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10.1371/journal.pgen.1003436 | Insulators Target Active Genes to Transcription Factories and Polycomb-Repressed Genes to Polycomb Bodies | Polycomb bodies are foci of Polycomb proteins in which different Polycomb target genes are thought to co-localize in the nucleus, looping out from their chromosomal context. We have shown previously that insulators, not Polycomb response elements (PREs), mediate associations among Polycomb Group (PcG) targets to form P... | We have studied the nuclear localization of genes that are regulated by Polycomb mechanisms. The genomes of higher eukaryotes contain hundreds of genes that are regulated by Polycomb mechanisms. Once repressed by Polycomb complexes, they tend to stay repressed; but, when activated, they bind Trithorax protein and tend ... | The default state for the organization of genomic material is the chromosomal territory occupied by the folding of the continuous chromatin fiber constituting a chromosome. From this territory, individual regions may loop out to partake in molecular activities such as transcription, heterochromatic silencing, Polycomb ... |
10.1371/journal.pgen.1006440 | Myosin phosphatase Fine-tunes Zebrafish Motoneuron Position during Axonogenesis | During embryogenesis the spinal cord shifts position along the anterior-posterior axis relative to adjacent tissues. How motor neurons whose cell bodies are located in the spinal cord while their axons reside in adjacent tissues compensate for such tissue shift is not well understood. Using live cell imaging in zebrafi... | Embryonic development requires tight coordination between tissues as they frequently grow at different rates. Such differential growth rates can cause shifts between neighboring tissues, and are a particular challenge for individual cells that span multiple tissues, in part because mechanical tension on such cells is p... | It has been long recognized that during embryonic development of multicellular organisms, differential growth rates and morphogenetic movements of adjacent tissues are highly coordinated [1, 2]. For example, the developing vertebral column and the spinal cord exhibit differential growth rates and shift relative to one ... |
10.1371/journal.pntd.0006513 | Molecular detection of Leishmania infantum DNA and host blood meal identification in Phlebotomus in a hypoendemic focus of human leishmaniasis in northern Algeria | Leishmania parasites are transmitted by female phlebotomine sand flies that maintain the enzootic cycle by circulating between sylvatic and domestic mammals. Humans are part of this cycle as accidental hosts due to the vector’s search for a source of blood. In Algeria, Human Leishmaniases (HL) are endemic and represent... | Leishmaniases are a group of diseases with various clinical manifestations caused by parasites (Leishmania spp.). More than 20 Leishmania species that affect human and mammals are transmitted by the bite of an infected female phlebotomine sand flies. In Algeria, two main forms of the disease exist: visceral leishmanias... | Leishmaniases are neglected vector-born tropical diseases caused by more than twenty parasite species belonging to the Leishmania genus (Kinetoplastida: Trypanosomatidae) and transmitted to humans by the bite of Phlebotominae (Diptera: Psychodidae) sand flies [1]. Leishmania parasites have a digenetic life cycle, alter... |
10.1371/journal.pcbi.1005003 | Prospective Coding by Spiking Neurons | Animals learn to make predictions, such as associating the sound of a bell with upcoming feeding or predicting a movement that a motor command is eliciting. How predictions are realized on the neuronal level and what plasticity rule underlies their learning is not well understood. Here we propose a biologically plausib... | Sensory inputs are often predictable. Lightning is followed by thunder, a falling object causes noise when hitting the ground, our skin gets wet when we jump into the water. Humans learn regularities like these without effort. Learned predictions allow to cover the ears in anticipation of thunder or close the eyes just... | Animals can learn to predict upcoming stimuli. In delayed paired-associate tasks, animals learn to respond to pairs of stimuli (e.g. images A1-B1 and A2-B2) separated by a delay. These tasks can be solved by either keeping a memory of the first stimulus (A1 or A2) during the delay period (retrospective coding) or antic... |
10.1371/journal.ppat.1006607 | Structures of foot and mouth disease virus pentamers: Insight into capsid dissociation and unexpected pentamer reassociation | Foot-and-mouth disease virus (FMDV) belongs to the Aphthovirus genus of the Picornaviridae, a family of small, icosahedral, non-enveloped, single-stranded RNA viruses. It is a highly infectious pathogen and is one of the biggest hindrances to the international trade of animals and animal products. FMDV capsids (which a... | This is the first structure of dissociated pentamers for FMDV, and indeed for any picornavirus. We also present the first visualization of a picornavirus particle assembled from pentamers comprising VP1, 2 and 3. The formation of regular assemblies rather than random aggregates has enabled us to solve the structure to ... | The Picornaviridae are small, non-enveloped, single-stranded RNA viruses, comprising numerous genera including the Enterovirus genus (e.g. poliovirus, human rhinovirus, enterovirus 71), Aphthovirus genus (e.g. FMDV and Equine rhinitis A virus—ERAV) and Cardiovirus genus (e.g. mengovirus). Foot-and-mouth disease virus (... |
10.1371/journal.pcbi.1000442 | Identification of a Topological Characteristic Responsible for the Biological Robustness of Regulatory Networks | Attribution of biological robustness to the specific structural properties of a regulatory network is an important yet unsolved problem in systems biology. It is widely believed that the topological characteristics of a biological control network largely determine its dynamic behavior, yet the actual mechanism is still... | Living organisms exert very complicated control on the functionality of their components. Such control systems can often operate in a surprisingly robust manner, in spite of constant perturbations from fluctuating internal conditions and a volatile external environment. What feature makes such control mechanisms robust... | Biological regulatory networks play an essential role in all living organisms. The investigation of their general behaviors is an important subject in the current research of systems biology. Recently, the reliable functionality of these networks has attracted much attention [1]; it has been widely recognized that some... |
10.1371/journal.pbio.1002515 | Topological Small-World Organization of the Fibroblastic Reticular Cell Network Determines Lymph Node Functionality | Fibroblastic reticular cells (FRCs) form the cellular scaffold of lymph nodes (LNs) and establish distinct microenvironmental niches to provide key molecules that drive innate and adaptive immune responses and control immune regulatory processes. Here, we have used a graph theory-based systems biology approach to deter... | Fibroblastic reticular cells (FRCs) in lymph nodes are organized in a highly connected cellular network that not only acts as a scaffold for lymphocyte migration but also provides key factors for induction and maintenance of immune responses. By utilizing high-resolution microscopy coupled with computational approaches... | Efficient interactions between the immune system and microbial antigens are initiated and maintained in secondary lymphoid organs (SLOs) that are strategically positioned at routes of pathogen invasion. Lymph nodes (LNs), for example, are found at convergence points of larger lymph vessels, which drain extracellular fl... |
10.1371/journal.pbio.1001764 | Different Levels of Catabolite Repression Optimize Growth in Stable and Variable Environments | Organisms respond to environmental changes by adapting the expression of key genes. However, such transcriptional reprogramming requires time and energy, and may also leave the organism ill-adapted when the original environment returns. Here, we study the dynamics of transcriptional reprogramming and fitness in the mod... | When microbes grow in a mixture of different nutrients, they repress the metabolism of nonpreferred nutrients such as complex carbohydrates until preferred nutrients, like glucose, are depleted. While this “catabolite repression” allows cells to use the most efficient nutrients first, it also comes at a cost because th... | A stable environment generally favors organisms that are well-adapted to that specific niche [1]–[3]. However, in many cases, adaptation to one environment comes at costs to fitness in alternative niches [1],[4]–[9]. Aside from the fitness tradeoffs, adaptation through mutation is relatively slow. Thus to deal with cer... |
10.1371/journal.ppat.1000860 | Two Coregulated Efflux Transporters Modulate Intracellular Heme and Protoporphyrin IX Availability in Streptococcus agalactiae | Streptococcus agalactiae is a major neonatal pathogen whose infectious route involves septicemia. This pathogen does not synthesize heme, but scavenges it from blood to activate a respiration metabolism, which increases bacterial cell density and is required for full virulence. Factors that regulate heme pools in S. ag... | The infectious route of numerous bacterial pathogens includes septicemia, where bacteria are exposed to heme-rich blood. Heme (iron protoporphyrin IX) is generally considered a bacterial iron source. However, while some pathogens do not biosynthesize heme, they use environmental heme to activate key functions. For exam... | Heme (iron protoporphyrin IX) is a redox-active molecule, and a cofactor for numerous cell functions used in oxygen sensing and signal transmission, metabolism, and metal homeostasis [1][–][3]. In addition to its varied activities as a cofactor, heme promotes toxic oxygen radical production [4]. The duality between hem... |
10.1371/journal.ppat.1007877 | The YIN and YANG of lipoproteins in developing and preventing infectious arthritis by Staphylococcus aureus | Rapid bone destruction often leads to permanent joint dysfunction in patients with septic arthritis, which is mainly caused by Staphylococcus aureus (S. aureus). Staphylococcal cell wall components are known to induce joint inflammation and bone destruction. Here, we show that a single intra-articular injection of S. a... | Rapid bone destruction often leads to permanent joint dysfunction in septic arthritis, which is mainly caused by S. aureus. Despite advances in the use of antibiotics, permanent reductions in joint function occur in up to 50% of patients, who may also need joint replacement surgery. Additional challenge is posed by inc... | Despite colonizing more than half of the human population at some stage during their life [1], Staphylococcus aureus (S. aureus) is a highly pathogenic microorganism responsible for a broad range of infections in humans [2]. Septic arthritis, considered to be one of the most aggressive joint diseases, is most commonly ... |
10.1371/journal.pmed.1002405 | Tuberculosis detection and the challenges of integrated care in rural China: A cross-sectional standardized patient study | Despite recent reductions in prevalence, China still faces a substantial tuberculosis (TB) burden, with future progress dependent on the ability of rural providers to appropriately detect and refer TB patients for further care. This study (a) provides a baseline assessment of the ability of rural providers to correctly... | Despite remarkable progress against the disease in recent decades, China still faces a significant tuberculosis (TB) burden, particularly in poor rural areas where patients have been shown to face significant delays in diagnosis compared to urban areas.
Existing evidence on the quality of TB care in China is based on s... | National prevalence surveys conducted by the Chinese Center for Disease Control and Prevention (CCDC) show that between 1990 and 2010 smear-positive prevalence of tuberculosis (TB) decreased by 65%, from 170 to 59 per 100,000 [1]. Though improved socioeconomic conditions almost certainly helped, better treatment of tho... |
10.1371/journal.pcbi.1002197 | B Cell Activation Triggered by the Formation of the Small Receptor Cluster: A Computational Study | We proposed a spatially extended model of early events of B cell receptors (BCR) activation, which is based on mutual kinase-receptor interactions that are characteristic for the immune receptors and the Src family kinases. These interactions lead to the positive feedback which, together with two nonlinearities resulti... | B cells are activated in response to binding of appropriate ligands, which induces the aggregation of B cell receptors. The formation of even small clusters containing less than 1% of all the receptors is sufficient for activation. This observation led us to a model in which the receptor cluster serves only as a switch... | B lymphocytes activation is initiated by B cell receptor (BCR) aggregation following antigen engagement. Activated B cells can differentiate to form extrafollicular plasma-blasts responsible for the rapid antibody production and early protective immune responses. Alternatively, they can differentiate into plasma cells,... |
10.1371/journal.pcbi.0030133 | Optimal Timing and Duration of Induction Therapy for HIV-1 Infection | The tradeoff between the need to suppress drug-resistant viruses and the problem of treatment toxicity has led to the development of various drug-sparing HIV-1 treatment strategies. Here we use a stochastic simulation model for viral dynamics to investigate how the timing and duration of the induction phase of inductio... | Clinicians treating HIV infection must balance the need to suppress viral replication against the harmful side effects and significant cost of antiretroviral therapy. Inadequate therapy often results in the emergence of resistant viruses and treatment failure. These difficulties are especially acute in resource-poor se... | The failure of antiretroviral therapies to completely suppress viral replication in some patients represents a major difficulty in the management of HIV infection. In therapy-naive patients without clinically apparent resistance mutations, triple-drug therapy with two nucleoside–analog reverse transcriptase inhibitors ... |
10.1371/journal.pcbi.1002897 | Delay Selection by Spike-Timing-Dependent Plasticity in Recurrent Networks of Spiking Neurons Receiving Oscillatory Inputs | Learning rules, such as spike-timing-dependent plasticity (STDP), change the structure of networks of neurons based on the firing activity. A network level understanding of these mechanisms can help infer how the brain learns patterns and processes information. Previous studies have shown that STDP selectively potentia... | Our brain's ability to perform cognitive processes, such as object identification, problem solving, and decision making, comes from the specific connections between neurons. The neurons carry information as spikes that are transmitted to other neurons via connections with different strengths and propagation delays. Exp... | Spike-timing-dependent plasticity (STDP) is an experimentally observed learning rule that changes synaptic strengths based on the relative timing of pre- and post-synaptic spikes (action potentials) [1]–[4]. Gerstner et. al. first proposed it as an unsupervised Hebbian learning rule that could select feed-forward conne... |
10.1371/journal.pntd.0000420 | Filarial Lymphedema Is Characterized by Antigen-Specific Th1 and Th17 Proinflammatory Responses and a Lack of Regulatory T Cells | Lymphatic filariasis can be associated with development of serious pathology in the form of lymphedema, hydrocele, and elephantiasis in a subset of infected patients.
To elucidate the role of CD4+ T cell subsets in the development of lymphatic pathology, we examined specific sets of cytokines in individuals with filari... | Lymphatic filariasis afflicts over 120 million people worldwide. While the infection is mostly clinically asymptomatic, approximately 40 million people suffer from overt, morbid clinical pathology, characterized by swelling of the scrotal area and lower limbs (hydrocele and lymphedema). Host immunologic factors that de... | Although two-thirds of the 120 million people infected with Wuchereria bancrofti, the major causative agent of human lymphatic filariasis, have subclinical infections, ∼40 million have lymphedema and/or other pathologic manifestations including hydroceles (and other forms of urogenital disease), episodic adenolymphangi... |
10.1371/journal.ppat.1000407 | Helicobacter pylori Usurps Cell Polarity to Turn the Cell Surface into a Replicative Niche | Helicobacter pylori (Hp) intimately interacts with the gastric epithelial surface and translocates the virulence factor CagA into host cells in a contact-dependent manner. To study how Hp benefits from interacting with the cell surface, we developed live-cell microscopy methods to follow the fate of individual bacteria... | Helicobacter pylori (Hp) is a bacterium that chronically infects the human stomach, in some cases leading to diseases such as stomach cancer and ulcers. The bacteria live in close proximity to the epithelial lining and can adhere directly to the host cell membrane and deliver toxins. We utilized live-cell imaging and a... | In order to cause infection bacteria have to colonize a specialized niche within the host. This implies adaptations that allow bacteria to reach, extract nutrients from, and replicate within particular anatomical and physiological environments in the host. Bacteria that colonize mucosal surfaces, for example, have to r... |
10.1371/journal.pntd.0003069 | Cystic Echinococcosis in the Province of Álava, North Spain: The Monetary Burden of a Disease No Longer under Surveillance | Cystic echinococcosis (CE) is endemic in Spain but has been considered non-endemic in the province of Álava, Northern Spain, since 1997. However, Álava is surrounded by autonomous regions with some of the highest CE prevalence proportions in the nation, casting doubts about the current classification. The purpose of th... | Historically, cystic echinococcosis (CE) is one of the most important zoonotic diseases in Spain. The initiation of a number of control campaigns in the second half of the 1980s has led to a substantial reduction of the number of CE infections both in humans and livestock species. As a consequence of this initial succe... | Cystic echinococcosis (CE or hydatid disease) caused by the larval stage of the taeniid tapeworm Echinococcus granulosus is an important zoonotic disease with a worldwide distribution. Domestic transmission of the infection relies on dogs as definitive hosts and a range of livestock ungulate intermediate hosts, mainly ... |
10.1371/journal.pntd.0001876 | Controlling Dengue with Vaccines in Thailand | Dengue is a mosquito-borne infectious disease that constitutes a growing global threat with the habitat expansion of its vectors Aedes aegyti and A. albopictus and increasing urbanization. With no effective treatment and limited success of vector control, dengue vaccines constitute the best control measure for the fore... | An estimated 40% of the world's population is at risk of infection with dengue, a mosquito-borne disease that can lead to hospitalization or death. Dengue vaccines are currently being tested in clinical trials and at least one product will likely be available within a couple of years. Before widespread deployment, one ... | Dengue is a mosquito-borne disease, caused by a flavivirus with four serotypes, responsible for an estimated 500,000 hospitalizations and 20,000 deaths per year, mostly in the tropics [1], although these are probably conservative estimates. The toll of dengue may rise with the increasing range of its primary vectors, A... |
10.1371/journal.pcbi.1002922 | Stimulus-dependent Maximum Entropy Models of Neural Population Codes | Neural populations encode information about their stimulus in a collective fashion, by joint activity patterns of spiking and silence. A full account of this mapping from stimulus to neural activity is given by the conditional probability distribution over neural codewords given the sensory input. For large populations... | In the sensory periphery, stimuli are represented by patterns of spikes and silences across a population of sensory neurons. Because the neurons form an interconnected network, the code cannot be understood by looking at single cells alone. Recent recordings in the retina have enabled us to study populations of a hundr... | Neurons represent and transmit information using temporal sequences of short stereotyped bursts of electrical activity, or spikes [1]. Much of what we know about this encoding has been learned by studying the mapping between stimuli and responses at the level of single neurons, and building detailed models of what stim... |
10.1371/journal.pgen.1005920 | Hybrid Dysgenesis in Drosophila simulans Associated with a Rapid Invasion of the P-Element | In a classic example of the invasion of a species by a selfish genetic element, the P-element was horizontally transferred from a distantly related species into Drosophila melanogaster. Despite causing ‘hybrid dysgenesis’, a syndrome of abnormal phenotypes that include sterility, the P-element spread globally in the co... | Some genes perform necessary organismal functions, others hijack the cellular machinery to replicate themselves, potentially harming the host in the process. These ‘selfish genes’ can spread through genomes and species; as a result, eukaryotic genomes are typically saddled with large amounts of parasitic DNA. Here, we ... | Discovered in the 1950’s by Barbara McClintock [1], transposable elements (TEs) are the ‘ultimate parasite’ [2,3]. They are genetically simple, with autonomous elements consisting of as little as one protein coding gene, but remarkably successful, comprising much of the bulk of large eukaryotic genomes [4,5]. Those tha... |
10.1371/journal.pbio.3000122 | Structure of the DP1–DP2 PolD complex bound with DNA and its implications for the evolutionary history of DNA and RNA polymerases | PolD is an archaeal replicative DNA polymerase (DNAP) made of a proofreading exonuclease subunit (DP1) and a larger polymerase catalytic subunit (DP2). Recently, we reported the individual crystal structures of the DP1 and DP2 catalytic cores, thereby revealing that PolD is an atypical DNAP that has all functional prop... | PolD is an unusual archaeal replicative DNA polymerase (DNAP) in that it has all the functional properties of a replicative DNAP but with a catalytic core reminiscent of an RNA polymerase (RNAP). We now describe the cryo–electron microscopy (cryo-EM) structure of a DNA-bound heterodimeric DP1–DP2 PolD complex from the ... | All forms of life have evolved multiple DNA polymerases (DNAPs) in order to maintain their genomes [1]. Highly processive and accurate replicative DNAPs are responsible for duplicating the genome, and a variety of specialized DNAPs are involved in DNA repair and in resolving the Okazaki fragments. Over the years, all D... |
10.1371/journal.pcbi.1000343 | Probing the Flexibility of Large Conformational Changes in Protein Structures through Local Perturbations | Protein conformational changes and dynamic behavior are fundamental for such processes as catalysis, regulation, and substrate recognition. Although protein dynamics have been successfully explored in computer simulation, there is an intermediate-scale of motions that has proven difficult to simulate—the motion of indi... | Many proteins undergo large motions to carry out their biological functions. The exact nature of these motions is typically inferred from the crystal structures of the protein trapped in different states, which normally constitutes a difficult series of experiments. As molecular dynamics is generally accepted to accura... | Protein dynamics play a critical role in a wide variety of biological processes such as catalysis, substrate recognition and binding, allosteric regulation and protein stability [1]. The dynamic behavior associated with these biological functions can involve motions as subtle as a sidechain displacement to large-scale ... |
10.1371/journal.pgen.1001124 | The SR Protein B52/SRp55 Is Required for DNA Topoisomerase I Recruitment to Chromatin, mRNA Release and Transcription Shutdown | DNA- and RNA-processing pathways are integrated and interconnected in the eukaryotic nucleus to allow efficient gene expression and to maintain genomic stability. The recruitment of DNA Topoisomerase I (Topo I), an enzyme controlling DNA supercoiling and acting as a specific kinase for the SR-protein family of splicing... | DNA Topoisomerase I (Topo I) is a very well known enzyme capable of removing DNA topological constrains during transcription. In mammals, Topo I also harbours an intrinsic protein kinase activity required to achieve specific phosphorylation of factors in charge of maturating the transcript and exporting it from the tra... | Messenger RNA (mRNA) transcribed by the RNA polymerase II (RNA Pol II) undergoes several maturation steps: capping, splicing and polyadenylation, before its export into the cytoplasm (for review see [1]). All these steps are tightly coupled to ongoing transcription so that RNA emerging from the polymerase is immediatel... |
10.1371/journal.pgen.1007671 | De novo mutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay | Mutations that alter signaling of RAS/MAPK-family proteins give rise to a group of Mendelian diseases known as RASopathies. However, among RASopathies, the matrix of genotype-phenotype relationships is still incomplete, in part because there are many RAS-related proteins and in part because the phenotypic consequences ... | While many causes of developmental disabilities have been identified, a large number of affected children cannot be diagnosed despite extensive medical testing. Previously unknown genetic factors are likely to be the culprits in many of these cases. Using DNA sequencing, and by sharing information among many doctors an... | Developmental delay and intellectual disability (DD/ID) affect about 1–2% of individuals worldwide [1]. Many highly penetrant genetic variants underlying DD/ID have been identified, but a large fraction of disease risk remains unexplained [2, 3]. While some DD/ID-cases may result from environmental factors and small-ef... |
10.1371/journal.pgen.1007817 | Mutations in Kinesin family member 6 reveal specific role in ependymal cell ciliogenesis and human neurological development | Cerebrospinal fluid flow is crucial for neurodevelopment and homeostasis of the ventricular system of the brain, with localized flow being established by the polarized beating of the ependymal cell (EC) cilia. Here, we report a homozygous one base-pair deletion, c.1193delT (p.Leu398Glnfs*2), in the Kinesin Family Membe... | Cerebrospinal fluid flow is crucial for neurodevelopment and homeostasis of the ventricular system of the brain. Localized flows of cerebrospinal fluid throughout the ventricular system of the brain are established from the polarized beating of the ependymal cell (EC) cilia. Here, we identified a homozygous truncating ... | The delicate balance of cerebrospinal fluid (CSF) production and flow is important for the morphogenesis and function of the brain during development and homeostasis. CSF circulation in human is largely due to gradients established by the secretion of CSF from the choroid plexuses, and its resorption at the arachnoid g... |
10.1371/journal.pmed.1002444 | HIV pre-exposure prophylaxis and early antiretroviral treatment among female sex workers in South Africa: Results from a prospective observational demonstration project | Operational research is required to design delivery of pre-exposure prophylaxis (PrEP) and early antiretroviral treatment (ART). This paper presents the primary analysis of programmatic data, as well as demographic, behavioural, and clinical data, from the TAPS Demonstration Project, which offered both interventions to... | Female sex workers are a vulnerable population at risk of HIV, and, in some areas of South Africa, nearly 3 out of 4 sex workers are already infected.
Pre-exposure prophylaxis (PrEP) and early antiretroviral treatment (ART) are interventions being piloted by national programmes to test whether (and how) they can be suc... | Rates of new HIV infections remain high, especially in key populations in sub-Saharan Africa, necessitating new options for HIV prevention and treatment [1,2]. Mathematical and clinical studies suggest that a programme combining current HIV prevention options with oral pre-exposure prophylaxis (PrEP), i.e., giving anti... |
10.1371/journal.ppat.1005672 | A Novel Mechanism of Host-Pathogen Interaction through sRNA in Bacterial Outer Membrane Vesicles | Bacterial outer membrane vesicle (OMV)-mediated delivery of proteins to host cells is an important mechanism of host-pathogen communication. Emerging evidence suggests that OMVs contain differentially packaged short RNAs (sRNAs) with the potential to target host mRNA function and/or stability. In this study, we used RN... | Pseudomonas aeruginosa is a gram-negative, opportunistic pathogen that accounts for about 10% of all hospital-acquired infections in the US and primarily infects immunocompromised hosts, including patients with chronic obstructive pulmonary disease and cystic fibrosis. Gram-negative bacteria like P. aeruginosa produce ... | Pseudomonas aeruginosa is a gram-negative, opportunistic pathogen that primarily infects immunocompromised hosts including cancer and AIDS patients, burn victims, patients on ventilators and individuals with chronic obstructive pulmonary disease and cystic fibrosis. According to the Centers for Disease Control and Prev... |
10.1371/journal.pntd.0000891 | Geographical Distribution of Intestinal Schistosomiasis and Soil-Transmitted Helminthiasis and Preventive Chemotherapy Strategies in Sierra Leone | A national baseline mapping of schistosomiasis and soil-transmitted helminthiasis (STH) was performed in Sierra Leone. The aim was to provide necessary tools for the Ministry of Health and Sanitation to plan the intervention strategies in the national integrated control program on neglected tropical diseases according ... | The common intestinal roundworm, whipworm and hookworm (together known as soil-transmitted helminthes - STHs) together with schistosomes or bilharzia are responsible for extensive ill health, reduced life expectancy and death in sub-Saharan Africa. These diseases are transmitted in areas of poor water supply and sanita... | Schistosomiasis and soil-transmitted helminthiasis (STH), two of the most important neglected tropical diseases, cause serious public health problems in sub-Saharan Africa [1]. There are two main forms of human schistosomiasis in sub-Saharan Africa, intestinal schistosomiasis caused by Schistosoma mansoni and urinary s... |
10.1371/journal.ppat.1001071 | UNC93B1 Mediates Host Resistance to Infection with Toxoplasma gondii | UNC93B1 associates with Toll-Like Receptor (TLR) 3, TLR7 and TLR9, mediating their translocation from the endoplasmic reticulum to the endolysosome, hence allowing proper activation by nucleic acid ligands. We found that the triple deficient ‘3d’ mice, which lack functional UNC93B1, are hyper-susceptible to infection w... | One third of the human population in the world is chronically infected with Toxoplasma gondii. While the majority of infected individuals are asymptomatic, toxoplasmosis is a major cause of congenital disease, abortion, and a life-threatening opportunistic disease in immunocompromised individuals. Early activation of t... | Toxoplasma gondii is a widespread obligate intracellular protozoan parasite, which establishes itself in the brain and muscle tissues, persisting for life in humans and other vertebrate hosts [1]. One of the most distinctive aspects of T. gondii life cycle is the establishment of an often benign chronic infection, whic... |
10.1371/journal.ppat.1007257 | HLA-C downregulation by HIV-1 adapts to host HLA genotype | HIV-1 can downregulate HLA-C on infected cells, using the viral protein Vpu, and the magnitude of this downregulation varies widely between primary HIV-1 variants. The selection pressures that result in viral downregulation of HLA-C in some individuals, but preservation of surface HLA-C in others are not clear. To bett... | HLA-C is a member of the major histocompatibility complex class-I (MHC-I) family of molecules which are integral to many responses of innate and adaptive immunity. HIV-1 can downregulate the expression level of HLA-C on infected cells, using the viral protein Vpu, but the magnitude of HLA-C downregulation varies widely... | Human Leukocyte Antigen class-I (HLA-I) molecules present peptides from intracellular proteins at the cell surface. Classical HLA-I molecules are highly polymorphic and expressed from three loci, HLA-A,—B and—C, which differ in some respects. Polymorphism is most pronounced for HLA-B, and HLA-A/B are expressed at aroun... |
10.1371/journal.pgen.1003250 | DNA–Methylome Analysis of Mouse Intestinal Adenoma Identifies a Tumour-Specific Signature That Is Partly Conserved in Human Colon Cancer | Aberrant CpG methylation is a universal epigenetic trait of cancer cell genomes. However, human cancer samples or cell lines preclude the investigation of epigenetic changes occurring early during tumour development. Here, we have used MeDIP-seq to analyse the DNA methylome of APCMin adenoma as a model for intestinal c... | The formation and progression of tumours to metastatic disease is driven by two major mechanisms, i.e. genetic alterations that activate oncogenes or inactivate tumour suppressor genes, and changes in the epigenome that cause variations in the expression of the genetic information. A deeper understanding of the interac... | Epigenetic mechanisms play critical roles in controlling the cellular transcript repertoire and ultimately cellular phenotypes. The methylation of cytosine bases of CpG dinucleotides, as well as the covalent modification of histone proteins represent major target sites of the protein complexes involved in epigenetic co... |
10.1371/journal.pgen.1007470 | Flexibility and constraint: Evolutionary remodeling of the sporulation initiation pathway in Firmicutes | The evolution of signal transduction pathways is constrained by the requirements of signal fidelity, yet flexibility is necessary to allow pathway remodeling in response to environmental challenges. A detailed understanding of how flexibility and constraint shape bacterial two component signaling systems is emerging, b... | Survival in a changing world requires signal transduction circuitry that can evolve to sense and respond to new environmental challenges. The Firmicute sporulation initiation (Spo0) pathway is a compelling example of a pathway with a circuit diagram that has changed over the course of evolution. In Clostridium acetobut... | Responses to changing environmental conditions are mediated by signal transduction pathways that recognize a signal, convey that signal into the cell, and initiate an appropriate cellular response. In bacteria, two-component signaling systems, typically comprised of a histidine kinase (HK) and a cognate response regula... |
10.1371/journal.ppat.1000175 | Pseudomonas aeruginosa Suppresses Host Immunity by Activating the DAF-2 Insulin-Like Signaling Pathway in Caenorhabditis elegans | Some pathogens have evolved mechanisms to overcome host immune defenses by inhibiting host defense signaling pathways and suppressing the expression of host defense effectors. We present evidence that Pseudomonas aeruginosa is able to suppress the expression of a subset of immune defense genes in the animal host Caenor... | Bacterial pathogens have evolved mechanisms to overcome the immune defenses that animals and plants deploy against them. In some cases, this involves directly interfering with the proper functioning of the immune system. Because pathogens that employ these strategies are often the most deadly and difficult to treat, it... | The innate immune system is a genetically-encoded host defense mechanism that constitutes the first line of defense against pathogens in plants and animals. Innate immunity in animals is evolutionarily ancient, and the molecular components of mammalian innate immunity are partly conserved in invertebrates such as Droso... |
10.1371/journal.ppat.1007938 | Endocytosis of flavivirus NS1 is required for NS1-mediated endothelial hyperpermeability and is abolished by a single N-glycosylation site mutation | Arthropod-borne flaviviruses cause life-threatening diseases associated with endothelial hyperpermeability and vascular leak. We recently found that vascular leak can be triggered by dengue virus (DENV) non-structural protein 1 (NS1) via the disruption of the endothelial glycocalyx-like layer (EGL). However, the molecu... | Vascular leak is a hallmark of severe dengue disease. Recently, our group revealed a critical role for NS1 in induction of endothelial hyperpermeability and vascular leakage in an endothelial cell-intrinsic manner. However, the upstream pathway triggered by NS1, as well as the molecular determinants of NS1 required for... | Dengue virus (DENV) is a mosquito-borne flavivirus, and infection with any of its four serotypes (DENV1-4) can result in inapparent infection, classic dengue fever, or dengue hemorrhagic fever/dengue shock syndrome–severe manifestations characterized by vascular leak that can lead to shock and death [1]. West Nile viru... |
10.1371/journal.pntd.0000951 | Evaluation of Urine CCA Assays for Detection of Schistosoma mansoni Infection in Western Kenya | Although accurate assessment of the prevalence of Schistosoma mansoni is important for the design and evaluation of control programs, the most widely used tools for diagnosis are limited by suboptimal sensitivity, slow turn-around-time, or inability to distinguish current from former infections. Recently, two tests tha... | Control efforts for schistosomiasis have in part been hampered by the lack of a sensitive and accurate test that can be utilized to rapidly map the prevalence of the disease in different areas. Recently, new tests have become commercially available that may address this problem. This study was designed to compare the n... | Recently, there has been increased interest in the development and assessment of control and elimination programs for schistosomiasis [1]. For design of effective control programs, it is important to determine an accurate estimate of infection prevalence in the program area. The method most commonly used for diagnosis ... |
10.1371/journal.pgen.1006247 | A let-7-to-miR-125 MicroRNA Switch Regulates Neuronal Integrity and Lifespan in Drosophila | Messenger RNAs (mRNAs) often contain binding sites for multiple, different microRNAs (miRNAs). However, the biological significance of this feature is unclear, since such co-targeting miRNAs could function coordinately, independently, or redundantly with one another. Here, we show that two co-transcribed Drosophila miR... | Deregulation of mRNAs that are targeted by multiple miRNAs is a common feature of a number of diseased states including neurodegenerative disorders. The currently accepted model is that the combined action of all binding miRNAs ensures target repression. Here, we show that two co-expressed miRNAs exert distinct outcome... | RNA-mediated post-transcriptional mechanisms regulate the accumulation and homeostasis of proteins not only during animal development but also during adulthood [1–3]. These mechanisms include regulation by microRNAs (miRNAs), a class of small non-coding RNAs that usually silence messenger RNAs (mRNAs) by binding to par... |
10.1371/journal.pmed.1002647 | Seasonal plasticity of cognition and related biological measures in adults with and without Alzheimer disease: Analysis of multiple cohorts | There are few data concerning the association between season and cognition and its neurobiological correlates in older persons—effects with important translational and therapeutic implications for the diagnosis and treatment of Alzheimer disease (AD). We aimed to measure these effects.
We analyzed data from 3,353 parti... | Season affects many aspects of human biology including human brain biology.
Several studies suggest that season may be associated with cognitive function in some populations of younger adults, but data from older adults is lacking and little is known about the underlying mechanisms.
We studied 3,353 older adults in the... | Seasonal rhythms modulate several aspects of human behavior and physiology including brain functions such as mood in seasonal affective disorder [1], symptom onset in schizophrenia [2], and functional MRI (fMRI) brain responses to cognitive tasks [3]. Several studies suggest that season may modulate cognition in younge... |
10.1371/journal.pntd.0006932 | Geographic variation in dengue seroprevalence and force of infection in the urban paediatric population of Indonesia | Understanding the heterogeneous nature of dengue transmission is important for prioritizing and guiding the implementation of prevention strategies. However, passive surveillance data in endemic countries are rarely adequately informative. We analyzed data from a cluster-sample, cross-sectional seroprevalence study in ... | Understanding the geographic distribution of dengue transmission intensity is of key importance for guiding dengue prevention strategies, including vaccination. We analyzed age-stratified data from a cross-sectional survey of 30 randomly selected urban sub-districts in Indonesia and estimated the force of infection (FO... | Dengue is the most widely distributed mosquito-borne viral infection; 40% of the world’s population is at risk, three-quarters of whom live in the Asia-Pacific region [1–3]. However, the burden of dengue disease remains poorly quantified in many dengue endemic countries in Asia because existing passive surveillance sys... |
10.1371/journal.pcbi.1002138 | Essential Requirements for Robust Signaling in Hfq Dependent Small RNA Networks | Bacteria possess networks of small RNAs (sRNAs) that are important for modulating gene expression. At the center of many of these sRNA networks is the Hfq protein. Hfq's role is to quickly match cognate sRNAs and target mRNAs from among a large number of possible combinations and anneal them to form duplexes. Here we s... | Bacteria have small RNAs (sRNAs) which are important modulators of gene expression. Many of these sRNAs require the Hfq protein to mediate their binding to specific target mRNAs which alters the translation and/or degradation of the mRNAs. The Hfq protein has a difficult task; it has to correctly pair cognate sRNAs and... | Small RNAs (sRNAs) regulate a wide variety of pathways in prokaryotes [reviewed in 1]. An important subset of these small RNAs act in trans with the aid of the Hfq protein to decrease (“silencing”) or increase (“activation”) the expression of specific target mRNAs. These trans-acting, Hfq-dependent sRNAs, which have im... |
10.1371/journal.pntd.0003165 | Where the Road Ends, Yaws Begins? The Cost-effectiveness of Eradication versus More Roads | A disabling and disfiguring disease that “begins where the road ends”, yaws is targeted by WHO for eradication by the year 2020. The global campaign is not yet financed. To evaluate yaws eradication within the context of the post-2015 development agenda, we perform a somewhat allegorical cost-effectiveness analysis of ... | A disabling and disfiguring disease that “begins where the road ends” (among poor and isolated communities), yaws is targeted by WHO for eradication by the year 2020. The global campaign is not yet financed. We provide benchmarks for the cost and health effects of global yaws eradication, based on evidence from four ya... | Yaws is one of two neglected tropical diseases (NTDs) targeted by the World Health Organization (WHO) for eradication. A 2013 World Health Assembly resolution calls for its eradication by the year 2020. A disabling and disfiguring disease that “begins where the road ends” it is found primarily among poor and isolated c... |
10.1371/journal.pbio.1000384 | A Large Fraction of Extragenic RNA Pol II Transcription Sites Overlap Enhancers | Mammalian genomes are pervasively transcribed outside mapped protein-coding genes. One class of extragenic transcription products is represented by long non-coding RNAs (lncRNAs), some of which result from Pol_II transcription of bona-fide RNA genes. Whether all lncRNAs described insofar are products of RNA genes, howe... | Mammalian genomes contain vast intergenic regions that are extensively transcribed and generate various types of short and long non-coding RNAs (ncRNAs). Although in some cases specific functions have been assigned to intergenic transcripts, the functional significance of this transcriptional output remains largely unk... | A most striking finding of modern genomic biology has been the identification of a large amount of transcription that occurs outside mapped protein-coding genes and generates a heterogeneous spectrum of transcripts [1],[2], which may in principle exert broad regulatory or effector functions [3]–[5]. These data imply th... |
10.1371/journal.pgen.1002899 | Melanophore Migration and Survival during Zebrafish Adult Pigment Stripe Development Require the Immunoglobulin Superfamily Adhesion Molecule Igsf11 | The zebrafish adult pigment pattern has emerged as a useful model for understanding the development and evolution of adult form as well as pattern-forming mechanisms more generally. In this species, a series of horizontal melanophore stripes arises during the larval-to-adult transformation, but the genetic and cellular... | Vertebrate pigment patterns are stunningly diverse and have been an important model of pattern formation for more than a century. Nevertheless, we still know remarkably little about the genes and cell behaviors that underlie the generation of specific patterns. To elucidate such mechanisms, a large number of pigment pa... | Pigment patterns are among the most striking of vertebrate traits and nowhere are these patterns more diverse than in teleost fishes [1]–[4]. In this group, a stunning array of pigment patterns function in predation avoidance, shoaling, and mate choice and are thought to have played important roles in speciation [5]–[8... |
10.1371/journal.ppat.1001129 | Crystal Structure of Legionella DotD: Insights into the Relationship between Type IVB and Type II/III Secretion Systems | The Dot/Icm type IVB secretion system (T4BSS) is a pivotal determinant of Legionella pneumophila pathogenesis. L. pneumophila translocate more than 100 effector proteins into host cytoplasm using Dot/Icm T4BSS, modulating host cellular functions to establish a replicative niche within host cells. The T4BSS core complex... | Bacterial pathogens deliver virulence factors such as exotoxins and effector proteins to host cells. To accomplish this bacteria utilize specialized secretion systems such as type III and type IV secretion systems. The type IV secretion systems (T4SS) play a central role in pathogenesis by many important pathogens incl... | Pathogenic bacteria transport functional proteins, such as effector proteins and exotoxins, across bacterial membranes. These bacterial proteins interact with host proteins to manipulate host cellular functions. Therefore, the secretion process plays a central role in bacterial pathogenesis. To accomplish this, bacteri... |
10.1371/journal.pntd.0007708 | Leishmaniasis and tumor necrosis factor alpha antagonists in the Mediterranean basin. A switch in clinical expression | Tumor necrosis factor alpha (TNF-α) blockers are recognized as a risk factor for reactivation of granulomatous infections. Leishmaniasis has been associated with the use of these drugs, although few cases have been reported.
We performed a retrospective observational study including patients with confirmed leishmaniasi... | Tumor necrosis factor alpha (TNF-α) blockers are widely used in numerous inflammatory diseases such rheumatoid arthritis, psoriasis or inflammatory bowel diseases. They have been recognized as a risk factor for reactivation of granulomatous infections. Although few cases have been reported, Leishmaniasis has been assoc... | Tumor Necrosis Factor-α (TNF-α) is a crucial cytokine in the inflammatory cascade by activating the type 1 T helper (Th1) immune response, enhancing the activity of the macrophages and essential for the formation and maintenance of granulomas [1].
Since TNF-α has been implicated in numerous immune-mediated disorders, ... |
10.1371/journal.pntd.0005375 | Unexpectedly high leprosy seroprevalence detected using a random surveillance strategy in midwestern Brazil: A comparison of ELISA and a rapid diagnostic test | Leprosy diagnosis is mainly based on clinical evaluation, although this approach is difficult, especially for untrained physicians. We conducted a temporary campaign to detect previously unknown leprosy cases in midwestern Brazil and to compare the performance of different serological tests.
A mobile clinic was station... | Leprosy is a disease that affects the skin and peripheral nervous system, caused by Mycobacterium leprae (M. leprae), that to survive hides itself within the host cells and grows slowly. Its diagnosis is difficult and requires trained physicians. Laboratorial tests are frequently negative depending on individual respon... | Leprosy diagnosis is mainly based on clinical evaluation [1]. This approach represents a low-cost strategy; however, it is subjective and dependent upon the experience of the examiner, a difficult task for untrained physicians [2].
Early recognition is critical for the prompt initiation of multidrug therapy (MDT) to p... |
10.1371/journal.pgen.1005998 | Arabidopsis AtMORC4 and AtMORC7 Form Nuclear Bodies and Repress a Large Number of Protein-Coding Genes | The MORC family of GHKL ATPases are an enigmatic class of proteins with diverse chromatin related functions. In Arabidopsis, AtMORC1, AtMORC2, and AtMORC6 act together in heterodimeric complexes to mediate transcriptional silencing of methylated DNA elements. Here, we studied Arabidopsis AtMORC4 and AtMORC7. We found t... | Keeping selfish genetic elements–such as transposons–silent, while maintaining access to genes, is a fundamental challenge for eukaryotes. Different pathways frequently converge in order to identify transposons and maintain their repression, and in Arabidopsis thaliana, transposons are marked with DNA methylation. Prev... | Maintaining regulatory access to genes while repressing the expression of potentially deleterious transposable elements is a fundamental challenge for living organisms. Eukaryotes achieve this in part by parsing their genomes into functional units characterized by distinct chromatin features [1,2]. The most stable chro... |
10.1371/journal.pgen.1002152 | Unexpected Role for Helicobacter pylori DNA Polymerase I As a Source of Genetic Variability | Helicobacter pylori, a human pathogen infecting about half of the world population, is characterised by its large intraspecies variability. Its genome plasticity has been invoked as the basis for its high adaptation capacity. Consistent with its small genome, H. pylori possesses only two bona fide DNA polymerases, Pol ... | Helicobacter pylori is the main cause of ulcers and gastric cancers. One the characteristics of this bacterial species is that it displays an amazing capacity to change its genetic information. This genetic variability provides H. pylori with an adaptation potential that allows it to successfully colonise the stomach o... | Phenotypic selection from a pool of genetic variants present in their population allows prokaryotes to successfully adapt to specific niches and changing environments. The gram-negative bacterium Helicobacter pylori is one of the most successful human pathogens. Indeed, it colonises the stomach mucosa of about half the... |
10.1371/journal.pntd.0003656 | Anthelmintic Activity In Vivo of Epiisopiloturine against Juvenile and Adult Worms of Schistosoma mansoni | Schistosomiasis is a serious disease currently estimated to affect more that 207 million people worldwide. Due to the intensive use of praziquantel, there is increasing concern about the development of drug-resistant strains. Therefore, it is necessary to search for and investigate new potential schistosomicidal compou... | Schistosomiasis, a disease caused by worms from the genus Schistosoma, is one of the most widespread neglected tropical diseases in the world. Due to the intensive use of praziquantel, some reports of drug resistance have emerged. Thus it is important to search for new chemotherapeutic agents for the treatment disease.... | Schistosomiasis is a disease mainly found in tropical regions, whose infectious agents are Schistosoma spp., including Schistosoma mansoni [1]. This disease is currently one of the most widely occurring neglected tropical diseases with high levels of incidence in Asia, Africa and Latin America. Studies have shown that ... |
10.1371/journal.pgen.1006256 | The Musashi 1 Controls the Splicing of Photoreceptor-Specific Exons in the Vertebrate Retina | Alternative pre-mRNA splicing expands the coding capacity of eukaryotic genomes, potentially enabling a limited number of genes to govern the development of complex anatomical structures. Alternative splicing is particularly prevalent in the vertebrate nervous system, where it is required for neuronal development and f... | Vertebrates possess extraordinarily complex nervous systems that are formed by hundreds of different types of neurons. This neuronal diversity is achieved in part through the expression of specific sets of genes. In addition, neurons use alternative splicing to a much higher degree than other cells to produce neuronal ... | Vertebrate nervous systems contain numerous types of neurons with characteristic morphology, connectivity, electrophysiological properties, and neurotransmitter signatures. Single cell transcriptome profiling studies reveal dozens of distinct gene expression profiles in the central nervous system (CNS) and the retina, ... |
10.1371/journal.pcbi.1003197 | Transcriptional Regulation of Lineage Commitment - A Stochastic Model of Cell Fate Decisions | Molecular mechanisms employed by individual multipotent cells at the point of lineage commitment remain largely uncharacterized. Current paradigms span from instructive to noise-driven mechanisms. Of considerable interest is also whether commitment involves a limited set of genes or the entire transcriptional program, ... | Stem cells have the capacity to both self-renew and differentiate into specialized cell lineages, thus sustaining tissue formation during embryonic development and permitting tissue homeostasis throughout adult life. Previous studies have suggested that stem cell commitment to a specific lineage may constitute a discre... | Understanding how primary stem and multipotent progenitor cells decide their fate is pivotal in studying mechanisms driving tissue development and maintenance in multicellular organisms. Despite considerable advances in ascribing key genes and regulatory circuits to specific lineages, the diversity of molecular mechani... |
10.1371/journal.ppat.1005523 | Initiation of RNA Polymerization and Polymerase Encapsidation by a Small dsRNA Virus | During the replication cycle of double-stranded (ds) RNA viruses, the viral RNA-dependent RNA polymerase (RdRP) replicates and transcribes the viral genome from within the viral capsid. How the RdRP molecules are packaged within the virion and how they function within the confines of an intact capsid are intriguing que... | Viral polymerases replicate the genome of the virus, which is essential for the synthesis of the progeny. All double-stranded (dsRNA) viruses have virion-associated polymerases that catalyze RNA synthesis within an intact capsid. Picobirnavirus (PBV) is a small dsRNA virus, and it has been shown that the capsid of PBV ... | Double-stranded (ds) RNA viruses are a diverse group of viruses that vary widely in host range (humans, animals, plants, fungi, and bacteria), genome segment number (one to twelve), and in the number of capsid layers, with many of them considered important pathogens of either agriculture or human health. A common featu... |
10.1371/journal.pgen.1005719 | The Eukaryotic Mismatch Recognition Complexes Track with the Replisome during DNA Synthesis | During replication, mismatch repair proteins recognize and repair mispaired bases that escape the proofreading activity of DNA polymerase. In this work, we tested the model that the eukaryotic mismatch recognition complex tracks with the advancing replisome. Using yeast, we examined the dynamics during replication of t... | During replication, errors that escape the replication machinery are identified and repaired by DNA mismatch repair proteins. A mismatch in the helix is recognized by MutS homologs and subsequent events include excision of the error-containing strand followed by re-synthesis. A critical step in this process is directin... | During cell division, accurate DNA replication is essential to preserve the integrity of the genome and defects in this process result in diseases including hereditary and sporadic cancers [1]. In eukaryotes, the replicative DNA polymerases, Polε and Polδ, perform leading and lagging strand synthesis respectively [2–5]... |
10.1371/journal.pbio.2001110 | How to Use a Chemotherapeutic Agent When Resistance to It Threatens the Patient | When resistance to anticancer or antimicrobial drugs evolves in a patient, highly effective chemotherapy can fail, threatening patient health and lifespan. Standard practice is to treat aggressively, effectively eliminating drug-sensitive target cells as quickly as possible. This prevents sensitive cells from acquiring... | When resistance to anticancer or antimicrobial drugs evolves in a patient, highly effective chemotherapy can fail, threatening patient health and lifespan. Standard practice is to prevent sensitive cells from acquiring resistance by eliminating them as quickly as possible with aggressive chemotherapy. This approach, ho... | How should an anticancer or antimicrobial drug be used when the emergence of drug resistance is a major threat to the quality and duration of a patient’s life? This threat is prominent in a variety of clinical settings, including bacterial infections (e.g., [1–6]) and many cancers for which only temporary remission is ... |
10.1371/journal.pcbi.1004364 | Thermodynamics and H2 Transfer in a Methanogenic, Syntrophic Community | Microorganisms in nature do not exist in isolation but rather interact with other species in their environment. Some microbes interact via syntrophic associations, in which the metabolic by-products of one species serve as nutrients for another. These associations sustain a variety of natural communities, including tho... | Natural and engineered microbial communities can contain up to hundreds of interacting microbes. These interactions may be positive, negative, or neutral, as well as obligate or facultative. Syntrophy is an obligate, positive interaction, in which one species lives off the metabolic by-products of another. Syntrophic a... | Microorganisms in nature engage in a variety of interactions with other species in their environment. Syntrophy is one such type of inter-species interaction in which one species lives off the metabolic by-products of another [1–3]. Synthetic methanogenic communities [4] are typically tightly constrained by thermodynam... |
10.1371/journal.pgen.1004499 | Obesity-Linked Homologues TfAP-2 and Twz Establish Meal Frequency in Drosophila melanogaster | In all animals managing the size of individual meals and frequency of feeding is crucial for metabolic homeostasis. In the current study we demonstrate that the noradrenalin analogue octopamine and the cholecystokinin (CCK) homologue Drosulfakinin (Dsk) function downstream of TfAP-2 and Tiwaz (Twz) to control the numbe... | The size of individual meals and feeding frequency are important for homeostatic control. Due to the complex neuroendocrine system regulating human food intake it is difficult to uncover the mechanisms underlying eating disorders. The genetically tractable model system Drosophila melanogaster has a comparatively simple... | The human genes TFAP2B (encoding AP-2β) and KCTD15 were strongly linked to obesity in multiple genome-wide association studies (GWAS) [1]–[4], though it is still not understood how they regulate obesity. In the fruit fly Drosophila melanogaster, TFAP2B and KCTD15 are both highly conserved, encoded by TfAP-2 and Tiwaz (... |
10.1371/journal.pntd.0000226 | Immunity to Distinct Sand Fly Salivary Proteins Primes the Anti-Leishmania Immune Response towards Protection or Exacerbation of Disease | Leishmania parasites are transmitted in the presence of sand fly saliva. Together with the parasite, the sand fly injects biologically active salivary components that favorably change the environment at the feeding site. Exposure to bites or to salivary proteins results in immunity specific to these components. Mice im... | In vector-borne diseases, the role of vectors has been overlooked in the search for vaccines. Nonetheless, there is a body of evidence showing the importance of salivary proteins of vectors in pathogen transmission. Leishmaniasis is a neglected vector-borne disease transmitted by sand flies. Pre-exposure to sand fly sa... | In leishmaniasis, phlebotomine sand flies transmit Leishmania parasites to a mammalian host by depositing the parasite in the skin during probing and feeding. Together with the parasite, sand flies deposit a repertoire of salivary components that assist the sand fly in getting a blood meal [1]. Some of these salivary p... |
10.1371/journal.ppat.1000866 | A Differential Role for Macropinocytosis in Mediating Entry of the Two Forms of Vaccinia Virus into Dendritic Cells | Vaccinia virus (VACV) is being developed as a recombinant viral vaccine vector for several key pathogens. Dendritic cells (DCs) are specialised antigen presenting cells that are crucial for the initiation of primary immune responses; however, the mechanisms of uptake of VACV by these cells are unclear. Therefore we exa... | Vaccinia virus (VACV) is a relative of the smallpox virus and was used for many decades as a successful vaccine that contributed to the eradication of smallpox. Today, through genetic recombination technology, VACV shows potential as a modern vaccine for many unconquered diseases including HIV and cancer. Dendritic cel... | Vaccinia virus (VACV) is best known for its role as a vaccine in the global eradication of smallpox. Research on VACV has been pursued with renewed fervour in recent years in light of its potential use as an effective vaccine vector for viral and parasitic infections as well as cancer. Exploiting certain aspects of the... |
10.1371/journal.pgen.1005148 | Transgenerational Inheritance of Diet-Induced Genome Rearrangements in Drosophila | Ribosomal RNA gene (rDNA) copy number variation modulates heterochromatin formation and influences the expression of a large fraction of the Drosophila ge-nome. This discovery, along with the link between rDNA, aging, and disease, high-lights the importance of understanding how natural rDNA copy number variation arises... | We show that altering the nutritional medium of Drosophila cultures, emulating dietary largess in the wild, increases expression of the high copy-number ribosomal RNA genes and results in rDNA instability and loss. The reduction in gene copy number occurs both in somatic and germ cells, such that altered copy numbers a... | It is clear that an organism’s gene expression patterns are responsive to environmental input. Often, this influence is not limited to short-term regulatory changes, but can persist through multiple cell divisions and can, in some cases, be transmitted to offspring. Typically, such changes are identified as “epigenetic... |
10.1371/journal.pgen.1002075 | Epistasis between Beneficial Mutations and the Phenotype-to-Fitness Map for a ssDNA Virus | Epistatic interactions between genes and individual mutations are major determinants of the evolutionary properties of genetic systems and have therefore been well documented, but few quantitative data exist on epistatic interactions between beneficial mutations, presumably because such mutations are so much rarer than... | Epistasis, the extent to which the effects of a mutation depend on its genetic context, can have profound effects on the evolutionary process and strongly affects our understanding of the prevalence of sexual reproduction. It has been investigated in a diverse array of organisms but almost exclusively for deleterious m... | The nature of epistatic interactions between loci or mutations is a major component of evolutionary theories. For example, epistasis is thought to have been important in the evolution of sexual reproduction [1], [2] and reproductive isolation between incipient species [3]–[6]. In models of adaptation and fitness landsc... |
10.1371/journal.pgen.1007863 | Diapause induces functional axonal regeneration after necrotic insult in C. elegans | Many neurons are unable to regenerate after damage. The ability to regenerate after an insult depends on life stage, neuronal subtype, intrinsic and extrinsic factors. C. elegans is a powerful model to test the genetic and environmental factors that affect axonal regeneration after damage, since its axons can regenerat... | Diapause entry and hibernation have the striking ability to protect the nervous system from diverse types of damage. Here we show that the diapausing dauer larvae of C. elegans regenerate broken mechanosensory neurons that were damaged by the hyperactivation of degenerins (MEC-4d) or by axotomy during diapause. This re... | Animals that enter diapause or hibernate not only survive for long periods of time without eating, but also preserve their nervous systems [1– 3]. This protection has been proposed to be a result of a high capacity for detoxification and maintenance of low oxidative stress [1– 4].
The bacterivore nematode Caenorhabdit... |
10.1371/journal.pntd.0003645 | Molecular Epidemiology of Rabies Viruses Circulating in Two Rabies Endemic Provinces of Laos, 2011–2012: Regional Diversity in Southeast Asia | Although rabies is endemic in Laos, genetic characterization of the viruses in this country is limited. There are growing concerns that development in the region may have increased transport of dog through Laos for regional dog meat consumption, and that this may cause spillover of the viruses from dogs brought here fr... | Laos is a land-locked rabies-endemic country in Southeast Asia that is surrounded by five rabies-endemic countries. Thus, there is increasing concern that the epidemiology of rabies in Laos is influenced by infrastructure development and economic activities, including international transport of dogs for meat consumptio... | Globally, an estimated 60,000 people die of rabies annually, and more than 31,000 of these deaths occur in Asia [1,2]. Among various Asian regions, the countries of the Association of South East Asian Nations (ASEAN) have been working towards substantial economic development. A call for elimination of rabies by 2020 hi... |
10.1371/journal.pgen.1007643 | Identification of UHRF2 as a novel DNA interstrand crosslink sensor protein | The Fanconi Anemia (FA) pathway is important for repairing interstrand crosslinks (ICLs) between the Watson-Crick strands of the DNA double helix. An initial and essential stage in the repair process is the detection of the ICL. Here, we report the identification of UHRF2, a paralogue of UHRF1, as an ICL sensor protein... | Fanconi Anemia is a genetic disease where patients typically have congenital abnormalities, develop bone marrow failure and suffer from cancer predisposition. The cells in patients have a reduced ability to repair a type of DNA damage where the two strands of the DNA double helix are physically linked together, and thi... | DNA interstrand crosslinks (ICLs) can obstruct the critical processes of transcription and replication [1]. If unrepaired, an ICL can perturb accurate chromosome segregation during mitosis when replication has not been completed due to the crosslink, this can additionally lead to replication fork collapse causing doubl... |
10.1371/journal.pmed.1002574 | Estimating the real-world effects of expanding antiretroviral treatment eligibility: Evidence from a regression discontinuity analysis in Zambia | Although randomized trials have established the clinical efficacy of treating all persons living with HIV (PLWHs), expanding treatment eligibility in the real world may have additional behavioral effects (e.g., changes in retention) or lead to unintended consequences (e.g., crowding out sicker patients owing to increas... | Universal treatment with ART regardless of CD4 count (i.e., treat-all) is based on randomized controlled trials showing the biologic efficacy of ART, but the public impact of expanding ART eligibility also depends on the behavior of patients and the capacity of health systems to absorb an influx of new patients.
Direct... | Although randomized controlled trials (RCTs) have demonstrated that antiretroviral therapy (ART) in persons living with HIV (PLWHs), irrespective of CD4 levels, has broad clinical benefits, policies to expand HIV eligibility in the real world may have important additional effects that are not captured in the context of... |
10.1371/journal.pntd.0002873 | Spatial Distribution of the Risk of Dengue and the Entomological Indicators in Sumaré, State of São Paulo, Brazil | Dengue fever is a major public health problem worldwide, caused by any of four virus (DENV-1, DENV-2, DENV-3 and DENV-4; Flaviviridae: Flavivirus), transmitted by Aedes aegypti mosquito. Reducing the levels of infestation by A. aegypti is one of the few current strategies to control dengue fever. Entomological indicato... | Dengue is a disease caused by a virus which has four serotypes DENV-1, DENV-2, DENV-3 and DENV-4. In Americas, A. aegypti is acknowledged as the only dengue vector in America. Currently the only strategy to prevent dengue is controlling A. aegypti mosquitoes. The generalized additive model was used to understand the re... | Dengue is a disease caused by any of four virus (DENV-1, DENV-2, DENV-3 and DENV-4; Flaviviridae: Flavivirus) and has become a major global health issue. An epidemic similar to dengue was registered in 1699 in Central America. In Philadelphia, USA, a major epidemic occurred in 1780 and epidemics became common in the ea... |
10.1371/journal.pntd.0002732 | Prevalence of Trachoma at Sub-District Level in Ethiopia: Determining When to Stop Mass Azithromycin Distribution | To eliminate blinding trachoma, the World Health Organization emphasizes implementing the SAFE strategy, which includes annual mass drug administration (MDA) with azithromycin to the whole population of endemic districts. Prevalence surveys to assess impact at the district level are recommended after at least 3 years o... | Trachoma, the leading cause of preventable blindness, is targeted for “elimination as a public health problem” by the year 2020. National programs are implementing the recommended strategy of surgery, antibiotics, facial cleanliness, and environmental improvements (SAFE) to meet this target. Many programs are currently... | Trachoma accounts for approximately 3% of global blindness and is targeted for “elimination as a public health problem” by the year 2020 [1], [2]. Trachoma is estimated to be endemic in 53 countries of which 35 have begun scaling-up or have fully implemented the recommended SAFE strategy for reaching the elimination ta... |
10.1371/journal.pgen.1006475 | The C. elegans Discoidin Domain Receptor DDR-2 Modulates the Met-like RTK–JNK Signaling Pathway in Axon Regeneration | The ability of specific neurons to regenerate their axons after injury is governed by cell-intrinsic regeneration pathways. However, the signaling pathways that orchestrate axon regeneration are not well understood. In Caenorhabditis elegans, initiation of axon regeneration is positively regulated by SVH-2 Met-like gro... | An axon’s ability to regenerate after injury is governed by cell-intrinsic regeneration pathways. The C. elegans JNK MAP kinase pathway is required for the regrowth of neurons after injury. Previously, we identified several svh genes involved in JNK-mediated signaling. Among them, the svh-1 and svh-2 genes encode a gro... | The ability of a neuron to regenerate in response to injury is modulated by a balance of extrinsic factors that promote or inhibit axon outgrowth, and by intrinsic processes that regulate axon growth potential. Most invertebrate neurons are able to regenerate, as are neurons in the mammalian peripheral nervous system. ... |
10.1371/journal.pcbi.1000083 | Reconstruction of Protein Backbones from the BriX Collection of Canonical Protein Fragments | As modeling of changes in backbone conformation still lacks a computationally efficient solution, we developed a discretisation of the conformational states accessible to the protein backbone similar to the successful rotamer approach in side chains. The BriX fragment database, consisting of fragments from 4 to 14 resi... | Large-scale DNA sequencing efforts produce large amounts of protein sequence data. However, in order to understand the function of a protein, its tertiary three-dimensional structure is required. Despite worldwide efforts in structural biology, experimental protein structures are determined at a significantly slower pa... | High-resolution structure determination of proteins and protein complexes via experimental methods occurs at a significantly slower pace than the collection of novel protein sequences. As a result, less than 30% of human proteins have a known structure in the Protein Data Bank and the percentage for other species is si... |
10.1371/journal.pgen.0030096 | Network-Based Analysis of Affected Biological Processes in Type 2 Diabetes Models | Type 2 diabetes mellitus is a complex disorder associated with multiple genetic, epigenetic, developmental, and environmental factors. Animal models of type 2 diabetes differ based on diet, drug treatment, and gene knockouts, and yet all display the clinical hallmarks of hyperglycemia and insulin resistance in peripher... | Type 2 diabetes mellitus currently affects millions of people. It is clinically characterized by insulin resistance in addition to an impaired glucose response and associated with numerous complications including heart disease, stroke, neuropathy, and kidney failure, among others. Accurate identification of the underly... | Type 2 diabetes mellitus (DM2) is a metabolic disorder characterized by abnormal hepatic glucose output, insulin resistance, and impaired insulin production [1,2]. DM2 has reached epidemic proportions and currently affects about 170 million people worldwide, with the figure projected to more than double by 2030 [3]. Th... |
10.1371/journal.pbio.1000570 | Stress-Induced Out-of-Context Activation of Memory | Inappropriate recollections and responses in stressful conditions are hallmarks of post-traumatic stress disorder and other anxiety and mood disorders, but how stress contributes to the disorders is unclear. Here we show that stress itself reactivates memories even if the memory is unrelated to the stressful experience... | This work identifies a powerful effect of stressful experiences on memories. We report that a single intensely stressful experience can activate memories in a situation that has essentially no physical or motivational relationship to the stressful experience. Using a forced-swim test as a stressor in rats, we find that... | Inappropriate negative responses in emotionally neutral circumstances and the development of negative associations to harmless stimuli are core, debilitating features of post-traumatic stress disorder (PTSD), depression, and a host of anxiety and mood disorders. The possibility that stress itself might promote inapprop... |
10.1371/journal.pgen.1007381 | SHOC1 is a ERCC4-(HhH)2-like protein, integral to the formation of crossover recombination intermediates during mammalian meiosis | Chromosome segregation errors during meiosis result in the formation of aneuploid gametes and are the leading cause of pregnancy loss and birth defects in humans. Proper chromosome segregation requires pairwise associations of maternal and paternal homologous chromosomes. Chiasmata, which are the cytological manifestat... | Meiosis is a specialized type of cell division in which haploid gametes are generated to counterbalance the doubling of the chromosome number occurring at fertilization. Proper chromosome segregation requires pairwise associations of the maternal and paternal homologous chromosomes. This is provided by chiasmata, which... | Cells in meiosis undergo two rounds of chromosome segregation after only one round of DNA replication. This highly regulated, specialized cell division generates haploid gametes containing a single copy of each chromosome. For maternal and paternal copies of each chromosome to segregate properly, the homologs must firs... |
10.1371/journal.ppat.1002822 | Activation and Proteolytic Activity of the Treponema pallidum Metalloprotease, Pallilysin | Treponema pallidum is a highly invasive pathogen that undergoes rapid dissemination to establish widespread infection. Previous investigations identified the T. pallidum adhesin, pallilysin, as an HEXXH-containing metalloprotease that undergoes autocatalytic cleavage and degrades laminin and fibrinogen. In the current ... | Syphilis, caused by the spirochete Treponema pallidum, is a chronic sexually transmitted disease which infects 12 million people annually. Treponema pallidum is highly invasive and undergoes widespread dissemination via the circulatory system. Similar to other invasive pathogens, T. pallidum has been shown to express a... | The expression of host-interacting proteases has been shown to contribute to the pathogenesis of bacteria of medical interest by promoting host colonization and immune evasion, acquisition of nutrients, tissue invasion and dissemination of infection. Several pathogenic bacteria, including Streptococcus pneumoniae [1], ... |
10.1371/journal.pntd.0002981 | The Population Structure of Vibrio cholerae from the Chandigarh Region of Northern India | Cholera infection continues to be a threat to global public health. The current cholera pandemic associated with Vibrio cholerae El Tor has now been ongoing for over half a century.
Thirty-eight V. cholerae El Tor isolates associated with a cholera outbreak in 2009 from the Chandigarh region of India were characterised... | Vibrio cholerae is a diarrheal pathogen that is responsible for substantial morbidity and mortality worldwide. Historically, seven pandemics of cholera have been recognized, with classical biotype strains associated with the sixth and the El Tor biotype with the seventh (current) pandemic. Recently multi-drug resistant... | Cholera, caused by the Gram-negative bacterium Vibrio cholerae, is classically associated with rapidly dehydrating watery diarrhoea. Although more than 200 serogroups of V. cholerae have been identified; only the O1 and O139 serogroups are associated with epidemic and pandemic outbreaks. Historically, seven pandemics o... |
10.1371/journal.pcbi.1004126 | Model-Free RNA Sequence and Structure Alignment Informed by SHAPE Probing Reveals a Conserved Alternate Secondary Structure for 16S rRNA | Discovery and characterization of functional RNA structures remains challenging due to deficiencies in de novo secondary structure modeling. Here we describe a dynamic programming approach for model-free sequence comparison that incorporates high-throughput chemical probing data. Based on SHAPE probing data alone, ribo... | Despite the clear functional importance of structure in RNA molecules, it remains very difficult to correctly identify and annotate similar RNA structures because their sequences are often poorly conserved even for RNAs that form very similar higher-order structures. A solution is to use a metric that identifies struct... | RNA is a central participant in gene expression and regulation [1]. However, for a vast majority of RNA transcripts, the positions and roles of higher-order structure are unknown. Sequence comparison approaches can be powerful tools in the discovery and annotation of functional RNA motifs. In related functional RNAs, c... |
10.1371/journal.ppat.1004754 | Cerebrospinal Fluid Cytokine Profiles Predict Risk of Early Mortality and Immune Reconstitution Inflammatory Syndrome in HIV-Associated Cryptococcal Meningitis | Understanding the host immune response during cryptococcal meningitis (CM) is of critical importance for the development of immunomodulatory therapies. We profiled the cerebrospinal fluid (CSF) immune-response in ninety patients with HIV-associated CM, and examined associations between immune phenotype and clinical out... | Cryptococcal meningitis is a severe opportunistic infection, estimated to kill several hundred thousand HIV-infected individuals each year. One of the factors contributing to this high death toll is the inadequacy of antifungal treatments. As few novel antifungal drugs are being developed, several groups have started t... | Cryptococcal meningitis (CM) is a leading cause of mortality in HIV-infected patients in low-resource settings [1, 2]. Current treatments for CM are inadequate, with high associated mortality [3–5], and high incidence of immune reconstitution inflammatory syndrome (IRIS) amongst those who survive and start antiretrovir... |
10.1371/journal.pgen.1000494 | GLS-1, a Novel P Granule Component, Modulates a Network of Conserved RNA Regulators to Influence Germ Cell Fate Decisions | Post-transcriptional regulatory mechanisms are widely used to influence cell fate decisions in germ cells, early embryos, and neurons. Many conserved cytoplasmic RNA regulatory proteins associate with each other and assemble on target mRNAs, forming ribonucleoprotein (RNP) complexes, to control the mRNAs translational ... | Germ cells differ from somatic cells in their unique potential to reproduce a multicellular organism. The immortal germ line links the successive generations in all metazoans, but its development is remarkably diverse. How germline development and survival are regulated in different organisms is far from understood. On... | Germ line and early embryonic gene expression rely largely on cytoplasmic mRNA control mechanisms, allowing for maximum flexibility of control [1]. A striking example is the unique ability of germ cells to transiently differentiate into gametes before forming a totipotent zygote upon fertilization. Many conserved cytop... |
10.1371/journal.pcbi.1003764 | Dendritic Nonlinearities Reduce Network Size Requirements and Mediate ON and OFF States of Persistent Activity in a PFC Microcircuit Model | Technological advances have unraveled the existence of small clusters of co-active neurons in the neocortex. The functional implications of these microcircuits are in large part unexplored. Using a heavily constrained biophysical model of a L5 PFC microcircuit, we recently showed that these structures act as tunable mo... | Working memory, the ability to retain information for a short period of time, is a fundamental cognitive function that shapes behavior. The cellular correlate of working memory is the prolonged spiking (persistent) activity of neurons in the prefrontal cortex. Impairments of prefrontal cortex functionalities and workin... | Small, tightly interconnected “clusters” of cortical neurons have recently been discovered in regions such as the visual, somatosensory and prefrontal cortex (PFC) [1]–[6], yet their role in cognitive processes remains unexplored. In the PFC, such microcircuits have been suggested to participate in persistent activity,... |
10.1371/journal.pgen.1000311 | Developmental Constraints on Vertebrate Genome Evolution | Constraints in embryonic development are thought to bias the direction of evolution by making some changes less likely, and others more likely, depending on their consequences on ontogeny. Here, we characterize the constraints acting on genome evolution in vertebrates. We used gene expression data from two vertebrates:... | Because embryonic development must proceed correctly for an animal to survive, changes in evolution are constrained according to their effects on development. Changes that disrupt development too dramatically are thus rare in evolution. While this has been long observed at the morphological level, it has been more diff... | To what extent do the processes of embryonic development constrain genome evolution? Correlations between developmental timing and morphological divergence have long been observed, but the mechanisms and molecular basis of such patterns are poorly understood. The most commonly used measure of selective pressure on the ... |
10.1371/journal.pgen.1006720 | A Wnt-planar polarity pathway instructs neurite branching by restricting F-actin assembly through endosomal signaling | Spatial arrangement of neurite branching is instructed by both attractive and repulsive cues. Here we show that in C. elegans, the Wnt family of secreted glycoproteins specify neurite branching sites in the PLM mechanosensory neurons. Wnts function through MIG-1/Frizzled and the planar cell polarity protein (PCP) VANG-... | Extrinsic cues instruct neurite branching patterns through cytoskeletal remodeling at precise locations. We show that the Wnt glycoproteins signal through the Frizzled receptor and the Planar Cell Polarity (PCP) protein VANG-1 to instruct neurite branching in the nematode C. elegans, by restricting F-actin assembly to ... | Branching of the axon or dendrite expands the connectivity of neural circuits and is critical for the functions of the nervous system. Transcription factors have been shown to specify the morphology of neuronal branch arbors as part of cell fate determination [1]. In addition, diffusible, secreted cues also regulate ne... |
10.1371/journal.ppat.1005735 | VgrG and PAAR Proteins Define Distinct Versions of a Functional Type VI Secretion System | The Type VI secretion system (T6SS) is widespread among bacterial pathogens and acts as an effective weapon against competitor bacteria and eukaryotic hosts by delivering toxic effector proteins directly into target cells. The T6SS utilises a bacteriophage-like contractile machinery to expel a puncturing device based o... | Pathogenic bacteria use a biological nanomachine called the ‘Type VI secretion system’ (T6SS) to fire toxic proteins into other cells. These target cells can be rival bacterial cells, allowing the T6SS-wielding bacteria to outcompete other pathogens or harmless bacteria, or cells of a human, animal or plant, to help th... | Bacteria utilise a variety of mechanisms to deliver specific proteins to the extracellular environment or directly into a target cell, processes collectively termed protein secretion. Bacterial protein secretion systems play a critical role in pathogenicity and can also be instrumental for interaction with other bacter... |
10.1371/journal.pntd.0000210 | Molecular Genetics Reveal That Silvatic Rhodnius prolixus Do Colonise Rural Houses | Rhodnius prolixus is the main vector of Chagas disease in Venezuela. Here, domestic infestations of poor quality rural housing have persisted despite four decades of vector control. This is in contrast to the Southern Cone region of South America, where the main vector, Triatoma infestans, has been eliminated over larg... | Chagas disease is spread by blood-feeding insects (triatomine bugs) that colonise poor-quality houses. Disease control relies primarily on killing domestic bugs by spraying dwellings with residual insecticide. In Venezuela, sustained control has proved difficult despite four decades of campaigns. Considered the main ve... | Chagas disease is a chronic parasitic disease transmitted by triatomine bugs (Reduviidae: Triatominae) and limited in distribution to the Americas. The causative agent is the protozoan Trypanosoma cruzi. Rhodnius prolixus is the primary vector in Venezuela and Colombia and is one of the main targets of the Andean Pact ... |
10.1371/journal.pgen.1000549 | Genomic Analysis of the Basal Lineage Fungus Rhizopus oryzae Reveals a Whole-Genome Duplication | Rhizopus oryzae is the primary cause of mucormycosis, an emerging, life-threatening infection characterized by rapid angioinvasive growth with an overall mortality rate that exceeds 50%. As a representative of the paraphyletic basal group of the fungal kingdom called “zygomycetes,” R. oryzae is also used as a model to ... | Rhizopus oryzae is a widely dispersed fungus that can cause fatal infections in people with suppressed immune systems, especially diabetics or organ transplant recipients. Antibiotic therapy alone is rarely curative, particularly in patients with disseminated infection. We sequenced the genome of a pathogenic R. oryzae... | The fungal kingdom comprises an estimated 1.5 million diverse members spanning over 1 billion years of evolutionary history. Within the fungal kingdom, four major groups (“Phyla”)—the Chytridiomycota, Zygomycota, Ascomycota and Basidiomycota— are traditionally recognized [1],[2] (Figure 1). Recent phylogenetic studies ... |
10.1371/journal.pbio.1001511 | Structural Basis of Rap Phosphatase Inhibition by Phr Peptides | Two-component systems, composed of a sensor histidine kinase and an effector response regulator (RR), are the main signal transduction devices in bacteria. In Bacillus, the Rap protein family modulates complex signaling processes mediated by two-component systems, such as competence, sporulation, or biofilm formation, ... | In microorganisms, two component signaling systems are widely used to sense and respond to environmental changes, including quorum-sensing of Phr oligopeptides. Although the minimal machinery required for these systems comprises a sensor histidine kinase and an effector response regulator (RR), ancillary proteins, term... | Bacteria communicate with each another and coordinate essential processes such as biofilm formation, sporulation, competence, virulence, or swarming motility in different ways. Quorum sensing is one of these mechanisms regulated by cell population density, and is mediated by self-generated extracellular signal molecule... |
10.1371/journal.pntd.0003553 | Spatio-Temporal Distribution of Aedes aegypti (Diptera: Culicidae) Mitochondrial Lineages in Cities with Distinct Dengue Incidence Rates Suggests Complex Population Dynamics of the Dengue Vector in Colombia | Aedes aegypti is the primary vector of the four serotypes of dengue virus (DENV1-4), Chikungunya and yellow fever virus to humans. Previous population genetic studies have revealed a particular genetic structure among the vector populations in the Americas that suggests differences in the ability to transmit DENV. In C... | Knowledge on the population structure of Aedes aegypti, the main vector of the dengue virus (DENV), is essential to improving dengue fever prevention strategies in endemic countries. In Colombia, despite the epidemiological relevance of dengue fever, the genetic population structure and phylogeography of the vector Ae.... | Dengue is one of the major public health problems in the tropics and is the second-most deadly vector-borne disease in the world after malaria [1]. The mosquito Aedes aegypti is the main vector of the four serotypes of dengue flaviviruses (DENV1-4) and yellow fever virus (YFV), and is a known vector of Chikungunya viru... |
10.1371/journal.pntd.0004627 | Impact of Trichiasis Surgery on Quality of Life: A Longitudinal Study in Ethiopia | Trachomatous trichiasis significantly reduces vision and health related quality of life (QoL). Although trichiasis surgery is widely performed to treat trichiasis, there is little data on the effect of surgery on QoL. We measured the impact of trichiasis surgery on vision and health related QoL in a longitudinal study ... | We previously reported that Trachomatous Trichiasis (TT) has a profound impact on vision and heath related quality of life (QoL), even when vision is not impaired. The World Health Organization (WHO) recommends corrective eyelid surgery for trichiasis to reduce the risk of vision loss. However, trichiasis surgery may a... | Trachoma, an eye disease caused by Chlamydia trachomatis, is the leading infectious cause of blindness worldwide [1]. The infection can lead to progressive conjunctival scarring and subsequently trachomatous trichiasis, the in-turning of eyelashes. Trichiasis in turn can cause constant painful abrasion to the cornea, i... |
10.1371/journal.ppat.1004109 | Structural and Biochemical Characterization Reveals LysGH15 as an Unprecedented “EF-Hand-Like” Calcium-Binding Phage Lysin | The lysin LysGH15, which is derived from the staphylococcal phage GH15, demonstrates a wide lytic spectrum and strong lytic activity against methicillin-resistant Staphylococcus aureus (MRSA). Here, we find that the lytic activity of the full-length LysGH15 and its CHAP domain is dependent on calcium ions. To elucidate... | The staphylococcal phage lysin LysGH15 demonstrates great potential against methicillin-resistant Staphylococcus aureus (MRSA). Here, we report that the lytic activity of LysGH15 and its CHAP domain is dependent on calcium ions. To elucidate the molecular mechanism, we determined the structures of three individual LysG... | Although Staphylococcus aureus is a common habitant of the human skin and respiratory tract, several highly pathogenic strains are major causes of hospital-associated infections and can be life threatening, particularly in immunocompromised patients [1]. Over the past three decades, the incidence of methicillin-resista... |
10.1371/journal.ppat.1002519 | Essential Roles for Soluble Virion-Associated Heparan Sulfonated Proteoglycans and Growth Factors in Human Papillomavirus Infections | A subset of human papillomavirus (HPV) infections is causally related to the development of human epithelial tumors and cancers. Like a number of pathogens, HPV entry into target cells is initiated by first binding to heparan sulfonated proteoglycan (HSPG) cell surface attachment factors. The virus must then move to di... | A subset of the >120 different types of human papillomaviruses (HPVs) are the most common cause of sexually transmitted infections. Certain HPVs are also associated with approximately 5% of all cancers worldwide. Like many pathogens, HPVs bind first to heparan sulfate proteoglycans (HSPGs) on cells before moving to mor... | Human papillomaviruses (HPVs) are small, DNA-containing viruses that infect mucosal and cutaneous epithelium to cause benign and malignant tumors, including many anogenital, oropharyngeal and some skin cancers [1], [2]. HPVs demonstrate remarkable host restrictions and have strict tropism for stratifying squamous epith... |
10.1371/journal.pntd.0007249 | Active surveillance identified a neglected burden of macular cases of Post Kala-azar Dermal Leishmaniasis in West Bengal | Post Kala-azar Dermal Leishmaniasis (PKDL) develops in patients apparently cured of Visceral Leishmaniasis (VL), and is the strongest contender for being the disease reservoir. Therefore, existence of a few cases is sufficient to trigger an epidemic of VL in a given community, emphasizing the need for its active detect... | Post Kala-azar Dermal Leishmaniasis (PKDL) is a dermal condition that occurs in South Asia in 10–20% of patients after apparent cure from Visceral Leishmaniasis (VL). It presents with macular or papulonodular lesions that harbor Leishmania parasites, thus playing a major role in the transmission cycle. Accordingly, dev... | Leishmaniasis are a group of neglected tropical diseases caused by the parasite Leishmania and demonstrates clinical pleomorphism with regard to the causative species, disease reservoirs, vectors as also host-immune responses. It can manifest as life-threatening and/or disfiguring lesions ranging from innocuous self-he... |
10.1371/journal.ppat.1000635 | Co-Regulation of NF-κB and Inflammasome-Mediated Inflammatory Responses by Myxoma Virus Pyrin Domain-Containing Protein M013 | NF-κB and inflammasomes both play central roles in orchestrating anti-pathogen responses by rapidly inducing a variety of early-response cytokines and chemokines following infection. Myxoma virus (MYXV), a pathogenic poxvirus of rabbits, encodes a member of the cellular pyrin domain (PYD) superfamily, called M013. The ... | Myxoma virus (MYXV), a rabbit-specific poxvirus pathogen, encodes diverse immunomodulatory proteins that can collectively overcome essentially all of the host immune defenses. MYXV-encoded protein M013, a member of the cellular PYRIN domain-containing superfamily of proteins, was previously shown to be important for vi... | The nuclear factor κB (NF-κB) family comprise a set of related transcription factors that regulate multiple cellular pathways associated with immune responses, inflammation, apoptosis, cell growth and survival [1],[2]. The mammalian NF-κB family members include NF-κB1 (p105 and p50), NF-κB2 (p100 and p52), RelA (p65), ... |
10.1371/journal.pgen.1006921 | Mutations in the Caenorhabditis elegans orthologs of human genes required for mitochondrial tRNA modification cause similar electron transport chain defects but different nuclear responses | Several oxidative phosphorylation (OXPHOS) diseases are caused by defects in the post-transcriptional modification of mitochondrial tRNAs (mt-tRNAs). Mutations in MTO1 or GTPBP3 impair the modification of the wobble uridine at position 5 of the pyrimidine ring and cause heart failure. Mutations in TRMU affect modificat... | Post-transcriptional modification of tRNAs is a universal process, thought to be essential for optimizing the functions of tRNAs. In humans, defects in the modification at position 2 (performed by protein TRMU) and 5 (carried out by proteins GTPBP3 and MTO1) of the uridine located at the wobble position of mitochondria... | Mitochondria are essential bioenergetic and biosynthetic eukaryotic organelles. Via oxidative phosphorylation (OXPHOS), they produce most of the cellular ATP; via the tricarboxylic acid cycle, they generate intermediate metabolites and reducing equivalents (NADH and FADH2). The coupling between mitochondrial activity a... |
10.1371/journal.ppat.1006027 | K63-Linked Ubiquitination Targets Toxoplasma gondii for Endo-lysosomal Destruction in IFNγ-Stimulated Human Cells | Toxoplasma gondii is the most common protozoan parasitic infection in man. Gamma interferon (IFNγ) activates haematopoietic and non-haematopoietic cells to kill the parasite and mediate host resistance. IFNγ-driven host resistance pathways and parasitic virulence factors are well described in mice, but a detailed under... | Toxoplasma gondii is an intracellular parasite that can invade nucleated cells of any warm-blooded animal into a compartment known as a parasitophorous vacuole (PV). The production of gamma interferon (IFNγ) drives the restriction and killing of Toxoplasma. It is not fully known how the parasite inside the PV is elimin... | Host cells invaded by intracellular pathogens have to mount a rapid recognition and cell-autonomous defence program to curb the replication of the intruder [1]. The cytokine gamma interferon (IFNγ) can stimulate cell-autonomous defence in immune or non-immune cells and is produced early during infection with many intra... |
10.1371/journal.pntd.0004606 | Environmental Mapping of Paracoccidioides spp. in Brazil Reveals New Clues into Genetic Diversity, Biogeography and Wild Host Association | Paracoccidioides brasiliensis and Paracoccidioides lutzii are the etiological agents of Paracoccidioidomycosis (PCM), and are easily isolated from human patients. However, due to human migration and a long latency period, clinical isolates do not reflect the spatial distribution of these pathogens. Molecular detection ... | Paracoccidioides brasiliensis and Paracoccidioides lutzii are the fungal species responsible for one of the most important mycoses of Latin America, Paracoccidioidomycosis (PCM). These fungi can grow in soil from forests, deforested areas, sugarcane, coffee, and rice plantations, as well as pasturelands, and they are s... | The study of biological and ecological aspects of Paracoccidioides brasiliensis [1,2] and Paracoccidioides lutzii [3] has been developed by several research groups in recent years. In particular, investigators have been seeking to isolate and/or detect those pathogens in clinical and environmental samples in order to o... |
10.1371/journal.ppat.1005129 | Candida albicans Inhibits Pseudomonas aeruginosa Virulence through Suppression of Pyochelin and Pyoverdine Biosynthesis | Bacterial-fungal interactions have important physiologic and medical ramifications, but the mechanisms of these interactions are poorly understood. The gut is host to trillions of microorganisms, and bacterial-fungal interactions are likely to be important. Using a neutropenic mouse model of microbial gastrointestinal ... | Pseudomonas aeruginosa and Candida albicans are two medically important human pathogens that often co-infect or co-colonize the same human niches, such as the gut. In a normal healthy host, P. aeruginosa and C. albicans can colonize the gut without any significant pathologic sequelae. But in immunocompromised hosts, bo... | The bacterium Pseudomonas aeruginosa and the fungus Candida albicans, two medically important human pathogens, co-infect or co-colonize numerous sites on the human body, including the gut [1], lung (including respiratory ventilator) [2–4], burn wound [5], genitourinary tract [1], and skin sites (including vascular cath... |
10.1371/journal.pgen.1006676 | Global analysis of translation termination in E. coli | Terminating protein translation accurately and efficiently is critical for both protein fidelity and ribosome recycling for continued translation. The three bacterial release factors (RFs) play key roles: RF1 and 2 recognize stop codons and terminate translation; and RF3 promotes disassociation of bound release factors... | Proteins are the cellular workhorses, performing essentially all of the functions required for cell and organismal survival. But, it takes a great deal of energy to make proteins, making it critical that proteins are made accurately and in the proper time frame. After a ribosome synthesizes a protein, release factors c... | Ribosomes translate the genetic information in the mRNA to a linear sequence of amino acids in the polypeptide chain through a process consisting of initiation, elongation, termination and recycling. During initiation, the 30S subunit of the bacterial ribosome and various initiation factors assemble at the initiation c... |
10.1371/journal.pntd.0001693 | The ATP-Binding Cassette Proteins of the Deep-Branching Protozoan Parasite Trichomonas vaginalis | The ATP binding cassette (ABC) proteins are a family of membrane transporters and regulatory proteins responsible for diverse and critical cellular process in all organisms. To date, there has been no attempt to investigate this class of proteins in the infectious parasite Trichomonas vaginalis. We have utilized a comb... | The parasite Trichomonas vaginalis infects in excess of 100 million people per year, and is a contributory factor to enhanced transmission rates of HIV, the causative virus in AIDS. As such, T. vaginalis infection is an important public health concern. Understanding the biology of the organism is important to determine... | Trichomonas vaginalis is a human-infective parasitic protozoan that is the most prevalent causative agent for non-viral sexually transmitted infections, with an estimated annual incidence of at least 170 million new cases of trichomoniasis worldwide [1]. Characteristic of other parabasalids in the order Trichomonadida,... |
10.1371/journal.ppat.1002957 | De novo GTP Biosynthesis Is Critical for Virulence of the Fungal Pathogen Cryptococcus neoformans | We have investigated the potential of the GTP synthesis pathways as chemotherapeutic targets in the human pathogen Cryptococcus neoformans, a common cause of fatal fungal meningoencephalitis. We find that de novo GTP biosynthesis, but not the alternate salvage pathway, is critical to cryptococcal dissemination and surv... | The fungal pathogen Cryptococcus neoformans is responsible for up to a million deaths annually, and the currently available antifungal medicines used to combat this infection are limited and patently inadequate. We have investigated the GTP biosynthesis pathway as a new drug target, a pathway that has been a chemothera... | Fungal infections of humans are highly refractive to pharmacological intervention due to the similarities in eukaryotic cell physiology. The limited array of fungal cell-specific features has therefore been the focus of antifungal drug research for many years, with the fungal cell wall and cell membrane being primary t... |
10.1371/journal.pbio.1001697 | Functional Brachyury Binding Sites Establish a Temporal Read-out of Gene Expression in the Ciona Notochord | The appearance of the notochord represented a milestone in Deuterostome evolution. The notochord is necessary for the development of the chordate body plan and for the formation of the vertebral column and numerous organs. It is known that the transcription factor Brachyury is required for notochord formation in all ch... | Transcription factors control where and when gene expression is switched on by binding to specific stretches of DNA known as cis-regulatory modules (CRMs). In this study, we investigated the architecture and composition of CRMs that direct gene expression in the notochord—a transient rod-like structure found in all emb... | The transcription factor Brachyury plays a paramount role in mesoderm formation in animals with widely diverse body plans [1],[2]. In chordate embryos ranging from sea squirts to mice, Brachyury is required for the formation of the notochord from axial mesoderm [3],[4]. In addition to its prominent function in notochor... |
10.1371/journal.pbio.1001288 | Mutations in the Mitochondrial Methionyl-tRNA Synthetase Cause a Neurodegenerative Phenotype in Flies and a Recessive Ataxia (ARSAL) in Humans | An increasing number of genes required for mitochondrial biogenesis, dynamics, or function have been found to be mutated in metabolic disorders and neurological diseases such as Leigh Syndrome. In a forward genetic screen to identify genes required for neuronal function and survival in Drosophila photoreceptor neurons,... | Neurodegenerative diseases, as a group, are relatively common and often devastating to those who suffer from them. Key insights are emerging from the study of homologues of identified human disease-causing genes in model organisms such as fruit flies, worms, and mice. In this study, we used the fruit fly to identify no... | A number of neurological diseases are associated with mitochondrial dysfunction. For example, mutations in the mitochondrial genome have been found in a wide range of disorders including Leber's Hereditary Optic Neuropathy (LHON), Neuropathy, Ataxia and Retinitis Pigmentosa (NARP), Mitochondrial myopathy, Encephalopath... |
10.1371/journal.pgen.1003201 | Human Disease-Associated Genetic Variation Impacts Large Intergenic Non-Coding RNA Expression | Recently it has become clear that only a small percentage (7%) of disease-associated single nucleotide polymorphisms (SNPs) are located in protein-coding regions, while the remaining 93% are located in gene regulatory regions or in intergenic regions. Thus, the understanding of how genetic variations control the expres... | Large intergenic non-coding RNAs (lincRNAs) are the largest class of non-coding RNA molecules in the human genome. Many genome-wide association studies (GWAS) have mapped disease-associated genetic variants (SNPs) to, or in, the vicinity of such lincRNA regions. However, it is not clear how these SNPs can affect the di... | It is now evident that most of the human genome is transcribed to produce not only protein-coding transcripts but also large numbers of non-coding RNAs (ncRNAs) of different size [1], [2]. Well-characterized short ncRNAs include microRNAs, small interfering RNAs, and piwi-interacting RNAs, whereas the large intergenic ... |
10.1371/journal.pcbi.1000099 | Regulation of Signal Duration and the Statistical Dynamics of Kinase Activation by Scaffold Proteins | Scaffolding proteins that direct the assembly of multiple kinases into a spatially localized signaling complex are often essential for the maintenance of an appropriate biological response. Although scaffolds are widely believed to have dramatic effects on the dynamics of signal propagation, the mechanisms that underli... | Signal transduction is the science of cellular communication. Cells detect signals from their environment and use them to make decisions such as whether or when to proliferate. Tight regulation of signal transduction is required for all healthy cells, and aberrant signaling leads to countless diseases such as cancer an... | In the context of signal transduction, cells integrate signals derived from membrane proximal events and convert them into the appropriate cell decision. Within the complex networks that integrate these signals lies a highly conserved motif involving the sequential activation of multiple protein kinases. Signal propaga... |
10.1371/journal.ppat.1006395 | Paradoxical myeloid-derived suppressor cell reduction in the bone marrow of SIV chronically infected macaques | Myeloid derived suppressor cells (MDSCs), which suppress anti-tumor or anti-viral immune responses, are expanded in the peripheral blood and tissues of patients/animals with cancer or viral infectious diseases. We here show that in chronic SIV infection of Indian rhesus macaques, the frequency of MDSCs in the bone marr... | Both cancer and infectious diseases including HIV/AIDS lead to the accumulation of myeloid-derived suppressor cells (MDSCs), which can effectively suppress anti-tumor and anti-viral T cell responses to dampen protective immunity. Using a macaque model, we found unexpectedly that the MDSCs in bone marrow (BM) decreased ... | Myeloid-derived Suppressor Cells (MDSCs) are immature cells of myeloid origin, frequently found in tumor microenvironments and in the blood of cancer patients [1–3]. Bone marrow (BM) is the reservoir for MDSCs. Under homeostatic conditions, there is a delicate balance between the immature MDSCs and matured myeloid cell... |
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