correlated and complex, form of motion of the entire protein. An... | Biological macromolecules are dynamic objects. In the case of proteins, such movements form a continuum ranging from bond and angle vibrations, sub-rotameric and rotameric side-chain rearrangements [1], loop or domain movements through to folding. Such movements are closely related to function and play important roles ... |
10.1371/journal.pcbi.1005607 | Advances in using Internet searches to track dengue | Dengue is a mosquito-borne disease that threatens over half of the world’s population. Despite being endemic to more than 100 countries, government-led efforts and tools for timely identification and tracking of new infections are still lacking in many affected areas. Multiple methodologies that leverage the use of Int... | As communicable diseases spread in our societies, people frequently turn to the Internet to search for medical information. In recent years, multiple research teams have investigated how to utilize Internet users’ search activity to track infectious diseases around our planet. In this article, we show that a methodolog... | Dengue fever poses a growing health and economic problem throughout the tropical and sub-tropical world. Dengue is today one of the fastest-growing and most important mosquito-borne viral diseases in the world, with an estimated 390 million infections each year and threatening an estimated 3.9 billion people in 128 cou... |
10.1371/journal.pntd.0006762 | Contact tracing performance during the Ebola epidemic in Liberia, 2014-2015 | During the Ebola virus disease (EVD) epidemic in Liberia, contact tracing was implemented to rapidly detect new cases and prevent further transmission. We describe the scope and characteristics of contact tracing in Liberia and assess its performance during the 2014–2015 EVD epidemic.
We performed a retrospective descr... | Contact tracing is comprised of three main steps: identifying, listing, and monitoring persons who have been exposed to infected individuals, with the goal of rapidly diagnosing and treating new cases and preventing further spread of infection. This approach has been used to control transmission of infectious diseases ... | In March 2014, Liberia detected its first cases of Ebola virus disease (EVD) in Lofa, a northern county bordering Guinea and Sierra Leone [1]. The Liberian Ministry of Health (MOH) (formerly Ministry of Health and Social Welfare) established a national task force and initiated control efforts, including contact tracing... |
10.1371/journal.ppat.0030159 | Small-Molecule Inhibition of HIV pre-mRNA Splicing as a Novel Antiretroviral Therapy to Overcome Drug Resistance | The development of multidrug-resistant viruses compromises antiretroviral therapy efficacy and limits therapeutic options. Therefore, it is an ongoing task to identify new targets for antiretroviral therapy and to develop new drugs. Here, we show that an indole derivative (IDC16) that interferes with exonic splicing en... | Over the two decades highly active antiretroviral therapy (HAART) for the treatment of HIV infection has led to a significant decline in morbidity and mortality rates among HIV-infected individuals. HAART uses a combination of molecules that target the virus itself. However, naturally occurring and extensive genetic va... | The increasing prevalence of drug-resistant human immunodeficiency virus type 1 (HIV-1) has highlighted the challenging issue of the optimal treatment of HIV-1-infected patients [1–3]. Current routine drug regimens, typically consisting of various combinations of compounds targeting the viral proteins reverse transcrip... |
10.1371/journal.ppat.1005964 | HIV Cell-to-Cell Spread Results in Earlier Onset of Viral Gene Expression by Multiple Infections per Cell | Cell-to-cell spread of HIV, a directed mode of viral transmission, has been observed to be more rapid than cell-free infection. However, a mechanism for earlier onset of viral gene expression in cell-to-cell spread was previously uncharacterized. Here we used time-lapse microscopy combined with automated image analysis... | How quickly infection occurs should be an important determinant of viral fitness, but mechanisms which could accelerate the onset of viral gene expression were previously undefined. In this work we use time-lapse microscopy to quantify the timing of the HIV viral cycle and show that onset of viral gene expression can b... | Cell-to-cell spread of HIV is a mechanism of viral transmission whereby interaction between an infected donor cell and an infectable target cell leads to the directed transmission of virions to the target cell. Such interactions can occur between donor and target cells by various mechanisms [1–12], all of which involve... |
10.1371/journal.pcbi.1003926 | ECOD: An Evolutionary Classification of Protein Domains | Understanding the evolution of a protein, including both close and distant relationships, often reveals insight into its structure and function. Fast and easy access to such up-to-date information facilitates research. We have developed a hierarchical evolutionary classification of all proteins with experimentally dete... | Protein structural domain databases offer a vital resource for structural bioinformatics. These databases provide functional inference for homologous structures, supply templates for structural prediction experiments, and differentiate between homologs and analogs. The rate of structure determination and deposition has... | The billions of proteins in extant species constitute a bewilderingly diverse protein world. To understand this world, systematic classifications are needed to reduce its complexity and to bring order to its relationships. As proteins are the products of evolution, their phylogeny provides a natural foundation for a me... |
10.1371/journal.pntd.0004681 | Predicting Dengue Fever Outbreaks in French Guiana Using Climate Indicators | Dengue fever epidemic dynamics are driven by complex interactions between hosts, vectors and viruses. Associations between climate and dengue have been studied around the world, but the results have shown that the impact of the climate can vary widely from one study site to another. In French Guiana, climate-based mode... | Climatic determinants are amongst the most frequently cited in studies aimed at understanding and explaining the dynamics of vector-borne infections, and dengue in particular. French Guiana, a French overseas territory in which the vector Aedes aegypti is well established, experiences an epidemic cycle of dengue with l... | Dengue fever (DF) is one of the most important mosquito-borne diseases in the world [1,2]. Recent estimates indicate that there are 390 million dengue infections per year, of which 96 million manifest as disease [3]. Infection is caused by the dengue virus (DENV), which has four closely related serotypes (DENV1 to DENV... |
10.1371/journal.pgen.1007816 | BLM prevents instability of structure-forming DNA sequences at common fragile sites | Genome instability often arises at common fragile sites (CFSs) leading to cancer-associated chromosomal rearrangements. However, the underlying mechanisms of how CFS protection is achieved is not well understood. We demonstrate that BLM plays an important role in the maintenance of genome stability of structure-forming... | Common fragile sites (CFSs) are large chromosomal regions which are more prone to breakage than other places in the genome. They are a part of normal chromosome structure and are present in all human beings, but are also hotspots for chromosomal rearrangement during oncogenesis. Understanding how CFSs are protected to ... | Genome instability is a hallmark of cancer cells [1]. Certain chromosomal loci, such as CFSs are hotspots for genome instability and are prone to chromosomal rearrangement [2]. CFSs are part of normal chromosomal regions that are present in all individuals, but are more susceptible to breakage than other genome loci un... |
10.1371/journal.pcbi.1004883 | Modularity Induced Gating and Delays in Neuronal Networks | Neural networks, despite their highly interconnected nature, exhibit distinctly localized and gated activation. Modularity, a distinctive feature of neural networks, has been recently proposed as an important parameter determining the manner by which networks support activity propagation. Here we use an engineered biol... | The capacity to transmit information between connected parts of a neuronal network is fundamental to its function. The organization of network connections (the topology of the network) is therefore expected to play an important role in determining network transmission. Since modular topology characterizes many brain ci... | Activity gating and control over propagation are fundamental capacities of neural circuits. It is widely accepted that population-level gating is strongly affected by changing the balance between excitation and inhibition in connected sub-populations of neurons [1–6]. However, while the role of excitation-inhibition ha... |
10.1371/journal.pgen.1006117 | Chromosomal Translocations in the Parasite Leishmania by a MRE11/RAD50-Independent Microhomology-Mediated End Joining Mechanism | The parasite Leishmania often relies on gene rearrangements to survive stressful environments. However, safeguarding a minimum level of genome integrity is important for cell survival. We hypothesized that maintenance of genomic integrity in Leishmania would imply a leading role of the MRE11 and RAD50 proteins consider... | The parasite Leishmania relies on gene rearrangements to survive stressful conditions. However, maintaining a minimum level of genomic integrity is crucial for cell survival. Studies in other organisms have provided evidence that the DNA repair proteins MRE11 and RAD50 are involved in chromosomes organization, protecti... | Genomic integrity maintenance is essential for cellular development and viability [1–3]. Failure to repair DNA will lead to genomic instability (reviewed in [4–7]). DNA structural changes can manifest as inversion, deletion, duplication, translocation, chromosome end-to-end fusion, aneuploidy [8–10] and some of these e... |
10.1371/journal.pgen.1004225 | An Insulin-to-Insulin Regulatory Network Orchestrates Phenotypic Specificity in Development and Physiology | Insulin-like peptides (ILPs) play highly conserved roles in development and physiology. Most animal genomes encode multiple ILPs. Here we identify mechanisms for how the forty Caenorhabditis elegans ILPs coordinate diverse processes, including development, reproduction, longevity and several specific stress responses. ... | Insulin signaling is widely implicated in regulating diverse physiological processes ranging from metabolism to longevity across many animal species. Many animals have multiple insulin-like peptides that can regulate the activity of this signaling pathway. For example, while humans have ten, including the well-studied ... | The organization and integration of multiple signals endow intercellular regulatory networks with information processing capabilities. For example, hormones modulate physiology and maintain homeostasis in variable environments [reviewed in 1], and morphogens give rise to intricate patterns during development [reviewed ... |
10.1371/journal.pntd.0006372 | Risk factors for human acute leptospirosis in northern Tanzania | Leptospirosis is a major cause of febrile illness in Africa but little is known about risk factors for human infection. We conducted a cross-sectional study to investigate risk factors for acute leptospirosis and Leptospira seropositivity among patients with fever attending referral hospitals in northern Tanzania.
We e... | Leptospirosis is an under-recognized but important cause of febrile illness and death in Africa. The bacteria that cause leptospirosis have their usual life cycle in animals; humans are infected as accidental hosts. There is considerable variation between countries as to which reservoir animals and human activities are... | Leptospirosis is a zoonotic bacterial infection and is increasingly recognized as an important cause of fever in Africa [1]. Leptospirosis was a leading cause of severe febrile illness in a study conducted in northern Tanzania during 2007–8, where it was diagnosed in 8.8% of participants [2]. The annual incidence of se... |
10.1371/journal.pcbi.1000179 | Discarding Functional Residues from the Substitution Table Improves Predictions of Active Sites within Three-Dimensional Structures | Substitutions of individual amino acids in proteins may be under very different evolutionary restraints depending on their structural and functional roles. The Environment Specific Substitution Table (ESST) describes the pattern of substitutions in terms of amino acid location within elements of secondary structure, so... | Identification of residues responsible for a specific function of a protein can provide clues about the mechanism of action. Computational approaches to identifying functional residues have emerged as low-cost alternatives to experimental methods by providing fast and large-scale analyses. Moreover, the demand for such... | Proteins existing in living organisms have been selected through the process of evolution. However, much of the amino acid variation between orthologues appears to be selectively neutral [1] as far as the whole organism is concerned and accepted amino acid substitutions result in equal fitness. It has been long underst... |
10.1371/journal.pntd.0001420 | Activation of the Innate Immune Response against DENV in Normal Non-Transformed Human Fibroblasts | When mosquitoes infected with DENV are feeding, the proboscis must traverse the epidermis several times (“probing”) before reaching a blood vessel in the dermis. During this process, the salivary glands release the virus, which is likely to interact first with cells of the various epidermal and dermal layers, cells whi... | In this work, we demonstrate that that both human whole skin and freshly isolated skin fibroblasts are productively infected with Dengue virus (DENV). In addition, primary skin fibroblast cultures were established and subsequently infected with DENV-2; we showed in these cells the presence of the viral antigen NS3, and... | Dengue virus (DENV) has become one of the most important arthropod-borne viral infections of humans, with approximately 100 million cases per year. The etiological agent is a positive-sense, single-stranded RNA virus that belongs to the Flaviviridae family, of which there are four antigenically related serotypes (DENV-... |
10.1371/journal.pbio.1001031 | Direct Observation of the Myosin Va Recovery Stroke That Contributes
to Unidirectional Stepping along Actin | Myosins are ATP-driven linear molecular motors that work as cellular force
generators, transporters, and force sensors. These functions are driven by
large-scale nucleotide-dependent conformational changes, termed
“strokes”; the “power stroke” is the force-gen... | Myosin Va is a “two-legged” ATP-dependent linear molecular motor that
transports cellular organelles by “stepping” along actin filaments
in a processive manner analogous to human walking, the two “feet”
alternating between forward and backward positions. Durin... | Myosin is an ATP-driven linear molecular motor that produces force and unidirectional
movement along actin filaments. The “swinging lever arm” hypothesis
proposes that small nucleotide-dependent movements at the catalytic ATPase active
site are amplified by rotation of th... |
10.1371/journal.ppat.1005555 | FleA Expression in Aspergillus fumigatus Is Recognized by Fucosylated Structures on Mucins and Macrophages to Prevent Lung Infection | The immune mechanisms that recognize inhaled Aspergillus fumigatus conidia to promote their elimination from the lungs are incompletely understood. FleA is a lectin expressed by Aspergillus fumigatus that has twelve binding sites for fucosylated structures that are abundant in the glycan coats of multiple plant and ani... | Inhaled Aspergillus fumigatus conidia are effectively eliminated from the lung by the coordinated actions of mucociliary clearance and macrophage killing, but the mechanisms of attachment of Aspergillus fumigatus (A. fumigatus) conidia to the airway mucus gel are unknown. In addition, the mechanisms of phagocytosis of ... | Aspergillus fumigatus (A. fumigatus) is an ubiquitous opportunistic pathogen that causes invasive and often fatal lung infection, particularly in immunocompromised patients [1]. Aspergillus fumigatus produces small hydrophobic conidia that are easily inhaled into the lungs and require robust host defense mechanisms to ... |
10.1371/journal.pgen.1004254 | Worldwide Patterns of Ancestry, Divergence, and Admixture in Domesticated Cattle | The domestication and development of cattle has considerably impacted human societies, but the histories of cattle breeds and populations have been poorly understood especially for African, Asian, and American breeds. Using genotypes from 43,043 autosomal single nucleotide polymorphism markers scored in 1,543 animals, ... | The DNA of domesticated plants and animals contains information about how species were domesticated, exported, and bred by early farmers. Modern breeds were developed by lengthy and complex processes; however, our use of 134 breeds and new analytical models enabled us to reveal some of the processes that created modern... | High-throughput genotyping assays have allowed population geneticists to use genome-wide marker sets to analyze the histories of many species, including human [1], cattle [2]–[4], sheep [5], dog [6], horse [7], yeast [8], mouse [9], [10], rice [11], [12], maize [13]–[16], grape [17], and wheat [18]. We previously descr... |
10.1371/journal.ppat.1000863 | In Vitro Reconstitution of SARS-Coronavirus mRNA Cap Methylation | SARS-coronavirus (SARS-CoV) genome expression depends on the synthesis of a set of mRNAs, which presumably are capped at their 5′ end and direct the synthesis of all viral proteins in the infected cell. Sixteen viral non-structural proteins (nsp1 to nsp16) constitute an unusually large replicase complex, which includes... | In 2003, an emerging coronavirus (CoV) was identified as the etiological agent of severe acute respiratory syndrome (SARS). SARS-CoV replicates and transcribes its large RNA genome using a membrane-bound enzyme complex containing a variety of viral nonstructural proteins. A critical step during RNA synthesis is the add... | In 2003, the severe acute respiratory syndrome coronavirus (SARS-CoV), which was likely transmitted from bats, was responsible for a worldwide SARS-outbreak [1]. Coronaviruses belong to the order Nidovirales and are characterized by the largest positive-strand RNA ((+) RNA) genomes (around 30,000 nt) known in the virus... |
10.1371/journal.pcbi.1007015 | Evolution of major histocompatibility complex gene copy number | MHC genes, which code for proteins responsible for presenting pathogen-derived antigens to the host immune system, show remarkable copy-number variation both between and within species. However, the evolutionary forces driving this variation are poorly understood. Here, we use computer simulations to investigate whethe... | Highly polymorphic genes of the Major Histocompatibility Complex (MHC) code for proteins responsible for presenting antigens to lymphocytes, thus initiating adaptive immune response. The polymorphism is driven by coevolution with parasites which are selected to evade recognition by MHC proteins. Expressing many MHC mol... | Major histocompatibility complex (MHC) genes code for proteins that present pathogen-derived oligopeptides (antigens) to T-cells, thus initiating an adaptive immune response. MHC genes are highly polymorphic, with dozens to hundreds of variants typically segregating in natural populations (reviewed in [1–3]). This extr... |
10.1371/journal.pgen.1007395 | Distinctive types of postzygotic single-nucleotide mosaicisms in healthy individuals revealed by genome-wide profiling of multiple organs | Postzygotic single-nucleotide mosaicisms (pSNMs) have been extensively studied in tumors and are known to play critical roles in tumorigenesis. However, the patterns and origin of pSNMs in normal organs of healthy humans remain largely unknown. Using whole-genome sequencing and ultra-deep amplicon re-sequencing, we ide... | Genomic mosaicism led by postzygotic mutation is the major cause of cancers and many non-cancer developmental disorders. Theoretically, postzygotic mutations should be accumulated during the developmental process of healthy individuals, but the genome-wide characterization of postzygotic mosaicisms across many organ ty... | Postzygotic mutations refer to DNA changes arising after the formation of the zygote that lead to genomic mosaicisms in a single individual [1, 2]. Unlike de novo or inherited germline mutations, postzygotic mutations only affect a fraction of cells in multicellular organisms, and individuals carrying a functional mosa... |
10.1371/journal.pntd.0004724 | Genomic African and Native American Ancestry and Chagas Disease: The Bambui (Brazil) Epigen Cohort Study of Aging | The influence of genetic ancestry on Trypanosoma cruzi infection and Chagas disease outcomes is unknown.
We used 370,539 Single Nucleotide Polymorphisms (SNPs) to examine the association between individual proportions of African, European and Native American genomic ancestry with T. cruzi infection and related outcomes... | Chagas disease (ChD), which is caused by the protozoan Trypanosoma cruzi, affects approximately 8 million people worldwide. ChD is known as a neglected tropical disease. The disease is endemic in South and Central American countries, and is an emerging issue in North America and Europe. This study examined, for the fir... | Chagas disease (ChD), which is caused by the protozoan Trypanosoma cruzi, affects approximately 5.7 million people in 21 Latin American countries [1]. ChD is known as a neglected tropical disease and is an emerging issue in North America and Europe [2–5]. ChD is autochthonous in South and Central America but T. cruzi i... |
10.1371/journal.pgen.1004526 | Asymmetric Division and Differential Gene Expression during a Bacterial Developmental Program Requires DivIVA | Sporulation in the bacterium Bacillus subtilis is a developmental program in which a progenitor cell differentiates into two different cell types, the smaller of which eventually becomes a dormant cell called a spore. The process begins with an asymmetric cell division event, followed by the activation of a transcripti... | A central feature of developmental programs is the establishment of asymmetry and the production of genetically identical daughter cells that display different cell fates. Sporulation in the bacterium Bacillus subtilis is a simple developmental program in which the cell divides asymmetrically to produce two daughter ce... | Asymmetric cell division and differential gene expression are hallmarks that underlie the differentiation of a progenitor cell into two genetically identical, but morphologically dissimilar daughter cells [1]–[5]. The rod shaped Gram-positive bacterium Bacillus subtilis, which normally divides by binary fission to prod... |
10.1371/journal.pgen.1007617 | Tudor-domain containing protein 5-like promotes male sexual identity in the Drosophila germline and is repressed in females by Sex lethal | For sexually reproducing organisms, production of male or female gametes depends on specifying the correct sexual identity in the germline. In D. melanogaster, Sex lethal (Sxl) is the key gene that controls sex determination in both the soma and the germline, but how it does so in the germline is unknown, other than th... | Like humans, all sexually reproducing organisms require gametes to reproduce. Gametes are made by specialized cells called germ cells, which must have the correct sexual identity information to properly make sperm or eggs. In fruit flies, germ cell sexual identity is controlled by the RNA-binding protein Sxl, which is ... | Sex determination is an essential process in sexually reproducing species, as the production of eggs and sperm depends on the sexual identity of the germ cells and somatic cells of the gonad. In some animals, such as the medaka fish and the house fly, the sexual identity of the soma determines the sexual identity of th... |
10.1371/journal.pgen.1007023 | High rate of adaptation of mammalian proteins that interact with Plasmodium and related parasites | Plasmodium parasites, along with their Piroplasm relatives, have caused malaria-like illnesses in terrestrial mammals for millions of years. Several Plasmodium-protective alleles have recently evolved in human populations, but little is known about host adaptation to blood parasites over deeper evolutionary timescales.... | Malaria caused by the parasite Plasmodium falciparum remains the third-most deadly infectious disease of humans. Over the last 75,000 years, partial genetic resistance to malaria has evolved several times, earning malaria the title of "one of the strongest selective forces on the human genome." Yet, these human adaptat... | Malaria is one of the world's most notorious infectious diseases, responsible for billions of illnesses and millions of deaths in the last fifty years alone [1]. Human malaria is caused by five species in the genus Plasmodium, which are evolutionarily related to Babesia, Theileria, and other parasites in the order Piro... |
10.1371/journal.pntd.0006238 | Developing a Buruli ulcer community of practice in Bankim, Cameroon: A model for Buruli ulcer outreach in Africa | In the Cameroon, previous efforts to identify Buruli ulcer (BU) through the mobilization of community health workers (CHWs) yielded poor results. In this paper, we describe the successful creation of a BU community of practice (BUCOP) in Bankim, Cameroon composed of hospital staff, former patients, CHWs, and traditiona... | Buruli ulcer (BU) is a neglected tropical disease primarily found in West Africa largely effecting the rural poor. BU has a known cause and cure, but an unknown route of transmission and a poorly understood incubation period. If not treated early and in a timely manner, BU often progresses to an advanced state requirin... | Buruli ulcer (BU) is one of several neglected tropical skin diseases that afflict the rural population of sub-Saharan Africa, especially the poor living in areas with limited access to health infrastructure [1,2]. BU stands out as one of the most disabling of all neglected tropical diseases. The large majority of cases... |
10.1371/journal.pgen.1002199 | Genome-Wide Association Analysis of Incident Coronary Heart Disease (CHD) in African Americans: A Short Report | African Americans have the highest rate of mortality due to coronary heart disease (CHD). Although multiple loci have been identified influencing CHD risk in European-Americans using a genome-wide association (GWAS) approach, no GWAS of incident CHD has been reported for African Americans. We performed a GWAS for incid... | In the United States, African Americans are at high risk for coronary heart disease (CHD). Although environmental and social factors have a role, genetic factors also contribute to CHD risk and mortality. Research to identify genetic factors for CHD susceptibility has been carried out mostly in Europeans and European A... | Coronary heart disease (CHD) is the leading cause of death worldwide [1]. In the United States, African Americans are the most vulnerable population with regard to CHD risk factors and mortality. A recent American Heart Association report showed that African Americans are twice as likely to die from a heart-related dis... |
10.1371/journal.ppat.1006810 | Memory CD8 T cells mediate severe immunopathology following respiratory syncytial virus infection | Memory CD8 T cells can provide protection from re-infection by respiratory viruses such as influenza and SARS. However, the relative contribution of memory CD8 T cells in providing protection against respiratory syncytial virus (RSV) infection is currently unclear. To address this knowledge gap, we utilized a prime-boo... | Memory CD8 T cells have been shown to provide protection against many respiratory viruses. However, the ability of memory CD8 T cells to provide protection against RSV has not been extensively examined. Unexpectedly, mice with pre-existing CD8 T cell memory, in the absence of memory CD4 T cells and antibodies, exhibite... | Respiratory syncytial virus (RSV) is a major cause of severe disease in young children, the elderly, and immunocompromised populations [1–6]. Furthermore, RSV is the leading cause of infant hospitalizations creating an immense healthcare burden for treatment and prevention [1, 2, 7–11]. There is currently no licensed v... |
10.1371/journal.pntd.0002586 | Impact of Six Rounds of Mass Drug Administration on Brugian Filariasis and Soil-Transmitted Helminth Infections in Eastern Indonesia | The lymphatic filarial parasite Brugia timori occurs only in eastern Indonesia where it causes high morbidity. The absence of an animal reservoir, the inefficient transmission by Anopheles mosquitoes and the high sensitivity to DEC/albendazole treatment make this species a prime candidate for elimination by mass drug a... | The impact of six annual rounds of mass drug administration (MDA) using DEC combined with albendazole on brugian filariasis and soil-transmitted helminths (STH) was evaluated. Microfilaria rates of B. timori dropped quickly after MDA and were below 1% for 34 months after stopping intervention when the study ended. The ... | Lymphatic filariasis (LF) has been targeted by the World Health Organization for global elimination by the year 2020 [1]. During the years 2000 to 2009 the Global Program to Eliminate Lymphatic Filariasis (GPELF) has provided >2.8 billion treatments with anti-filarial drugs to a minimum of 885 million individuals livin... |
10.1371/journal.ppat.1002372 | Galactosaminogalactan, a New Immunosuppressive Polysaccharide of Aspergillus fumigatus | A new polysaccharide secreted by the human opportunistic fungal pathogen Aspergillus fumigatus has been characterized. Carbohydrate analysis using specific chemical degradations, mass spectrometry, 1H and 13C nuclear magnetic resonance showed that this polysaccharide is a linear heterogeneous galactosaminogalactan comp... | Aspergillus fumigatus is an opportunistic human fungal pathogen that causes a wide range of diseases including allergic reactions and local or systemic infections such as invasive pulmonary aspergillosis that has emerged in the recent years as a leading cause of infection related mortality among immunocompromised patie... | Aspergillus fumigatus is an opportunistic human fungal pathogen that causes a wide range of diseases including allergic reactions and local or systemic infections such as invasive pulmonary aspergillosis (IA) that has emerged in recent years as a leading cause of infection-related mortality among immunocompromised pati... |
10.1371/journal.ppat.1004751 | CD169-Mediated Trafficking of HIV to Plasma Membrane Invaginations in Dendritic Cells Attenuates Efficacy of Anti-gp120 Broadly Neutralizing Antibodies | Myeloid dendritic cells (DCs) can capture HIV-1 via the receptor CD169/Siglec-1 that binds to the ganglioside, GM3, in the virus particle membrane. In turn, HIV-1 particles captured by CD169, an I-type lectin, whose expression on DCs is enhanced upon maturation with LPS, are protected from degradation in CD169+ virus-c... | Dendritic cells (DCs) are professional antigen presenting cells, and their sentinel roles are important to elicit a potent antiviral immunity. However, HIV-1 has exploited DCs to spread infection by several mechanisms. One such mechanism is the DC-mediated trans-infection pathway, whereby DCs transmit captured virus to... | Myeloid dendritic cells (DCs) are professional antigen presenting cells that play sentinel roles in sensing pathogens and priming adaptive immunity [1]. HIV has, however, exploited DCs to spread to CD4+ T cells and thus DCs have been suggested to play a role in systemic HIV dissemination from peripheral mucosa to secon... |
10.1371/journal.pgen.1005372 | Arabidopsis PCH2 Mediates Meiotic Chromosome Remodeling and Maturation of Crossovers | Meiotic chromosomes are organized into linear looped chromatin arrays by a protein axis localized along the loop-bases. Programmed remodelling of the axis occurs during prophase I of meiosis. Structured illumination microscopy (SIM) has revealed dynamic changes in the chromosome axis in Arabidopsis thaliana and Brassic... | In the reproductive cells of many eukaryotes, a process called meiosis generates haploid gametes. During meiosis, homologous parental chromosomes (homologs) recombine forming crossovers (CO) that provide genetic variation. CO formation generates physical links called chiasmata, which are essential for accurate homolog ... | During meiosis genetic crossovers (COs), the products of homologous recombination, in conjunction with sister chromatid cohesion establish physical links, referred to cytologically as chiasmata, between homologous chromosome pairs (homologs) to ensure accurate chromosome segregation at the first nuclear division that f... |
10.1371/journal.ppat.1005774 | Elevated Basal Pre-infection CXCL10 in Plasma and in the Small Intestine after Infection Are Associated with More Rapid HIV/SIV Disease Onset | Elevated blood CXCL10/IP-10 levels during primary HIV-1 infection (PHI) were described as an independent marker of rapid disease onset, more robust than peak viremia or CD4 cell nadir. IP-10 enhances the recruitment of CXCR3+ cells, which include major HIV-target cells, raising the question if it promotes the establish... | Chronic immune activation is a hallmark of HIV infection and contributes in multiple ways to HIV persistence. Here, we gained insights on the association between a pro-inflammatory chemokine, CXCL10/IP-10 and HIV infection in four cohorts of HIV+ individuals, studied at distinct stages of infection (before, primary and... | Chronic immune activation is a hallmark of HIV infection [1]. Effective combined-antiretroviral therapy (cART) reduces HIV viremia to undetectable levels, but milder chronic immune activation nonetheless persists and is associated with onset of both AIDS and non-AIDS illnesses [2, 3]. The mechanisms fuelling chronic in... |
10.1371/journal.ppat.1006060 | Disrupting Mosquito Reproduction and Parasite Development for Malaria Control | The control of mosquito populations with insecticide treated bed nets and indoor residual sprays remains the cornerstone of malaria reduction and elimination programs. In light of widespread insecticide resistance in mosquitoes, however, alternative strategies for reducing transmission by the mosquito vector are urgent... | Mosquito control is the only intervention that can reduce malaria transmission from very high levels to close to zero. However, current mosquito control methods are severely threatened by the rapid spread of insecticide resistance in anopheline mosquito populations that transmit the malaria-causing Plasmodium parasites... | Despite recent progress in combating the malaria parasite, nearly 200 million infections and around 500,000 deaths are caused by malaria annually, mostly in young children in sub-Saharan Africa [1, 2]. Even with new drugs and vaccines in the research pipeline [3], control of the Anopheles species that transmit human ma... |
10.1371/journal.ppat.1004302 | The Murine Gammaherpesvirus Immediate-Early Rta Synergizes with IRF4, Targeting Expression of the Viral M1 Superantigen to Plasma Cells | MHV68 is a murine gammaherpesvirus that infects laboratory mice and thus provides a tractable small animal model for characterizing critical aspects of gammaherpesvirus pathogenesis. Having evolved with their natural host, herpesviruses encode numerous gene products that are involved in modulating host immune responses... | Through coevolution with their hosts, gammaherpesviruses have acquired unique genes that aid in infection of a particular host. Here we study the regulation of the MHV68 M1 gene, which encodes a protein that modulates the host immune response. Using a strategy that allowed us to identify MHV68 infected cells in mice, w... | MHV68 is a naturally occurring murid gammaherpesvirus that has significant genetic and functional homology to the human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV). Among herpesviruses, there are a large number of genes involved in virus replication that are conserved ... |
10.1371/journal.pntd.0001970 | Chronic Helminth Infection Does Not Exacerbate Mycobacterium tuberculosis Infection | Chronic helminth infections induce a Th2 immune shift and establish an immunoregulatory milieu. As both of these responses can suppress Th1 immunity, which is necessary for control of Mycobacterium tuberculosis (MTB) infection, we hypothesized that chronic helminth infections may exacerbate the course of MTB.
Co-infect... | Tuberculosis prevalence is high in areas that are endemic for helminths, suggesting that many people are chronically infected with both pathogens. As parasitic helminths can suppress the host immune system to facilitate their own survival, they frequently impact the host immune response to bystander antigens. Thus, whi... | Tuberculosis and helminth infections affect approximately one third of the world's population. The geographic distributions of both diseases overlap substantially, making co-infections with both pathogens common.
In contrast to infections with most bacterial, viral, protozoan, and fungal pathogens, chronic helmi... |
10.1371/journal.pgen.1005390 | A Role for Macro-ER-Phagy in ER Quality Control | The endoplasmic-reticulum quality-control (ERQC) system shuttles misfolded proteins for degradation by the proteasome through the well-defined ER-associated degradation (ERAD) pathway. In contrast, very little is known about the role of autophagy in ERQC. Macro-autophagy, a collection of pathways that deliver proteins ... | ER-quality control (ERQC) ensures delivery of “native” proteins through the secretory pathway. Currently, ER-associated degradation (ERAD), which delivers misfolded proteins for degradation by the proteasome, is considered a major ERQC pathway, with autophagy as its backup. Until now, the role of autophagy, which shutt... | One third of all newly synthesized proteins enter the endoplasmic reticulum (ER). However, only a small fraction is transported to their final destination. A large fraction (30–75%) fails to fold and mature properly, does not pass the ER quality control (ERQC) and gets degraded [1]. Two different cellular pathways shut... |
10.1371/journal.pgen.1007220 | Potential and limits for rapid genetic adaptation to warming in a Great Barrier Reef coral | Can genetic adaptation in reef-building corals keep pace with the current rate of sea surface warming? Here we combine population genomics, biophysical modeling, and evolutionary simulations to predict future adaptation of the common coral Acropora millepora on the Great Barrier Reef (GBR). Genomics-derived migration r... | Coral reefs worldwide are suffering high mortality from severe thermal stress episodes induced by acute ocean warming events. Under the current rate of warming, will corals be gone before the end of this century? Here we combine population genomics with biophysical and evolutionary modeling to investigate adaptive pote... | Mass coral bleaching, caused by global warming, is devastating coral reefs around the world [1] but there is room for hope if corals can adapt to increasing temperatures from generation to generation [2]. Many coral species have wide distributions that span environments that differ dramatically in their thermal regimes... |
10.1371/journal.ppat.1002119 | Clathrin Facilitates the Morphogenesis of Retrovirus Particles | The morphogenesis of retroviral particles is driven by Gag and GagPol proteins that provide the major structural component and enzymatic activities required for particle assembly and maturation. In addition, a number of cellular proteins are found in retrovirus particles; some of these are important for viral replicati... | The assembly and maturation of infectious retroviruses is driven by two viral proteins, Gag and Pol. Additionally, a number of cellular proteins are found in retrovirus particles, many of which lack a known functional role. One such protein is clathrin, which normally mediates several physiological processes in cells a... | To establish a productive infection in host cells, retroviruses have evolved strategies that employ numerous host factors to facilitate their replication. Recently, several groups have applied genome-wide RNAi screens to identify hundreds of candidate host factors that may facilitate human immunodeficiency virus-1 (HIV... |
10.1371/journal.ppat.1003706 | CXCR3-Dependent CD4+ T Cells Are Required to Activate Inflammatory Monocytes for Defense against Intestinal Infection | Chemokines and their receptors play a critical role in orchestrating immunity to microbial pathogens, including the orally acquired Th1-inducing protozoan parasite Toxoplasma gondii. Chemokine receptor CXCR3 is associated with Th1 responses, and here we use bicistronic CXCR3-eGFP knock-in reporter mice to demonstrate u... | Inflammatory monocytes have recently emerged as important effectors in intestinal defense against enteric pathogens, but requirements for their activation are poorly defined. Here we use the protozoan Toxoplasma gondii, an orally acquired Th1-inducing pathogen, to study the requirements for inflammatory macrophage acti... | The intestinal mucosa is a critical effector site for elimination of enteric pathogens. Toxoplasma gondii, a ubiquitous protozoan parasite, is a prime example of such a pathogen. Mammals are infected with T. gondii primarily by the ingestion of tissue cysts from undercooked meat or oocysts excreted in the feces of feli... |
10.1371/journal.pntd.0005748 | Lymphatic filariasis patient identification in a large urban area of Tanzania: An application of a community-led mHealth system | Lymphatic filariasis (LF) is best known for the disabling and disfiguring clinical conditions that infected patients can develop; providing care for these individuals is a major goal of the Global Programme to Eliminate LF. Methods of locating these patients, knowing their true number and thus providing care for them, ... | Lymphatic filariasis (LF) can cause disabling conditions in infected patients including lymphoedema-elephantiasis (LE) and hydrocoele. Identifying the number and locations of these patients is the first step towards ensuring that these patients receive the care they require, however there is currently no standardised a... | Lymphatic filariasis (LF) is a neglected tropical disease (NTD) that can have a devastating impact on affected individuals, with clinical symptoms such as acute dermatolymphangioadenitis (ADLA, “acute attacks”), lymphoedema and elephantiasis, and hydrocoele, causing physical, mental and economic distress [1–6]. In reco... |
10.1371/journal.ppat.1002064 | Endemic Dengue Associated with the Co-Circulation of Multiple Viral Lineages and Localized Density-Dependent Transmission | Dengue is one of the most important infectious diseases of humans and has spread throughout much of the tropical and subtropical world. Despite this widespread dispersal, the determinants of dengue transmission in endemic populations are not well understood, although essential for virus control. To address this issue w... | Although dengue is a major cause of morbidity in many tropical and subtropical regions of the world, little is known about how the causative virus (dengue virus, DENV) spreads through endemic populations. To address this issue we undertook a phylogeny-based analysis of 751 complete genome sequences of DENV-1 sampled fr... | Dengue is the most important mosquito-borne viral disease of humans, annually responsible for approximately 40 million cases and some 20,000 deaths in tropical and subtropical regions [1]. Dengue is caused by one of four single-stranded positive-sense RNA viruses (DENV-1 to DENV-4, also referred to as serotypes) of the... |
10.1371/journal.pcbi.1004655 | Persistent Chaos of Measles Epidemics in the Prevaccination United States Caused by a Small Change in Seasonal Transmission Patterns | Epidemics of infectious diseases often occur in predictable limit cycles. Theory suggests these cycles can be disrupted by high amplitude seasonal fluctuations in transmission rates, resulting in deterministic chaos. However, persistent deterministic chaos has never been observed, in part because sufficiently large osc... | Measles epidemics continue to pose a significant public health risk wherever vaccination coverage is low. In such populations transmission rates tend to fluctuate seasonally, mirroring patterns of human aggregation, due to the timing of school terms, and/or the migration of workers and their families. Here we show empi... | Acute immunizing infections remain a leading cause of death worldwide, and have accounted for a significant portion of all morbidity and mortality throughout human history, especially among children and in countries without adequate vaccination coverage [1–4]. Understanding the processes that determine epidemic pattern... |
10.1371/journal.ppat.1004304 | EBNA3C Augments Pim-1 Mediated Phosphorylation and Degradation of p21 to Promote B-Cell Proliferation | Epstein–Barr virus (EBV), a ubiquitous human herpesvirus, can latently infect the human population. EBV is associated with several types of malignancies originating from lymphoid and epithelial cell types. EBV latent antigen 3C (EBNA3C) is essential for EBV-induced immortalization of B-cells. The Moloney murine leukemi... | The oncogenic serine/threonine kinase Pim-1 is upregulated in a number of human cancers including lymphomas, gastric, colorectal and prostate carcinomas. EBV nuclear antigen 3C (EBNA3C) is essential for EBV-induced transformation of human primary B-lymphocytes. Our current study revealed that EBNA3C significantly enhan... | Epstein-Barr virus (EBV), a ubiquitous lymphotropic herpesvirus, latently infects human populations worldwide [1]. EBV infection is typically asymptomatic and is an important etiological factor which contributes to different human malignancies [2]. EBV is consistently associated with nasopharyngeal carcinoma (NPC) [3],... |
10.1371/journal.pntd.0004704 | Using Rapid Diagnostic Tests as a Source of Viral RNA for Dengue Serotyping by RT-PCR - A Novel Epidemiological Tool | Dengue virus infection causes major public health problems in tropical and subtropical areas. In many endemic areas, including the Lao PDR, inadequate access to laboratory facilities is a major obstacle to surveillance and study of dengue epidemiology. Filter paper is widely used for blood collection for subsequent lab... | Dengue fever, caused by a virus transmitted by mosquitoes, is a public health problem in tropical and subtropical regions. Dengue Rapid Diagnostic Tests, in which a drop of blood is loaded onto a paper strip in a plastic cassette, are simple to use and have good diagnostic accuracy. They are becoming the test of choice... | The dengue virus (DENV) is an enveloped ssRNA flavivirus transmitted by Aedes mosquitoes [1]. Dengue infections are clinically classified by the World Health Organization (WHO) as dengue with or without warning signs and severe dengue [2]. It is an important public health problem affecting the tropical and subtropical ... |
10.1371/journal.pntd.0003601 | Exposure to Leishmania braziliensis Triggers Neutrophil Activation and Apoptosis | Neutrophils are the first line of defense against invading pathogens and are rapidly recruited to the sites of Leishmania inoculation. During Leishmania braziliensis infection, depletion of inflammatory cells significantly increases the parasite load whereas co-inoculation of neutrophils plus L. braziliensis had an opp... | Leishmania is the parasite responsible for the disease leishmaniasis, present in all continents. Leishmania parasites are spread through infected sand-flies and, during transmission into the vertebrate host, neutrophils are among the first cells to arrive at the infection site. Since neutrophils are key players at the ... | Neutrophils are essential components of the early inflammatory response, acting as the first line of defense against invading pathogens (rev. in [1]). Neutrophil recruitment to the infection site occurs in response to various stimuli and is followed by cell rolling and adhesion to the vasculature, processes mediated by... |
10.1371/journal.pgen.1007678 | A synonymous RET substitution enhances the oncogenic effect of an in-cis missense mutation by increasing constitutive splicing efficiency | Synonymous mutations continue to be filtered out from most large-scale cancer genome studies, but several lines of evidence suggest they can play driver roles in neoplastic disease. We investigated a case of an aggressive, apparently sporadic medullary thyroid carcinoma (MTC) harboring a somatic RET p.Cys634Arg mutatio... | Synonymous mutations—once considered “silent” because they do not alter the gene product’s amino-acid sequence—are now emerging as potential drivers of cancer. Our recent investigation of an aggressive medullary thyroid carcinoma (MTC) revealed a novel mechanism that could underlie such effects. The MTC analyzed harbor... | It is now clear that synonymous mutations—single-nucleotide substitutions that do not alter the amino acid encoded by the affected codon—can play functionally relevant roles in human disease [1]. Over three decades of research have shown that these mutations can affect protein synthesis and/or function by interfering w... |
10.1371/journal.pcbi.1006584 | Multi-scale computational study of the Warburg effect, reverse Warburg effect and glutamine addiction in solid tumors | Cancer metabolism has received renewed interest as a potential target for cancer therapy. In this study, we use a multi-scale modeling approach to interrogate the implications of three metabolic scenarios of potential clinical relevance: the Warburg effect, the reverse Warburg effect and glutamine addiction. At the int... | Cancer metabolism is an emerging hallmark of cancer. In the past decade, a renewed focus on cancer metabolism has led to several distinct hypotheses describing the role of metabolism in cancer. To complement experimental efforts in this field, a scale-bridging computational framework is needed to allow rapid evaluation... | Cancer remains one of the leading causes of death worldwide. A central challenge in understanding and treating cancer comes from its multi-scale nature, with interacting defects at the molecular, cellular and tissue scales. Specifically, the molecular profile at the intracellular level, behavior at the single-cell leve... |
10.1371/journal.ppat.1004662 | Prion Infections and Anti-PrP Antibodies Trigger Converging Neurotoxic Pathways | Prions induce lethal neurodegeneration and consist of PrPSc, an aggregated conformer of the cellular prion protein PrPC. Antibody-derived ligands to the globular domain of PrPC (collectively termed GDL) are also neurotoxic. Here we show that GDL and prion infections activate the same pathways. Firstly, both GDL and pri... | Prion diseases are a group of infectious, invariably fatal neurodegenerative diseases. Progress in developing therapeutics is slow, partly because animal models of prion diseases require stringent biosafety and are very slow. We recently found that treatment of cerebellar slices with antibodies targeting the globular d... | Prion diseases are lethal infectious diseases that propagate through the conversion of the cellular prion protein (PrPC) into a pathological conformer, the scrapie-associated prion protein (PrPSc) [1]. Neuronal expression of PrPC is required to mediate the neurotoxicity of PrPSc [2] and possibly also of other protein a... |
10.1371/journal.pcbi.1006751 | Modelling the transport of fluid through heterogeneous, whole tumours in silico | Cancers exhibit spatially heterogeneous, unique vascular architectures across individual samples, cell-lines and patients. This inherently disorganised collection of leaky blood vessels contribute significantly to suboptimal treatment efficacy. Preclinical tools are urgently required which incorporate the inherent vari... | The structure of tumours varies widely, with dense and chaotically-formed networks of blood vessels that differ between each individual tumour and even between different regions of the same tumour. This atypical environment can inhibit the delivery of anti-cancer therapies. Computational tools are urgently required whi... | Architectural heterogeneities in cancerous tissue limit the delivery of anti-cancer drugs by inhibiting their ability to circumnavigate the entire tumour to all cancerous cells [1]. In solid tumours, drug penetration to the tumour core is hindered by physiological barriers which can limit the delivery of targeted agent... |
10.1371/journal.pmed.1002844 | Kawasaki disease and 13-valent pneumococcal conjugate vaccination among young children: A self-controlled risk interval and cohort study with null results | Kawasaki disease is an acute vasculitis that primarily affects children younger than 5 years of age. Its etiology is unknown. The United States Vaccine Safety Datalink conducted postlicensure safety surveillance for 13-valent pneumococcal conjugate vaccine (PCV13), comparing the risk of Kawasaki disease within 28 days ... | Kawasaki disease is an acute vasculitis that primarily affects children younger than 5 years of age. It is the leading cause of acquired heart disease in children in developed countries, and its etiology is unknown.
Vaccine Safety Datalink investigators found a nonstatistically significant elevated risk of Kawasaki dis... | In 2000, the Food and Drug Administration (FDA) licensed the first pneumococcal conjugate vaccine (PCV), 7-valent PCV (PCV7; Prevnar; Wyeth), to protect young children against invasive disease caused by any of 7 serotypes of Streptococcus pneumoniae. Inclusion of PCV7 in the recommended child immunization program at 2,... |
10.1371/journal.pmed.1002457 | Lansoprazole use and tuberculosis incidence in the United Kingdom Clinical Practice Research Datalink: A population based cohort | Recent in vitro and animal studies have found the proton pump inhibitor (PPI) lansoprazole to be highly active against Mycobacterium tuberculosis. Omeprazole and pantoprazole have no activity. There is no evidence that, in clinical practice, lansoprazole can treat or prevent incident tuberculosis (TB) disease.
We studi... | A recent report describes preclinical laboratory findings showing lansoprazole has strong activity against M. tuberculosis, including drug-resistant strains.
Other proton pump inhibitors, omeprazole and pantoprazole had no such activity.
No clinical investigations of this possible protective association with lansoprazo... | In 2015, there were an estimated 10.4 million incident cases of tuberculosis (TB) globally resulting in approximately 1.4 million deaths [1]. There is little commercial or public investment in TB research and there are only six novel compounds currently in the TB drug development pipeline [2]. In 2015, there were an es... |
10.1371/journal.pntd.0002879 | Mycobacterium ulcerans Ecological Dynamics and Its Association with Freshwater Ecosystems and Aquatic Communities: Results from a 12-Month Environmental Survey in Cameroon | Mycobacterium ulcerans (MU) is the agent responsible for Buruli Ulcer (BU), an emerging skin disease with dramatic socioeconomic and health outcomes, especially in rural settings. BU emergence and distribution is linked to aquatic ecosystems in tropical and subtropical countries, especially to swampy and flooded areas.... | Buruli ulcer, caused by the pathogen Mycobacterium ulcerans (MU), is a severe skin disease occurring in tropical and subtropical countries. Strongly associated to freshwater ecosystems and especially swampy and flooded areas, transmission of this bacterium within ecosystems and across multiple aquatic organisms is stil... | Mycobacterium ulcerans (MU) is the agent responsible of Buruli ulcer (BU), an emerging human skin disease affecting human populations in tropical and subtropical regions [1]. While effective treatment is available through a combination of rifampicin-streptomycin for small lesions, with additional surgery required in so... |
10.1371/journal.pmed.1002224 | Haemolysis in G6PD Heterozygous Females Treated with Primaquine for Plasmodium vivax Malaria: A Nested Cohort in a Trial of Radical Curative Regimens | Radical cure of Plasmodium vivax malaria with 8-aminoquinolines (primaquine or tafenoquine) is complicated by haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD heterozygous females, because of individual variation in the pattern of X-chromosome inactivation (Lyonisation) in erythr... | Primaquine is the only widely available treatment to eliminate latent liver stages of P. vivax malaria and thereby prevent relapse (radical cure).
Primaquine can cause potentially severe haemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient patients. Hemizygous males and homozygous females are identified rel... | Primaquine is the only widely available drug that is effective against P. vivax hypnozoites, the latent forms that emerge from the liver to produce relapses of P. vivax malaria. The recommended regimen to prevent relapse of P. vivax malaria (called radical treatment) is primaquine given for 14 d at a daily dose of 0.25... |
10.1371/journal.pgen.1006728 | Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations | Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in peop... | Hypertension is a global health problem which affects disproportionally people of African descent. We conducted a genome-wide association study of blood pressure in 31,968 Africans and African Americans to identify genes conferring susceptibility to increased blood pressure. This research identified three novel genomic... | Genetic studies hold the promise of providing tools to better understand and treat clinical conditions. To achieve the clinical and public health goals of reducing hypertension and its sequelae, and to understand ethnic disparities in the risk for hypertension, there is a need to study susceptible populations for genet... |
10.1371/journal.ppat.0040014 | Campylobacter jejuni Survives within Epithelial Cells by Avoiding Delivery to Lysosomes | Campylobacter jejuni is one of the major causes of infectious diarrhea world-wide, although relatively little is know about its mechanisms of pathogenicity. This bacterium can gain entry into intestinal epithelial cells, which is thought to be important for its ability to persistently infect and cause disease. We found... | Campylobacter jejuni is one of the most common causes of food-borne illness in the United States and a major cause of diarrheal disease throughout the world. After infection through the oral route, this bacterium invades the cells of the intestinal epithelium, a property that is important for its ability to cause disea... | Campylobacter jejuni is the leading cause of bacterial food-borne illness in the United States and a major cause of diarrheal disease throughout the world [1]. C. jejuni infection is also an important pre-condition for Guillain-Barré paralysis [2]. Despite its public health importance, relatively little is known about ... |
10.1371/journal.ppat.1004340 | A Novel Signal Transduction Pathway that Modulates rhl Quorum Sensing and Bacterial Virulence in Pseudomonas aeruginosa | The rhl quorum-sensing (QS) system plays critical roles in the pathogenesis of P. aeruginosa. However, the regulatory effects that occur directly upstream of the rhl QS system are poorly understood. Here, we show that deletion of gene encoding for the two-component sensor BfmS leads to the activation of its cognate res... | The rhl quorum-sensing (QS) system allows P. aeruginosa to regulate diverse metabolic adaptations and virulence. However, how rhl QS system is regulated remains largely unknown. Here, we report that two-component sensor BfmS controls rhl QS system by repressing its cognate response regulator BfmR, which directly suppre... | Pseudomonas aeruginosa is an important opportunistic pathogen that accounts for 10% of all hospital-acquired infections [1], [2]. Most notably, P. aeruginosa is the leading cause of chronic pulmonary infections and mortality in cystic fibrosis (CF) patients [3]. The success of P. aeruginosa relies on the production and... |
10.1371/journal.pcbi.1002460 | Genome-Scale Modeling of Light-Driven Reductant Partitioning and Carbon Fluxes in Diazotrophic Unicellular Cyanobacterium Cyanothece sp. ATCC 51142 | Genome-scale metabolic models have proven useful for answering fundamental questions about metabolic capabilities of a variety of microorganisms, as well as informing their metabolic engineering. However, only a few models are available for oxygenic photosynthetic microorganisms, particularly in cyanobacteria in which ... | Cyanobacteria have been promoted as platforms for biofuel production due to their useful physiological properties such as photosynthesis, relatively rapid growth rates, ability to accumulate high amounts of intracellular compounds and tolerance to extreme environments. However, development of a computational model is a... | Cyanothece spp. are unicellular, diazotrophic cyanobacteria that temporally separate light-dependent oxygenic photosynthesis and glycogen accumulation from N2 fixation at night [1]. When grown under nutrient excess, Cyanothece sp. strain ATCC 51142 (thereafter Cyanothece 51142) cells can accumulate significant amounts ... |
10.1371/journal.pntd.0004212 | Environmental Transmission of Typhoid Fever in an Urban Slum | Enteric fever due to Salmonella Typhi (typhoid fever) occurs in urban areas with poor sanitation. While direct fecal-oral transmission is thought to be the predominant mode of transmission, recent evidence suggests that indirect environmental transmission may also contribute to disease spread.
Data from a population-ba... | Typhoid fever, a serious bloodstream infection caused by the bacterium Salmonella Typhi, is commonly associated with direct, person-to-person transmission as a result of improper hygiene and unsafe food/water handling practices. Recent evidence, however, suggests that individuals may be indirectly exposed to typhoid th... | Typhoid fever is a systemic, enteric disease caused by Salmonella enterica serovars Typhi and Paratyphi and has an estimated annual global incidence of 26.9 million cases, and causes 200,000 deaths per year [1]. Morbidity and mortality due to typhoid fever occurs primarily in young children in Africa and Asia [2, 3]. C... |
10.1371/journal.pntd.0005144 | Maternal Filarial Infection Influences the Development of Regulatory T Cells in Children from Infancy to Early Childhood | Children born from filarial infected mothers are comparatively more susceptible to filarial infection than the children born to uninfected mothers. But the mechanism of such increased susceptibility to infection in early childhood is not exactly known. Several studies have shown the association of active filarial infec... | Lymphatic filariasis caused by thread like filarial worms involves asymptomatic to acute and/or disfiguring chronic conditions like lymphoedema, elephantiasis and scrotal swelling. Infection occurs when filarial parasites are transmitted to humans through mosquitoes. Adult worms lodge in the lymphatic system and disrup... | Lymphatic filariasis (LF) is a major cause of chronic morbidity in the tropics and sub tropics. According to a recent estimate more than 1.4 billion people across the world are at the risk of infection [1]. To eliminate LF globally by 2020, WHO has introduced annual mass drug administration (MDA) in different endemic c... |
10.1371/journal.pbio.1000236 | Identification and Functional Characterization of N-Terminally Acetylated Proteins in Drosophila melanogaster | Protein modifications play a major role for most biological processes in living organisms. Amino-terminal acetylation of proteins is a common modification found throughout the tree of life: the N-terminus of a nascent polypeptide chain becomes co-translationally acetylated, often after the removal of the initiating met... | Widely hailed as the workhorses of the cell, proteins participate in virtually every process within a living organism. How well they perform these diverse tasks depends on successful passage through the intricate course of protein production, from transcription of the protein-encoded DNA template to processing and fold... | To attain full functionality and/or to reach their final cellular localization, many proteins undergo obligatory modification or processing. During this maturation process, proteins are concurrently properly folded, proteolytically processed, and enzymatically modified. Some of these processes occur co-translationally,... |
10.1371/journal.pntd.0007403 | PCR-RFLP analyses of Leishmania species causing cutaneous and mucocutaneous leishmaniasis revealed distribution of genetically complex strains with hybrid and mito-nuclear discordance in Ecuador | PCR-Restriction Fragment Length Polymorphism (RFLP) analyses targeting multiple nuclear genes were established for the simple and practical identification of Leishmania species without using expensive equipment. This method was applied to 92 clinical samples collected at 33 sites in 14 provinces of Ecuador, which have ... | Leishmaniasis caused by intracellular protozoa of the genus Leishmania is a neglected tropical disease widely distributing worldwide, especially in tropical and subtropical areas. Approximately 20 species are known to be pathogenic to humans, of which eight species have been recorded as causative agents of cutaneous an... | Leishmaniasis, caused by protozoan parasites of the genus Leishmania, is a neglected tropical disease widely distributed worldwide, especially in tropical and subtropical areas, affecting at least 12 million people in 96 countries [1]. Approximately 20 Leishmania species belonging to the subgenera Leishmania (Leishmani... |
10.1371/journal.ppat.1003493 | The Viral Chemokine MCK-2 of Murine Cytomegalovirus Promotes Infection as Part of a gH/gL/MCK-2 Complex | Human cytomegalovirus (HCMV) forms two gH/gL glycoprotein complexes, gH/gL/gO and gH/gL/pUL(128,130,131A), which determine the tropism, the entry pathways and the mode of spread of the virus. For murine cytomegalovirus (MCMV), which serves as a model for HCMV, a gH/gL/gO complex functionally homologous to the HCMV gH/g... | Several human herpesviruses form alternative gH/gL complexes which determine the tropism for different cell types. For murine cytomegalovirus (MCMV), a gH/gL/gO complex has recently been characterized. Here, we present the identification and characterization of an alternative gH/gL/MCK-2 complex which promotes MCMV spr... | Herpesviruses enter their host cells either by fusion of the viral envelope with the plasma membrane or with membranes of endocytotic vesicles. The fusion process is promoted by a concerted action of the conserved viral glycoproteins gB, gH, and gL [1] of which gH and gL consistently form a tight heterodimer [2], [3]. ... |
10.1371/journal.pntd.0000730 | Antiangiogenic and Antitumor Effects of Trypanosoma cruzi Calreticulin | In Latin America, 18 million people are infected with Trypanosoma cruzi, the agent of Chagas' disease, with the greatest economic burden. Vertebrate calreticulins (CRT) are multifunctional, intra- and extracellular proteins. In the endoplasmic reticulum (ER) they bind calcium and act as chaperones. Since human CRT (HuC... | In Latin America, 18 million people are infected with Trypanosoma cruzi, a protozoan that causes Chagas' disease. Vertebrate calreticulins (CRTs) are multifunctional, intra- and extracellular calcium binding, chaperone proteins. Since human CRT (HuCRT) inhibits capillary growth (angiogenesis) and suppresses tumor growt... | Chagas′ disease affects 16 million people in South America, with 14.000 deaths per year and 0.7 million disability-adjusted life-years [1]. T. cruzi has a variety of molecules that modulate several effector arms of the immune system [2], calreticulin (TcCRT) being one of them [3]. TcCRT, first isolated in our laborator... |
10.1371/journal.ppat.1000233 | FimH Adhesin of Type 1 Fimbriae Is a Potent Inducer of Innate Antimicrobial Responses Which Requires TLR4 and Type 1 Interferon Signalling | Components of bacteria have been shown to induce innate antiviral immunity via Toll-like receptors (TLRs). We have recently shown that FimH, the adhesin portion of type 1 fimbria, can induce the innate immune system via TLR4. Here we report that FimH induces potent in vitro and in vivo innate antimicrobial responses. F... | The innate immune system is an evolutionarily conserved defence mechanism that protects the host from infection by microbes such as viruses, bacteria and fungi. Incoming pathogens are recognized by a set of evolutionary conserved receptors, including the Toll-like receptors (TLRs), that can be found on the surface of e... | The innate immune system plays a crucial role in the early defence against microbial infections [1],[2],[3],[4],[5],[6]. A key aspect of the innate immune response is the synthesis and secretion of type I interferons (IFN) such as IFN-α and IFN-β. The innate immune system detects infections through germ-line encoded pa... |
10.1371/journal.pgen.1006116 | Super Resolution Fluorescence Microscopy and Tracking of Bacterial Flotillin (Reggie) Paralogs Provide Evidence for Defined-Sized Protein Microdomains within the Bacterial Membrane but Absence of Clusters Containing Detergent-Resistant Proteins | Biological membranes have been proposed to contain microdomains of a specific lipid composition, in which distinct groups of proteins are clustered. Flotillin-like proteins are conserved between pro—and eukaryotes, play an important function in several eukaryotic and bacterial cells, and define in vertebrates a type of... | Many membrane proteins are not uniformly distributed within biological membranes, and may prefer specific lipid environments to function optimally. Using super resolution fluorescence microscopy, we show that several Bacillus subtilis membrane proteins indeed cluster into structures of 60 to 110 nm, verifying the exist... | In spite of many decades of research on membrane proteins, the true arrangement of proteins and their dynamics within the lipid bilayer are still poorly defined. Many membrane proteins show non-uniform localization patterns [1, 2], and the existence of microdomains having different lipid compositions can be inferred fr... |
10.1371/journal.pcbi.1000685 | Computational Complementation: A Modelling Approach to Study Signalling Mechanisms during Legume Autoregulation of Nodulation | Autoregulation of nodulation (AON) is a long-distance signalling regulatory system maintaining the balance of symbiotic nodulation in legume plants. However, the intricacy of internal signalling and absence of flux and biochemical data, are a bottleneck for investigation of AON. To address this, a new computational mod... | Endogenous signals, such as phytohormones, play a vital role in plant development and function, controlling processes such as flowering, branching, disease response, and nodulation. However, the signalling mechanisms are so subtle and so complex that details about them remain largely unknown. In this study, we develop ... | Legumes are one of the largest families of flowering plants that occupy about 15% of Earth's arable surface; yet they provide 27% of the world's primary crop production and more than 35% of the world's processed vegetable oil [1], signifying their cropping potential. Legumes are also the major natural nitrogen-provider... |
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