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10.1371/journal.ppat.1007719 | T-cell derived acetylcholine aids host defenses during enteric bacterial infection with Citrobacter rodentium | The regulation of mucosal immune function is critical to host protection from enteric pathogens but is incompletely understood. The nervous system and the neurotransmitter acetylcholine play an integral part in host defense against enteric bacterial pathogens. Here we report that acetylcholine producing-T-cells, as a n... | The nervous system is an active contributor to the regulation of immune responses. Prior studies have identified a unique CD4+ T-cell population that can relay signals from the sympathetic nervous system. These specialized T-cells express the enzyme choline acetyltransferase (ChAT) and produce acetylcholine (ACh). Rele... | The recently revealed degree of integration between the nervous and immune systems are remarkable [1]. While it is well accepted that neurotransmitters can act on immune cells to alter cell activation and consequently host immune response, recent evidence demonstrates that select immune cell populations not only respon... |
10.1371/journal.pcbi.1003835 | Mesoscopic Model and Free Energy Landscape for Protein-DNA Binding Sites: Analysis of Cyanobacterial Promoters | The identification of protein binding sites in promoter sequences is a key problem to understand and control regulation in biochemistry and biotechnological processes. We use a computational method to analyze promoters from a given genome. Our approach is based on a physical model at the mesoscopic level of protein-DNA... | Binding of specific proteins to particular sites in the DNA sequence is a fundamental issue for gene regulation in molecular biology and genetic engineering. A deep understanding of cell physiology requires the analysis of a plethora of genes involving characterization of their promoter architectures that determine the... | Transcriptional regulation is the main mechanism for gene control in prokaryotes. In order to adapt optimal protein expression to nutritional and environmental conditions, a cascade of transcriptional regulators works as signal transducers determining the accessibility of RNA polymerase to bacterial promoters. In the l... |
10.1371/journal.pntd.0002509 | Infection with Usutu Virus Induces an Autophagic Response in Mammalian Cells | Usutu virus (USUV) is an African mosquito-borne flavivirus closely related to West Nile virus and Japanese encephalitis virus, which host range includes mainly mosquitoes and birds, although infections in humans have been also documented, thus warning about USUV as a potential health threat. Circulation of USUV in Afri... | The identification of cellular components and metabolic pathways involved in virus replication provides valuable information for the development of new antiviral strategies. Autophagy is one of these metabolic pathways with multiple implications during viral replication. Autophagy literally means self-digestion and con... | The variety of factors that have contributed to the emergence of the flavivirus West Nile virus (WNV) in the Americas and its re-emergence in other parts of the world could also provide a suitable scenario for the emergence of other arboviruses [1], [2], [3]. These potential threats for human and animal health include ... |
10.1371/journal.pmed.1002193 | Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis | Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive disease, and although no effective targeted therapies are available to date, about one-third of patients with TNBC achieve pathologic complete response (pCR) from standard-of-care anthracycline/taxane (ACT) chemotherapy. The heterogeneity of ... | Identifying chemosensitive triple negative breast cancers (TNBCs) could significantly impact the survival of patients with these difficult to treat cancers until novel targeted therapies become available.
We hypothesized that genomic somatic aberrations may provide important molecular clues about chemosensitivity in TN... | Triple negative breast cancer (TNBC) disproportionately affects younger women and women of African ancestry, contributing to health disparities. In the era of personalized cancer therapy, patients with TNBC remain at considerably higher risk of relapse and death than patients with other breast cancer subtypes, due to t... |
10.1371/journal.ppat.1002385 | Two Novel Transcriptional Regulators Are Essential for Infection-related Morphogenesis and Pathogenicity of the Rice Blast Fungus Magnaporthe oryzae | The cyclic AMP-dependent protein kinase A signaling pathway plays a major role in regulating plant infection by the rice blast fungus Magnaporthe oryzae. Here, we report the identification of two novel genes, MoSOM1 and MoCDTF1, which were discovered in an insertional mutagenesis screen for non-pathogenic mutants of M.... | Magnaporthe oryzae, the causal agent of rice blast disease, is an important model fungal pathogen for understanding the molecular basis of plant-fungus interactions. In M. oryzae, the conserved cAMP/PKA signaling pathway has been demonstrated to be crucial for regulating infection-related morphogenesis and pathogenicit... | Eukaryotic organisms, including fungi, can sense and respond to extracellular cues via various signaling pathways for regulating a variety of developmental and differential cellular processes. Among these pathways, the conserved cyclic AMP-dependent protein kinase A (cAMP/PKA) signaling pathway has been well studied. T... |
10.1371/journal.pntd.0007457 | “It’s just a fever”: Gender based barriers to care-seeking for visceral leishmaniasis in highly endemic districts of India: A qualitative study | Diagnosis and treatment for visceral leishmaniasis (VL) is considered to be delayed amongst poor, rural women in highly endemic districts of Bihar and Jharkhand. The objective of this study was to assess and understand barriers to VL diagnosis and treatment for women in endemic districts with a high burden of VL.
The s... | India bears the greatest burden of a fatal parasitic disease called visceral leishmaniasis (VL), popularly known as Kala Azar. The disease is confined mostly to hot spots in Bihar and Jharkhand in the eastern part of the country. Amongst factors hampering efforts to eliminate VL are delays from the onset of symptoms to... | Visceral leishmaniasis (VL) or Kala azar, is a vector-borne disease caused by the protozoan Leishmania donovani and transmitted through the bite of the phlebotomine sand fly. Up to 100,000 cases are estimated to occur globally every year [1], and the disease is normally fatal within two years if untreated [2]. The path... |
10.1371/journal.pcbi.1002466 | Coordinated Optimization of Visual Cortical Maps (I) Symmetry-based Analysis | In the primary visual cortex of primates and carnivores, functional architecture can be characterized by maps of various stimulus features such as orientation preference (OP), ocular dominance (OD), and spatial frequency. It is a long-standing question in theoretical neuroscience whether the observed maps should be int... | Neurons in the visual cortex form spatial representations or maps of several stimulus features. How are different spatial representations of visual information coordinated in the brain? In this paper, we study the hypothesis that the coordinated organization of several visual cortical maps can be explained by joint opt... | Neurons in the primary visual cortex are selective to a multidimensional set of visual stimulus features, including visual field position, contour orientation, ocular dominance, direction of motion, and spatial frequency [1], [2]. In many mammals, these response properties form spatially complex, two-dimensional patter... |
10.1371/journal.pgen.1003777 | Cell-Type Specific Features of Circular RNA Expression | Thousands of loci in the human and mouse genomes give rise to circular RNA transcripts; at many of these loci, the predominant RNA isoform is a circle. Using an improved computational approach for circular RNA identification, we found widespread circular RNA expression in Drosophila melanogaster and estimate that in hu... | Last year, we reported that circular RNA isoforms, previously thought to be very rare, are actually a pervasive feature of eukaryotic gene expression programs; indeed, the major RNA isoform from hundreds of human genes is a circle. Previous novel RNA species that initially appeared to be special cases, of dubious biolo... | Recently, we were surprised to find that the predominant RNA isoform from hundreds of human genes is a circle, and that circular RNAs were transcribed from thousands of genes in both human and mouse [1]. Circular RNA transcripts had been reported previously for a handful of genes. With the possible exceptions of the ci... |
10.1371/journal.ppat.1000944 | Two Novel Point Mutations in Clinical Staphylococcus aureus Reduce Linezolid Susceptibility and Switch on the Stringent Response to Promote Persistent Infection | Staphylococcus aureus frequently invades the human bloodstream, leading to life threatening bacteremia and often secondary foci of infection. Failure of antibiotic therapy to eradicate infection is frequently described; in some cases associated with altered S. aureus antimicrobial resistance or the small colony variant... | The treatment of serious infections caused by Staphylococcus aureus is complicated by the development of antibiotic resistance, and in some cases the appearance of more persistent bacteria that have a reduced growth rate resulting in small colony variants (SCV). Here we have shown using whole genome sequencing and gene... | The factors promoting persistence of bacterial infection in the face of apparently effective antimicrobial therapy have not been clearly defined. This particularly applies to Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA), which remains a major human pathogen that frequently causes invasive di... |
10.1371/journal.pbio.1000045 | Analysis of the Chloroplast Protein Kinase Stt7 during State Transitions | State transitions allow for the balancing of the light excitation energy between photosystem I and photosystem II and for optimal photosynthetic activity when photosynthetic organisms are subjected to changing light conditions. This process is regulated by the redox state of the plastoquinone pool through the Stt7/STN7... | To grow optimally, photosynthetic organisms need to constantly adjust to changing light conditions. One of these adjustments, called state transitions, allows light energy to be redistributed between the two photosynthetic reaction center complexes in a cell's chloroplasts. These complexes act in concert with other com... | Photosynthetic organisms are constantly subjected to changes in light conditions. These organisms have developed different mechanisms to rapidly acclimate to this changing environment. At one extreme, when the absorbed light excitation energy vastly exceeds the assimilation capacity of the photosynthetic apparatus, the... |
10.1371/journal.pcbi.1000174 | Identifying Cognate Binding Pairs among a Large Set of Paralogs: The Case of PE/PPE Proteins of Mycobacterium tuberculosis | We consider the problem of how to detect cognate pairs of proteins that bind when each belongs to a large family of paralogs. To illustrate the problem, we have undertaken a genomewide analysis of interactions of members of the PE and PPE protein families of Mycobacterium tuberculosis. Our computational method uses str... | We consider the problem of detecting protein interactions from genome sequences when the potential interacting partners belong to large families of similar (homologous) proteins. Many computational methods for predicting protein interactions rely on similarity to a pair of known interacting proteins. When the proteins ... | Tuberculosis remains a health problem of global importance [1]. Despite the availability of the genome sequence of Mycobacterium tuberculosis (Mtb) for nearly a decade [2], the biology of the pathogen, particularly the molecular mechanisms by which it achieves virulence, remains poorly understood. Probing the molecular... |
10.1371/journal.pcbi.1006785 | Assessing the performance of real-time epidemic forecasts: A case study of Ebola in the Western Area region of Sierra Leone, 2014-15 | Real-time forecasts based on mathematical models can inform critical decision-making during infectious disease outbreaks. Yet, epidemic forecasts are rarely evaluated during or after the event, and there is little guidance on the best metrics for assessment. Here, we propose an evaluation approach that disentangles dif... | During epidemics, reliable forecasts can help allocate resources effectively to combat the disease. Various types of mathematical models can be used to make such forecasts. In order to assess how good the forecasts are, they need to be compared to what really happened. Here, we describe different approaches to assessin... | Forecasting the future trajectory of cases during an infectious disease outbreak can make an important contribution to public health and intervention planning. Infectious disease modellers are now routinely asked for predictions in real time during emerging outbreaks [1]. Forecasting targets can revolve around expected... |
10.1371/journal.pbio.1000554 | Domain Swapping in Allosteric Modulation of DNA Specificity | SgrAI is a type IIF restriction endonuclease that cuts an unusually long recognition sequence and exhibits allosteric self-modulation of cleavage activity and sequence specificity. Previous studies have shown that DNA bound dimers of SgrAI oligomerize into an activated form with higher DNA cleavage rates, although prev... | Restriction endonucleases protect their bacterial hosts from viral infection by cleaving any invading viral DNA. One such enzyme, SgrAI, cleaves DNA very slowly but can be activated to cleave DNA 200 times more rapidly. Activation occurs when the enzyme interacts with two or more copies of DNA containing its recognitio... | Domain swapping involves the exchange of identical folding motifs between two copies of the same polypeptide chain [1], and as a result, a tight oligomer is formed. Such swapping has been found in many oligomeric proteins, where the swapped form is the biologically natural form [2] and in some cases where binding to a ... |
10.1371/journal.ppat.1001274 | HTLV-1 bZIP Factor Induces T-Cell Lymphoma and Systemic Inflammation In Vivo | Human T-cell leukemia virus type 1 (HTLV-1) is the causal agent of a neoplastic disease of CD4+ T cells, adult T-cell leukemia (ATL), and inflammatory diseases including HTLV-1 associated myelopathy/tropical spastic paraparesis, dermatitis, and inflammatory lung diseases. ATL cells, which constitutively express CD25, r... | Human T-cell leukemia virus type 1 (HTLV-1) is the first retrovirus that is associated with human diseases including an aggressive leukemia derived from CD4+ T cells, adult T-cell leukemia (ATL), and chronic inflammatory diseases of the central nervous system, lung, or skin. However, it remains to be elucidated how HTL... | Human T-cell leukemia virus type 1 (HTLV-1) was the first human retrovirus associated with human diseases including adult T-cell leukemia (ATL) [1], [2] and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP)[3], [4]. One of the virological attributes of HTLV-1 is that it transmits mainly by cell-to-cel... |
10.1371/journal.pntd.0000236 | The Effect of Azithromycin on Ivermectin Pharmacokinetics—A Population Pharmacokinetic Model Analysis | A recent drug interaction study reported that when azithromycin was administered with the combination of ivermectin and albendazole, there were modest increases in ivermectin pharmacokinetic parameters. Data from this study were reanalyzed to further explore this observation. A compartmental model was developed and 1,0... | This paper describes the use of a modeling and simulation approach to explore a reported pharmacokinetic interaction between two drugs (ivermectin and azithromycin), which along with albendazole, are being developed for combination use in neglected tropical diseases. This approach is complementary to more traditional p... | The operational efficiency of disease elimination programs in developing countries could be improved by integrating delivery of several interventions at local (village and district) levels [1]–[3]. In areas endemic for co-infection with filarial nematodes and Chlamydia trachomatis, one such integrated disease eliminati... |
10.1371/journal.pbio.1001150 | Active Control of Acoustic Field-of-View in a Biosonar System | Active-sensing systems abound in nature, but little is known about systematic strategies that are used by these systems to scan the environment. Here, we addressed this question by studying echolocating bats, animals that have the ability to point their biosonar beam to a confined region of space. We trained Egyptian f... | Most sensory systems have an active component, i.e. driven by an animal's behavior, which contributes directly to its perception. For example, eye movements are important for visual perception, sniffs are crucial for olfactory percepts, and finger movements for touch percepts. A classic example of an active-sensing sys... | The importance of “active sensing,” by which an animal actively interacts with the environment to adaptively control the acquisition of sensory information, is fundamental to perception across sensory modalities [1]–[7]. Echolocating bats emit ultrasonic signals and analyze the returning echoes to perceive their surrou... |
10.1371/journal.pcbi.1006027 | Neuronal gain modulability is determined by dendritic morphology: A computational optogenetic study | The mechanisms by which the gain of the neuronal input-output function may be modulated have been the subject of much investigation. However, little is known of the role of dendrites in neuronal gain control. New optogenetic experimental paradigms based on spatial profiles or patterns of light stimulation offer the pro... | New experimental techniques based on optogenetics allow neuronal activity to be manipulated with a high degree of spatial and temporal precision. This opens up new prospects for testing computational models of neuronal function, including questions such as the role of dendrites in neuronal gain control. However, compar... | Neuronal gain modulation occurs when the sensitivity of a neuron to one input is controlled by a second input. Its role in neuronal computation has been the subject of much investigation [1–4], and its dysfunction has been implicated in a range of disorders from attention deficit disorders, through to schizophrenia, au... |
10.1371/journal.pcbi.0030144 | Prediction of Gene Expression in Embryonic Structures of Drosophila melanogaster | Understanding how sets of genes are coordinately regulated in space and time to generate the diversity of cell types that characterise complex metazoans is a major challenge in modern biology. The use of high-throughput approaches, such as large-scale in situ hybridisation and genome-wide expression profiling via DNA m... | The task of deciphering the complex transcriptional regulatory networks controlling development is one of the major current challenges for molecular biology. The problem is difficult, if not impossible, to solve without a detailed knowledge of the spatiotemporal dynamics of gene expression. Thus, to understand developm... | As a result of a gradual developmental strategy known as epigenesis, an embryo comprising a few cell types is refined to generate a complex organism composed of many precisely organized anatomical structures. Understanding how the genome is dynamically deployed to generate such cellular diversity is a key challenge in ... |
10.1371/journal.pgen.1004252 | Synergistic Interactions between the Molecular and Neuronal Circadian Networks Drive Robust Behavioral Circadian Rhythms in Drosophila melanogaster | Most organisms use 24-hr circadian clocks to keep temporal order and anticipate daily environmental changes. In Drosophila melanogaster CLOCK (CLK) and CYCLE (CYC) initiates the circadian system by promoting rhythmic transcription of hundreds of genes. However, it is still not clear whether high amplitude transcription... | Circadian clocks allow organisms to predict daily environmental changes. These clocks time the sleep/wake cycles and many other physiological and cellular pathways to 24hs rhythms. The current model states that circadian clocks keep time by the use of biochemical feedback loops. These feedback loops are responsible for... | Most organisms use 24-hr circadian clocks to keep temporal order and anticipate daily environmental changes. These clocks are based on self-sustained biochemical oscillators that manifest at the molecular, physiological and behavioral levels [for review see [1], [2]]. Circadian clocks have been proposed to work on cell... |
10.1371/journal.pgen.1004493 | An Intronic microRNA Links Rb/E2F and EGFR Signaling | The importance of microRNAs in the regulation of various aspects of biology and disease is well recognized. However, what remains largely unappreciated is that a significant number of miRNAs are embedded within and are often co-expressed with protein-coding host genes. Such a configuration raises the possibility of a f... | Animal genomes encode hundreds of microRNA genes that impact all areas of biology by limiting the expression of their targets. What remains largely unappreciated is that a significant proportion of microRNA genes are embedded within protein-coding genes, and are often co-expressed with their hosts, which raises the pos... | MicroRNAs (miRNAs) are short non-coding RNAs that regulate the expression of mRNA targets, thereby modulating biological processes including development, proliferation, metabolism, homeostasis and tumorigenesis. While some miRNAs elicit strong effects, many miRNAs operate more subtly to buffer a system or response to a... |
10.1371/journal.pcbi.1005990 | Imaging of neural oscillations with embedded inferential and group prevalence statistics | Magnetoencephalography and electroencephalography (MEG, EEG) are essential techniques for studying distributed signal dynamics in the human brain. In particular, the functional role of neural oscillations remains to be clarified. For that reason, imaging methods need to identify distinct brain regions that concurrently... | The oscillatory activity of the brain produces a repertoire of signal dynamics that is rich and complex. Noninvasive recording techniques such as scalp magnetoencephalography and electroencephalography (MEG, EEG) are key methods to advance our comprehension of the role played by neural oscillations in brain functions a... | The role of neural oscillations in population codes of brain functions, and the possible mechanisms of inter-regional communication between brain regions are not entirely understood. Source imaging techniques with magnetoencephalography (MEG) or electroencephalography (EEG) are time-resolved, non-invasive tools used to... |
10.1371/journal.pcbi.1000473 | Microarray Comparative Genomic Hybridisation Analysis Incorporating Genomic Organisation, and Application to Enterobacterial Plant Pathogens | Microarray comparative genomic hybridisation (aCGH) provides an estimate of the relative abundance of genomic DNA (gDNA) taken from comparator and reference organisms by hybridisation to a microarray containing probes that represent sequences from the reference organism. The experimental method is used in a number of b... | We describe the first use of a method for the analysis of bacterial microarray comparative genomic hybridisation (aCGH) that includes information about the spatial organisation of genes in the reference bacterium. We demonstrate that using this information improves predictive performance over standard bacterial aCGH me... | Microarray comparative genomic hybridisation (aCGH) provides an estimate of the relative abundance of genomic DNA (gDNA) taken from comparator and reference organisms by hybridisation to a microarray containing probes that represent sequences from the reference organism. This method has been used in a number of biologi... |
10.1371/journal.pbio.1000618 | Chemotaxis: A Feedback-Based Computational Model Robustly Predicts
Multiple Aspects of Real Cell Behaviour | The mechanism of eukaryotic chemotaxis remains unclear despite intensive study.
The most frequently described mechanism acts through attractants causing actin
polymerization, in turn leading to pseudopod formation and cell movement. We
recently proposed an alt... | The efficiency, sensitivity, and huge dynamic range of eukaryotic cell chemotaxis
have proven very hard to explain. Cells respond to shallow gradients of
chemotactic molecules with directed movement, but the mechanisms remain elusive.
Most current models predi... | Eukaryotic chemotaxis—cell migration towards a source of attractants—is
both biologically important and theoretically interesting, so it has been widely
studied. Recently, a majority of authors have considered that chemotaxis is driven
by a “compass” [1]. The exact meanin... |
10.1371/journal.pgen.1008209 | Time of day and network reprogramming during drought induced CAM photosynthesis in Sedum album | Plants with facultative crassulacean acid metabolism (CAM) maximize performance through utilizing C3 or C4 photosynthesis under ideal conditions while temporally switching to CAM under water stress (drought). While genome-scale analyses of constitutive CAM plants suggest that time of day networks are shifted, or phased... | Crassulacean acid metabolism (CAM) photosynthesis represents an important adaptation to arid environments as CAM plants take up CO2 at night when evapotranspiration rates are lower. Genomes and large-scale datasets are available for several plants with constitutive CAM activity, but they provided little insight on how ... | Drought is the most pervasive abiotic stress and plants have evolved diverse strategies to mitigate the effects of water deficit [1]. Most water loss in plants occurs through transpiration as a byproduct of daytime stomata mediated CO2 uptake. Crassulacean acid metabolism (CAM) plants have evolved an alternative carbon... |
10.1371/journal.pcbi.1006020 | Deploying digital health data to optimize influenza surveillance at national and local scales | The surveillance of influenza activity is critical to early detection of epidemics and pandemics and the design of disease control strategies. Case reporting through a voluntary network of sentinel physicians is a commonly used method of passive surveillance for monitoring rates of influenza-like illness (ILI) worldwid... | Influenza contributes substantially to global morbidity and mortality each year, and epidemiological surveillance for influenza is typically conducted by sentinel physicians and health care providers recruited to report cases of influenza-like illness. While population coverage and representativeness, and geographic di... | Seasonal influenza represents an important public health burden worldwide, and even within a single year, there is substantial variation in disease burden across populations [1–3]. On the other hand, pandemic influenza, which has the potential to cause millions of fatalities, is characterized by even more uncertainty i... |
10.1371/journal.pgen.1006361 | The Skp1 Homologs SKR-1/2 Are Required for the Caenorhabditis elegans SKN-1 Antioxidant/Detoxification Response Independently of p38 MAPK | SKN-1/Nrf are the primary antioxidant/detoxification response transcription factors in animals and they promote health and longevity in many contexts. SKN-1/Nrf are activated by a remarkably broad-range of natural and synthetic compounds and physiological conditions. Defining the signaling mechanisms that regulate SKN-... | Oxidative stress is the result of imbalanced control of reactive oxidative species in cells, is a common occurrence during aerobic metabolism, and must be managed to limit cellular damage and disease. Many details about the signaling mechanisms utilized by animal cells in response to pro-oxidants remain to be discovere... | Reactive small molecules are common in natural environments and are produced as byproducts of oxygen metabolism. Reactive small molecules in excess can cause oxidative damage with widespread detrimental effects, but also function as signaling molecules for normal physiological processes [1]. Appropriate response to and... |
10.1371/journal.pcbi.1005216 | Kinase Inhibition Leads to Hormesis in a Dual Phosphorylation-Dephosphorylation Cycle | Many antimicrobial and anti-tumour drugs elicit hormetic responses characterised by low-dose stimulation and high-dose inhibition. While this can have profound consequences for human health, with low drug concentrations actually stimulating pathogen or tumour growth, the mechanistic understanding behind such responses ... | Hormesis is a highly controversial and poorly understood phenomenon. It describes the idea that an inhibitor molecule, like an anti-cancer or anti-microbial drug, can inadvertently stimulate cell growth instead of suppressing it. This can have a profound effect on human health leading to failures in clinical treatments... | Hormesis is a phenomenon describing biphasic dose response relationships that exhibit low-dose stimulation and high-dose inhibition [1]. Many medical agents such as antibacterials, antifungals, and anti-tumour drugs have been found to display hormetic response [2] with the earliest observations dating back to 1800s. In... |
10.1371/journal.pntd.0000917 | Revisiting the Immune Trypanolysis Test to Optimise Epidemiological Surveillance and Control of Sleeping Sickness in West Africa | Because of its high sensitivity and its ease of use in the field, the card agglutination test for trypanosomiasis (CATT) is widely used for mass screening of sleeping sickness. However, the CATT exhibits false-positive results (i) raising the question of whether CATT-positive subjects who are negative in parasitology a... | Human African trypanosomiasis (HAT) due to Trypanosoma brucei (T.b.) gambiense is usually diagnosed using two sequential steps: first the card agglutination test for trypanosomiasis (CATT) used for serological screening, followed by parasitological methods to confirm the disease. Currently, CATT will continue to be use... | Human African trypanosomiasis (HAT) or sleeping sickness is caused by two subspecies of the protozoan flagellate Trypanosoma brucei. In West and Central Africa, T.b. gambiense causes the chronic form of sleeping sickness, while in East Africa, T.b. rhodesiense causes the more fulminant form [1]. T.b. brucei is normally... |
10.1371/journal.pbio.2006842 | Gut microbiota diversity across ethnicities in the United States | Composed of hundreds of microbial species, the composition of the human gut microbiota can vary with chronic diseases underlying health disparities that disproportionally affect ethnic minorities. However, the influence of ethnicity on the gut microbiota remains largely unexplored and lacks reproducible generalizations... | Understanding microbiota similarities and differences across ethnicities has the potential to advance approaches aimed at personalized microbial discovery and treatment, particularly those involved in ethnic health disparities. Here, we explore whether or not self-declared ethnicity consistently varies with gut microbi... | The human gut microbiota at fine resolution varies extensively between individuals [1–3], and this variability frequently associates with diet [4–7], age [6, 8, 9], sex [6, 9, 10], body mass index (BMI) [1, 6], and diseases presenting as health disparities [11–14]. The overlapping risk factors and burden of many chroni... |
10.1371/journal.pntd.0007281 | Vector competence of Australian Aedes aegypti and Aedes albopictus for an epidemic strain of Zika virus | Recent epidemics of Zika virus (ZIKV) in the Pacific and the Americas have highlighted its potential as an emerging pathogen of global importance. Both Aedes (Ae.) aegypti and Ae. albopictus are known to transmit ZIKV but variable vector competence has been observed between mosquito populations from different geographi... | Zika virus (ZIKV) is a mosquito-borne pathogen that generally causes a mild febrile illness but mostly remains asymptomatic in 50–80% of infections. Infection during pregnancy can cause congenital malformations, notably microcephaly. In adults, it can cause Guillain-Barré syndrome. The recent ZIKV epidemic in the Ameri... | Over the past decade, Zika virus (ZIKV) has caused unprecedented epidemics in the Western Pacific and the Americas. ZIKV is a mosquito-borne, single-stranded RNA virus that belongs to the Flavivirus genus within the Flaviviridae family [1]. First discovered in Uganda in 1947 [2], ZIKV spread from equatorial Africa into... |
10.1371/journal.pgen.1002458 | Reduction of NADPH-Oxidase Activity Ameliorates the Cardiovascular Phenotype in a Mouse Model of Williams-Beuren Syndrome | A hallmark feature of Williams-Beuren Syndrome (WBS) is a generalized arteriopathy due to elastin deficiency, presenting as stenoses of medium and large arteries and leading to hypertension and other cardiovascular complications. Deletion of a functional NCF1 gene copy has been shown to protect a proportion of WBS pati... | Williams-Beuren Syndrome (WBS) is a rare developmental disorder characterized by distinctive facial, neurobehavioral, and cardiovascular features, caused by a heterozygous loss of genetic material (deletion) at the 7q11.23 chromosomal band. Elastin protein deficiency, due to deletion of one copy of the ELN gene, is res... | Williams-Beuren syndrome (WBS [MIM 194050]) is a developmental disorder with multisystemic manifestations and a prevalence of ∼1/10,000 newborns, caused by a segmental aneusomy of 1.55–1.83 Mb at chromosomal band 7q11.23, which includes ELN (coding for elastin [MIM 130160]) and 25–27 additional genes [1], [2]. The recu... |
10.1371/journal.ppat.1000805 | Dynamic Imaging of Experimental Leishmania donovani-Induced Hepatic Granulomas Detects Kupffer Cell-Restricted Antigen Presentation to Antigen-Specific CD8+ T Cells | Kupffer cells (KCs) represent the major phagocytic population within the liver and provide an intracellular niche for the survival of a number of important human pathogens. Although KCs have been extensively studied in vitro, little is known of their in vivo response to infection and their capacity to directly interact... | Leishmania donovani is a protozoan parasite that causes severe disease in humans with associated pathology in the spleen and liver. In experimental models of L. donovani infection, the hepatic response to infection is characterised by the presence of a focal mononuclear cell-rich inflammatory response (a granuloma) sur... | Kupffer cells (KCs), first identified in 1876, are now recognised as the major population of mononuclear phagocytes to inhabit the resting liver. Lining the sinusoids, KCs express a wide range of phagocytic and innate recognition receptors, including CD32 [1], lectin receptors [2] and TLRs (notably TLR2, 3, 4 and 9) [3... |
10.1371/journal.pgen.1006503 | Mitochondria and Caspases Tune Nmnat-Mediated Stabilization to Promote Axon Regeneration | Axon injury can lead to several cell survival responses including increased stability and axon regeneration. Using an accessible Drosophila model system, we investigated the regulation of injury responses and their relationship. Axon injury stabilizes the rest of the cell, including the entire dendrite arbor. After axo... | Unlike many other cell types, most neurons last a lifetime. When injured, these cells often activate survival and repair strategies rather than dying. One such response is regeneration of the axon after it is injured. Axon regeneration is a conserved process activated by the same signaling cascade in worms, flies and m... | The ability of neurons to survive injury, misfolded proteins, hypoxic stress and other deleterious conditions allows the nervous system to function for a lifetime without large-scale production of new neurons. Neuronal survival strategies buy the cells time to maintain or regain function. For example, neurons may remai... |
10.1371/journal.ppat.1006182 | Boosting of HIV envelope CD4 binding site antibodies with long variable heavy third complementarity determining region in the randomized double blind RV305 HIV-1 vaccine trial | The canary pox vector and gp120 vaccine (ALVAC-HIV and AIDSVAX B/E gp120) in the RV144 HIV-1 vaccine trial conferred an estimated 31% vaccine efficacy. Although the vaccine Env AE.A244 gp120 is antigenic for the unmutated common ancestor of V1V2 broadly neutralizing antibody (bnAbs), no plasma bnAb activity was induced... | Developing a successful HIV-1 vaccine remains a high global health priority. Several HIV-1 vaccine trials have been performed with only the RV144 vaccine trial showing vaccine efficacy, albeit modest. No broadly neutralizing antibody activity was identified in RV144 and inducing sterilizing immunity against a complex p... | Six HIV-1 vaccine efficacy trials have been performed [1–5], of which only one, the ALVAC-HIV and AIDSVAX B/E prime-boost RV144 trial, showed vaccine protection, with estimated vaccine efficacies of 60% at 12 months [6] and 31% at 42 months [7]. Plasma IgG antibodies binding to HIV-1 envelope variable region 2 (V2) and... |
10.1371/journal.pgen.1000589 | P-Type ATPase TAT-2 Negatively Regulates Monomethyl Branched-Chain Fatty Acid Mediated Function in Post-Embryonic Growth and Development in C. elegans | Monomethyl branched-chain fatty acids (mmBCFAs) are essential for Caenorhabditis elegans growth and development. To identify factors acting downstream of mmBCFAs for their function in growth regulation, we conducted a genetic screen for suppressors of the L1 arrest that occurs in animals depleted of the 17-carbon mmBCF... | Fatty acids serve diverse functions in organisms, including roles at the cell membrane to coordinate cell signaling processes. Monomethyl branched-chain fatty acids (mmBCFAs) are a special type of fatty acid that is commonly present in animals. Because mmBCFAs are a small component of the total fatty acid pool, their f... | Lipids play many critical roles in cellular function ranging from providing structural support within cell membranes to mediating signaling events. The importance of the particular fatty acid constituents of complex lipids is only beginning to be understood. While extensive analyses have been conducted to elucidate the... |
10.1371/journal.pntd.0002505 | The Improbable Transmission of Trypanosoma cruzi to Human: The Missing Link in the Dynamics and Control of Chagas Disease | Chagas disease has a major impact on human health in Latin America and is becoming of global concern due to international migrations. Trypanosoma cruzi, the etiological agent of the disease, is one of the rare human parasites transmitted by the feces of its vector, as it is unable to reach the salivary gland of the ins... | Chagas disease is a parasitic disease affecting about 10 million people, often living in poor conditions, and the disease contributes to impede their development. As several other infectious diseases (malaria, dengue or sleeping sickness), it is transmitted by blood-feeding insect vectors. While most other human pathog... | Vector-borne diseases represent one of the biggest challenges to current and future human wellbeing. They have severe impacts on many tropical and subtropical countries, where they are responsible for ∼10% of human deaths and contribute to impoverishment by imposing an annual burden of >50 millions of DALYs [1]. They a... |
10.1371/journal.ppat.1006589 | The transcription factor CHOP, an effector of the integrated stress response, is required for host sensitivity to the fungal intracellular pathogen Histoplasma capsulatum | The ability of intracellular pathogens to manipulate host-cell viability is critical to successful infection. Some pathogens promote host-cell survival to protect their replicative niche, whereas others trigger host-cell death to facilitate release and dissemination of the pathogen after intracellular replication has o... | Histoplasma capsulatum is the causative agent of histoplasmosis, a fungal infection that can be fatal in a wide range of mammalian hosts, including otherwise healthy, immunocompetent individuals. Histoplasma cells replicate to very high levels within host macrophages, eventually causing macrophage death and the release... | Death of the host cell has profound consequences for an intracellular pathogen. It may eliminate the pathogen’s replicative niche, or it may promote pathogen spread. The specific form of cell death can impact immune activation of the host: pyroptosis and necroptosis are highly inflammatory types of cell death whereas a... |
10.1371/journal.pcbi.1002965 | The Fidelity of Dynamic Signaling by Noisy Biomolecular Networks | Cells live in changing, dynamic environments. To understand cellular decision-making, we must therefore understand how fluctuating inputs are processed by noisy biomolecular networks. Here we present a general methodology for analyzing the fidelity with which different statistics of a fluctuating input are represented,... | Cells do not live in constant conditions, but in environments that change over time. To adapt to their surroundings, cells must therefore sense fluctuating concentrations and ‘interpret’ the state of their environment to see whether, for example, a change in the pattern of gene expression is needed. This task is achiev... | Cells are continuously challenged by extra- and intracellular fluctuations, or ‘noise’, [1]–[3]. We are only starting to unravel how fluctuating inputs and dynamic interactions with other stochastic, intracellular systems affect the behavior of biomolecular networks [4]–[9]. Such knowledge is, however, essential for st... |
10.1371/journal.pmed.1002659 | Community delivery of antiretroviral drugs: A non-inferiority cluster-randomized pragmatic trial in Dar es Salaam, Tanzania | With the increase in people living with HIV in sub-Saharan Africa and expanding eligibility criteria for antiretroviral therapy (ART), there is intense interest in the use of novel delivery models that allow understaffed health systems to successfully deal with an increasing demand for antiretroviral drugs (ARVs). This... | The number of individuals in sub-Saharan Africa needing antiretroviral therapy (ART) for HIV—and chronic disease care more broadly—is expected to increase over the coming decades, further straining already under-resourced health systems in the region.
Community delivery of antiretroviral drugs (ARVs) has the potential ... | Chronic diseases are rapidly replacing acute infectious diseases as the leading cause of the disease burden in sub-Saharan Africa (SSA) [1]. While many of these chronic conditions are non-communicable, HIV has also become a chronic illness as effective therapy allows HIV-positive individuals to survive into old age [2,... |
10.1371/journal.pcbi.1000243 | Malleable Machines in Transcription Regulation: The Mediator Complex | The Mediator complex provides an interface between gene-specific regulatory proteins and the general transcription machinery including RNA polymerase II (RNAP II). The complex has a modular architecture (Head, Middle, and Tail) and cryoelectron microscopy analysis suggested that it undergoes dramatic conformational cha... | Intrinsically disordered proteins/regions do not adopt well-defined three dimensional structures; instead, they function as conformational ensembles. They are distinguished in molecular recognition and involved in various regulatory processes. Several components in the transcription machinery–for example, the transacti... | The Mediator complex is a gigantic (1 MDa) multi-protein complex that plays a number of essential roles in eukaryotic gene regulation [1]. It functions as a co-activator, a co-repressor as well as a general transcription factor by transmitting information from the regulatory factors bound at enhancers to the RNAP II tr... |
10.1371/journal.pcbi.1000126 | Isolation-by-Distance and Outbreeding Depression Are Sufficient to Drive Parapatric Speciation in the Absence of Environmental Influences | A commonly held view in evolutionary biology is that speciation (the emergence of genetically distinct and reproductively incompatible subpopulations) is driven by external environmental constraints, such as localized barriers to dispersal or habitat-based variation in selection pressures. We have developed a spatially... | A commonly held view in evolutionary biology is that new species form in response to environmental factors, such as habitat differences or barriers to individual movements that sever a population. We have developed a computer model, called EvoSpace, that illustrates how new species can emerge when a species range becom... | The most common framework for understanding the process of biological speciation is geographical. For example, instances of speciation are typically allocated among three categories based on the extent of geographical separation between the daughter species. Allopatric speciation, in which a species range becomes sever... |
10.1371/journal.pntd.0003037 | Comparative Host Feeding Patterns of the Asian Tiger Mosquito, Aedes albopictus, in Urban and Suburban Northeastern USA and Implications for Disease Transmission | Aedes albopictus is an invasive species which continues expanding its geographic range and involvement in mosquito-borne diseases such as chikungunya and dengue. Host selection patterns by invasive mosquitoes are critically important because they increase endemic disease transmission and drive outbreaks of exotic patho... | Aedes albopictus is one of the most invasive and aggressive disease vectors in the world. The range of this species is currently still expanding, particularly into highly dense human population centers in temperate areas in the USA and Europe, raising the public health threat of emerging and re-emerging diseases such a... | Understanding the blood feeding patterns of mosquitoes is of paramount importance in determining their vector status in the maintenance and epidemic transmission of arboviruses. Blood feeding patterns of mosquito vectors provide insight into the ecological transmission cycles of pathogens and lead to more efficient dis... |
10.1371/journal.ppat.1005561 | IL-12p40/IL-10 Producing preCD8α/Clec9A+ Dendritic Cells Are Induced in Neonates upon Listeria monocytogenes Infection | Infection by Listeria monocytogenes (Lm) causes serious sepsis and meningitis leading to mortality in neonates. This work explored the ability of CD11chigh lineage DCs to induce CD8+ T-cell immune protection against Lm in mice before 7 days of life, a period symbolized by the absence of murine IL-12p70-producing CD11ch... | Lm is a gram-positive food-borne pathogen that is the ethiological agent of listeriosis, a worldwide disease reported most frequently in developed countries. It can cause spontaneous septic abortions, fatal meningitis or encephalitis in immunocompromised and pregnant individuals. The murine model of systemic Lm infecti... | Early life is a period of immune maturation characterized by a high susceptibility to infectious diseases. The underdeveloped immune system gives a Th2-biased response and has an impaired ability to develop long-lasting protective CD8+ T cell immunity [1, 2]. We are particularly interested in immune resistance to infec... |
10.1371/journal.pmed.1002311 | Reducing US cardiovascular disease burden and disparities through national and targeted dietary policies: A modelling study | Large socio-economic disparities exist in US dietary habits and cardiovascular disease (CVD) mortality. While economic incentives have demonstrated success in improving dietary choices, the quantitative impact of different dietary policies on CVD disparities is not well established. We aimed to quantify and compare the... | Suboptimal diet is a leading cause of cardiovascular disease, death, and health disparities. Dietary policies have the potential to reduce this burden.
However, the potential benefits of policies targeting fruit, vegetable, and sugar-sweetened beverage consumption in the whole US population and among those participatin... | Cardiovascular disease (CVD) is declining in the US [1–3]. However, CVD remains the leading cause of mortality, generating approximately 800,000 deaths and 6 million hospital admissions annually [2]. Crucially, these burdens are highly unequal across the population, in particular according to socio-economic status (SES... |
10.1371/journal.pcbi.1000968 | Infectious Disease Modeling of Social Contagion in Networks | Many behavioral phenomena have been found to spread interpersonally through social networks, in a manner similar to infectious diseases. An important difference between social contagion and traditional infectious diseases, however, is that behavioral phenomena can be acquired by non-social mechanisms as well as through... | Information, trends, behaviors and even health states may spread between contacts in a social network, similar to disease transmission. However, a major difference is that as well as being spread infectiously, it is possible to acquire this state spontaneously. For example, you can gain knowledge of a particular piece ... | Social network effects are of great importance for understanding human behavior. People interact with a varying number of individuals and with some individuals more than others, and this affects behavior in fundamental ways. Sociologists have long studied social influence through networks, and networks now routinely ap... |
10.1371/journal.pgen.1000957 | Integration of Light Signals by the Retinoblastoma Pathway in the Control of S Phase Entry in the Picophytoplanktonic Cell Ostreococcus | Although the decision to proceed through cell division depends largely on the metabolic status or the size of the cell, the timing of cell division is often set by internal clocks such as the circadian clock. Light is a major cue for circadian clock entrainment, and for photosynthetic organisms it is also the main sour... | Microalgae from phytoplankton play an essential role in the biogeochemical cycles through carbon dioxide assimilation in the oceans where they account for more than half of organic carbon production. Photosynthetic cells use light energy for cell growth, but light can also reset the circadian clock, which is involved i... | The cell division cycle (CDC) is a highly conserved and regulated process, which controls the proliferation of unicellular organisms and development and tissue renewal in multicellular organisms. In eukaryotes the main steps of CDC progression are controlled by Cyclin Dependent Kinases (CDKs). From human to algae, the ... |
10.1371/journal.ppat.1004895 | Edin Expression in the Fat Body Is Required in the Defense Against Parasitic Wasps in Drosophila melanogaster | The cellular immune response against parasitoid wasps in Drosophila involves the activation, mobilization, proliferation and differentiation of different blood cell types. Here, we have assessed the role of Edin (elevated during infection) in the immune response against the parasitoid wasp Leptopilina boulardi in Droso... | The events leading to a successful encapsulation of parasitoid wasp eggs in the larvae of the fruit fly Drosophila melanogaster are insufficiently understood. The formation of a capsule seals off the wasp egg, and this process is often functionally compared to the formation of granulomas in vertebrates. Like granuloma ... | Parasitoid wasps are natural enemies of insects such as the fruit fly Drosophila melanogaster. In the course of a successful wasp infection, a female wasp lays an egg in a fruit fly larva and the wasp larva hatches. Thereafter, the wasp larva develops inside the Drosophila larva using the host tissue as a source of nut... |
10.1371/journal.pcbi.1002292 | Estimated Comparative Integration Hotspots Identify Different Behaviors of Retroviral Gene Transfer Vectors | Integration of retroviral vectors in the human genome follows non random patterns that favor insertional deregulation of gene expression and may cause risks of insertional mutagenesis when used in clinical gene therapy. Understanding how viral vectors integrate into the human genome is a key issue in predicting these r... | Understanding how retroviral vectors integrate in the human genome is a major safety issue in gene therapy, since a concrete risk of developing tumors associated with the integration process has been observed in several clinical trials. Statistical analyses confirmed the non randomness of the integration. Where and why... | Seminal clinical studies have recently shown that transplantation of stem cells, genetically modified by retroviral vectors, may cure severe genetic diseases such as immunodeficiencies [1], [2], skin adhesion defects [3] and lysosomal storage disorders [4]. Unfortunately, some of these studies also showed the limitatio... |
10.1371/journal.pgen.1003337 | CELF Family RNA–Binding Protein UNC-75 Regulates Two Sets of Mutually Exclusive Exons of the unc-32 Gene in Neuron-Specific Manners in Caenorhabditis elegans | An enormous number of alternative pre–mRNA splicing patterns in multicellular organisms are coordinately defined by a limited number of regulatory proteins and cis elements. Mutually exclusive alternative splicing should be strictly regulated and is a challenging model for elucidating regulation mechanisms. Here we pro... | Tissue-specific and mutually exclusive alternative pre–mRNA splicing is a challenging model for elucidating regulation mechanisms. We previously demonstrated that evolutionarily conserved RBFOX family RNA–binding proteins ASD-1 and FOX-1 and a muscle-specific RNA–binding protein SUP-12 cooperatively direct muscle-speci... | Alternative splicing of pre-mRNAs is a major source of proteomic complexity in metazoans. More than 90% of human multi-exon genes undergo alternative pre-mRNA processing and many alternative splicing events are controlled in tissue- and cell-type dependent manners [1]. Mis-splicing of pre-mRNAs underlie many inherited ... |
10.1371/journal.ppat.1006108 | Probability of Transmission of Malaria from Mosquito to Human Is Regulated by Mosquito Parasite Density in Naïve and Vaccinated Hosts | Over a century since Ronald Ross discovered that malaria is caused by the bite of an infectious mosquito it is still unclear how the number of parasites injected influences disease transmission. Currently it is assumed that all mosquitoes with salivary gland sporozoites are equally infectious irrespective of the number... | Malaria is transmitted to humans by the bite of an infectious mosquito though it is unclear whether a mosquito with a high number of parasites is more infectious than one with only a few. Here we show that the greater the number of parasites within the salivary gland of the mosquito following blood-feeding the more lik... | Mosquito-to-human malaria transmission occurs when sporozoites from the salivary gland of the mosquito are injected into the skin during blood-feeding. Parasites then pass to the liver where they replicate, each sporozoite yielding many thousands of merozoites which go on to cause patent infection. Relatively little is... |
10.1371/journal.pbio.0050133 | Gamma Oscillations in Human Primary Somatosensory Cortex Reflect Pain Perception | Successful behavior requires selection and preferred processing of relevant sensory information. The cortical representation of relevant sensory information has been related to neuronal oscillations in the gamma frequency band. Pain is of invariably high behavioral relevance and, thus, nociceptive stimuli receive prefe... | Pain is a highly subjective sensation of inherent behavioral importance and is therefore expected to receive enhanced processing in relevant brain regions. We show that painful stimuli induce high-frequency oscillations in the electrical activity of the human primary somatosensory cortex. Amplitudes of these pain-induc... | Within the continuous flow of sensory information, a huge number of events compete for neural representation and perception. This sensory overflow requires the selection and preferential processing of relevant information in order to optimize the utilization of cerebral processing resources. Recently, induced neuronal ... |
10.1371/journal.pntd.0003706 | Community-Centered Responses to Ebola in Urban Liberia: The View from Below | The West African Ebola epidemic has demonstrated that the existing range of medical and epidemiological responses to emerging disease outbreaks is insufficient, especially in post-conflict contexts with exceedingly poor healthcare infrastructures. In this context, community-based responses have proven vital for contain... | In this study the authors analyzed data from the 2014 Ebola outbreak in Monrovia and Montserrado County, Liberia. The data were collected for the purposes of program design and evaluation by the World Health Organization (WHO) and the Government of Liberia (GOL), in order to identify: (1) local knowledge about EVD, (2)... | The West African Ebola epidemic emerged in the forest region of Guinea in late December 2013 and appeared to be contained until May 2014, when it rapidly accelerated its rate of incidence and crossed into urban areas in Sierra Leone and Liberia [1]. Upon entering Sierra Leone and Liberia, the rate of Ebola virus diseas... |
10.1371/journal.pcbi.1006874 | Genesis of the αβ T-cell receptor | The T-cell (TCR) repertoire relies on the diversity of receptors composed of two chains, called α and β, to recognize pathogens. Using results of high throughput sequencing and computational chain-pairing experiments of human TCR repertoires, we quantitively characterize the αβ generation process. We estimate the proba... | Receptors on the surface of T-cells recognize pathogens and initiate an immune response. Analyzing the sequences of human T-cell receptors we draw a detailed quantitative picture of the generation process of the two receptor chains allowing us to estimate the diversity of the complete repertoire. We discuss which eleme... | The adaptive immune system confers protection against many different pathogens using a diverse set of specialized receptors expressed on the surface of T-cells. The ensemble of the expressed receptors is called a repertoire and its diversity and composition encode the ability of the immune system to recognize antigens.... |
10.1371/journal.pmed.1002143 | Orthostatic Hypotension and the Long-Term Risk of Dementia: A Population-Based Study | Orthostatic hypotension (OH) is a common cause of transient cerebral hypoperfusion in the population. Cerebral hypoperfusion is widely implicated in cognitive impairment, but whether OH contributes to cognitive decline and dementia is uncertain. We aimed to determine the association between OH and the risk of developin... | Orthostatic hypotension is a common cause of transient cerebral hypoperfusion that is associated with subclinical brain disease, as well as increased risk of stroke.
Hypoperfusion has been implicated in the pathophysiology of dementia, but whether orthostatic hypotension affects the risk of dementia is uncertain.
Back ... | Cardiovascular health is now well-established as a key determinant in the prevention of dementia, including Alzheimer disease [1,2], but the mechanisms by which vascular damage leads to cognitive decline remain largely unknown. As cerebral hypoperfusion is widely implicated in dementia [3,4], cerebral haemodynamics hav... |
10.1371/journal.pgen.1002613 | The Functions of Mediator in Candida albicans Support a Role in Shaping Species-Specific Gene Expression | The Mediator complex is an essential co-regulator of RNA polymerase II that is conserved throughout eukaryotes. Here we present the first study of Mediator in the pathogenic fungus Candida albicans. We focused on the Middle domain subunit Med31, the Head domain subunit Med20, and Srb9/Med13 from the Kinase domain. The ... | In this study, we compared the roles of Mediator, a central transcriptional regulator in all eukaryotes, between the pathogenic fungus Candida albicans and the non-pathogenic model yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe. We discovered that Mediator has both shared and species-specific functions i... | The transcription factor complex Mediator is associated with RNA polymerase II and it has essential roles in transcription ([1], reviewed in [2]). The yeast Mediator is composed of 25 subunits, which are structurally and functionally organized into four modules [3]–[8]. The core complex is comprised of the Head, Middle... |
10.1371/journal.pcbi.1006610 | On variational solutions for whole brain serial-section histology using a Sobolev prior in the computational anatomy random orbit model | This paper presents a variational framework for dense diffeomorphic atlas-mapping onto high-throughput histology stacks at the 20 μm meso-scale. The observed sections are modelled as Gaussian random fields conditioned on a sequence of unknown section by section rigid motions and unknown diffeomorphic transformation of ... | New developments in neural tracing techniques have motivated the widespread use of histology as a modality for exploring the circuitry of the brain. Automated mapping of pre-labeled atlases onto modern large datasets of histological imagery is a critical step for elucidating the brain’s neural circuitry and shape. This... | Recent advances in brain imaging [1, 2], methods to label neurons [3], and computational methods have brought about a new era of neuroanatomical research, with a focus on comprehensively mapping brain circuits [4]. Mapping whole-brain circuitry is important for three distinct reasons: scientific understanding of how th... |
10.1371/journal.ppat.1002221 | APOBEC3A Is a Specific Inhibitor of the Early Phases of HIV-1 Infection in Myeloid Cells | Myeloid cells play numerous roles in HIV-1 pathogenesis serving as a vehicle for viral spread and as a viral reservoir. Yet, cells of this lineage generally resist HIV-1 infection when compared to cells of other lineages, a phenomenon particularly acute during the early phases of infection. Here, we explore the role of... | Macrophages and dendritic cells represent important targets for HIV-1 and the understanding of the complex relationship established between these cells and the virus is of the outmost importance. Here, we show that APOBEC3A, the least known member of the APOBEC3 family of cytidine deaminases, restricts HIV-1 specifical... | The apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 family (APOBEC3s) comprises 6 members of highly related cytidine deaminases [1]. The prototype of the family, APOBEC3G (or A3G), has been identified on the basis of its ability to inhibit HIV-1 infection in the absence of the Vif protein [2]. In thi... |
10.1371/journal.pntd.0005040 | Near-Infrared Spectroscopy, a Rapid Method for Predicting the Age of Male and Female Wild-Type and Wolbachia Infected Aedes aegypti | Estimating the age distribution of mosquito populations is crucial for assessing their capacity to transmit disease and for evaluating the efficacy of available vector control programs. This study reports on the capacity of the near-infrared spectroscopy (NIRS) technique to rapidly predict the ages of the principal den... | Aedes aegypti is the principal vector for dengue, chikungunya and Zika viruses. These viruses require a period of development inside the mosquito before they can be transmitted to humans. Depending on environmental factors, dengue and Zika viruses take an average of 8–10 days to replicate inside the mosquito [1,2] wher... | The mosquito Aedes aegypti is the primary vector for dengue, Zika and chikungunya viruses. Up to 100 million dengue cases occur annually [5,6] and an estimated 440,000–1,300,000 Zika cases were reported in early 2016. Notably, 3893 babies born to Zika infected mothers have been diagnosed with microcephaly [7,8]. Both Z... |
10.1371/journal.pgen.1006034 | Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure | Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of gen... | In this study, we applied a genome-wide mapping approach to study molecular determinants of mortality in subjects with heart failure. We identified a genetic variant on chromosome 5q22 that was associated with mortality in this group and observed that this variant conferred increased function of an enhancer region acti... | Heart failure (HF) is a common clinical condition in which the heart fails to maintain blood circulation adequate to meet the metabolic demands of the body without increased cardiac filling pressures. HF is the result of chronic ventricular remodelling initiated by myocardial injury, volume/pressure overload, or intrin... |
10.1371/journal.pntd.0004282 | Characterization of the Paracoccidioides Hypoxia Response Reveals New Insights into Pathogenesis Mechanisms of This Important Human Pathogenic Fungus | Hypoxic microenvironments are generated during fungal infection. It has been described that to survive in the human host, fungi must also tolerate and overcome in vivo microenvironmental stress conditions including low oxygen tension; however nothing is known how Paracoccidioides species respond to hypoxia. The genus P... | The genus Paracoccidioides is composed of species that are causative agents of paracoccidioidomycosis (PCM), a neglected human granulomatous mycosis, endemic in Latin America. To survive in the human host, fungi must tolerate and overcome in vivo micro environmental stress conditions, including low oxygen levels. Parac... | The genus Paracoccidioides is a complex of thermodimorphic fungi, and are causative agents of paracoccidioidomycosis (PCM) a deep systemic granulomatous mycosis, endemic in Latin America [1, 2]. Paracoccidioides spp. grows as yeast in host tissue and in vitro at 36°C, and as mycelium under saprobiotic and laboratory co... |
10.1371/journal.ppat.1006930 | Oxidative stress and protein damage responses mediate artemisinin resistance in malaria parasites | Due to their remarkable parasitocidal activity, artemisinins represent the key components of first-line therapies against Plasmodium falciparum malaria. However, the decline in efficacy of artemisinin-based drugs jeopardizes global efforts to control and ultimately eradicate the disease. To better understand the resist... | The emergence of artemisinin resistance within and beyond Southeast Asia is a looming threat that needs to be promptly addressed. With this in mind, we derived several artemisinin-resistant parasite lines in vitro in order to fully characterize the resistance phenotype at the cellular and molecular levels. In addition ... | Malaria remains the most prevalent and deadly vector-borne disease in the world, with an estimated two hundred million cases and over four hundred thousand deaths recorded in 2015[1]. Currently, the cornerstone of global malaria control programs is artemisinin combination therapy (ACT). ACT combines the highly potent, ... |
10.1371/journal.ppat.1001216 | Legionella Metaeffector Exploits Host Proteasome to Temporally Regulate Cognate Effector | Pathogen-associated secretion systems translocate numerous effector proteins into eukaryotic host cells to coordinate cellular processes important for infection. Spatiotemporal regulation is therefore important for modulating distinct activities of effectors at different stages of infection. Here we provide the first e... | Many bacterial pathogens encode a large array of “effector proteins” that are essential for successful infection. By definition, effector proteins are synthesized in bacteria and transported from bacteria into host cells. Within host cells, effector proteins directly interact with host factors in order to modulate thei... | Many bacterial pathogens encode a large array of “effector proteins,” that manipulate host cellular processes during infection. Effector proteins are translocated from bacteria directly into the cytosol of host cells. This process is mediated by dedicated bacterial protein delivery systems, including the type III and t... |
10.1371/journal.pcbi.1006234 | Subgraphs of functional brain networks identify dynamical constraints of cognitive control | Brain anatomy and physiology support the human ability to navigate a complex space of perceptions and actions. To maneuver across an ever-changing landscape of mental states, the brain invokes cognitive control—a set of dynamic processes that engage and disengage different groups of brain regions to modulate attention,... | Brain networks support the human ability to navigate a complex space of perceptions and actions through cognitive control. Here we ask, “How do brain networks coordinate task-relevant information as individuals adapt to cognitive demands imposed by a task?” We study the fMRI BOLD signal of twenty-eight healthy subjects... | In human cognition, internally-generated cognitive control processes modulate attention, facilitate task switching, and inhibit prepotent behavior [1]. One avenue by which the brain may rapidly traverse a cognitive state-space is through its functional interactions—coherent fluctuations in brain activity shaped by the ... |
10.1371/journal.pntd.0006817 | Clinical manifestations of dengue in relation to dengue serotype and genotype in Malaysia: A retrospective observational study | Malaysia experienced an unprecedented dengue outbreak from the year 2014 to 2016 that resulted in an enormous increase in the number of cases and mortality as compared to previous years. The causes that attribute to a dengue outbreak can be multifactorial. Viral factors, such as dengue serotype and genotype, are the co... | The study highlights interesting relationship between viral factors and clinical manifestation of dengue disease during an outbreak. The viral factors which include serotype and genotype of dengue virus were studied to discover if the clinical manifestation in patients were serotype and genotype-specific. As most clini... | Since the 1950’s, dengue has become a serious health problem in the South-East Asia region. In 1902, Malaysia experienced its first case of dengue [1]. Since then, Malaysia has increasingly become popular for perpetual dengue endemic issues, resulting from the continuous rise in reported dengue infection cases. The cou... |
10.1371/journal.pntd.0001304 | Metagenomic Analysis of Taxa Associated with Lutzomyia longipalpis, Vector of Visceral Leishmaniasis, Using an Unbiased High-Throughput Approach | Leishmaniasis is one of the most diverse and complex of all vector-borne diseases worldwide. It is caused by parasites of the genus Leishmania, obligate intramacrophage protists characterised by diversity and complexity. Its most severe form is visceral leishmaniasis (VL), a systemic disease that is fatal if left untre... | Leishmaniasis is a vector-borne disease with a complex ecology and epidemiology. It has three main clinical forms of which visceral leishmaniasis (VL) is the most severe, as it is fatal if untreated. It is caused by a protist parasite, Leishmania spp., and is transmitted to humans by phlebotomine sandflies. The best me... | Leishmaniasis is a vector-borne neglected infectious disease of worldwide incidence and its most severe clinical form is visceral leishmaniasis (VL). Each year VL causes an estimated 500,000 new cases and more than 59,000 deaths [1], a death toll that is only surpassed by malaria among the parasitic diseases [2]. Furth... |
10.1371/journal.pgen.1007519 | The lncRNA male-specific abdominal plays a critical role in Drosophila accessory gland development and male fertility | Although thousands of long non-coding RNAs (lncRNA) have been identified in the genomes of higher eukaryotes, the precise function of most of them is still unclear. Here, we show that a >65 kb, male-specific, lncRNA, called male-specific abdominal (msa) is required for the development of the secondary cells of the Dros... | In many animals, the male seminal fluid induces physiology changes in the mated female that increase a male’s reproductive success. These changes are often referred to as the post-mating response (PMR). In Drosophila, the seminal fluid proteins responsible for generating the PMR are made in a specialized gland, analogo... | Recent studies have shown that the genomes of many higher eukaryotes contain a large number of non-coding transcripts [1] [2] [3] [4] [5] [6]. Elucidating the function of these “non-coding” transcripts is now the topic of intense research. So far, much of the research done on these non-coding RNAs (ncRNAs) has concentr... |
10.1371/journal.pgen.1006521 | Tbx5 Buffers Inherent Left/Right Asymmetry Ensuring Symmetric Forelimb Formation | The forelimbs and hindlimbs of vertebrates are bilaterally symmetric. The mechanisms that ensure symmetric limb formation are unknown but they can be disrupted in disease. In Holt-Oram Syndrome (HOS), caused by mutations in TBX5, affected individuals have left-biased upper/forelimb defects. We demonstrate a role for th... | Externally, the human form appears bilaterally symmetric. For example, each of our pairs of arms and legs are the same length. This external symmetry masks many asymmetries found in internal organs. In most people the heart is found on the left side of the chest. The stomach, liver and spleen are also positioned asymme... | The external body plan of most metazoans is bilaterally symmetric. How this symmetry is achieved has fascinated biologists for centuries and is exemplified by Leonardo Da Vinci’s description of the “Vitruvian Man” that describes some of the uniform proportions of the human body. In vertebrates, external bilateral symme... |
10.1371/journal.pgen.1005710 | GDNF Overexpression from the Native Locus Reveals its Role in the Nigrostriatal Dopaminergic System Function | Degeneration of nigrostriatal dopaminergic system is the principal lesion in Parkinson’s disease. Because glial cell line-derived neurotrophic factor (GDNF) promotes survival of dopamine neurons in vitro and in vivo, intracranial delivery of GDNF has been attempted for Parkinson’s disease treatment but with variable su... | Intracranial delivery of GDNF has been attempted for Parkinson’s disease (PD) treatment but with variable success. For improving GDNF-based therapies, knowledge on physiological role of endogenous GDNF at the sites of its expression is important. However, due to limitations of existing genetic model systems, such knowl... | Exogenously applied glial cell line-derived neurotrophic factor (GDNF) promotes the survival, function, and neurite growth of nigrostriatal dopamine (DA) neurons both in vitro and in vivo [1,2]. The classic motor deficit in Parkinson’s disease is characterized by a gradual loss of nigrostriatal DA neurons, leading to a... |
10.1371/journal.pbio.1001407 | Generation of Functional Blood Vessels from a Single c-kit+ Adult Vascular Endothelial Stem Cell | In adults, the growth of blood vessels, a process known as angiogenesis, is essential for organ growth and repair. In many disorders including cancer, angiogenesis becomes excessive. The cellular origin of new vascular endothelial cells (ECs) during blood vessel growth in angiogenic situations has remained unknown. Her... | Angiogenesis—the growth of blood vessels—is essential for organ growth and repair, but also occurs during tumorigenesis and in certain inflammatory disorders. All blood vessels are lined by endothelial cells (ECs)—thin, flattened cells that form a continuous monolayer throughout the entire circulatory system. The cellu... | The early blood vessels of the embryo and yolk sac in mammals develop by aggregation of de-novo-forming angioblasts into a primitive vascular plexus (vasculogenesis). Blood vessels arise from endothelial precursors, which share an origin with hematopoietic progenitors [1]–[3]. In adults, the growth of blood vessels is ... |
10.1371/journal.ppat.1007171 | Selected HLA-B allotypes are resistant to inhibition or deficiency of the transporter associated with antigen processing (TAP) | Major histocompatibility complex class I (MHC-I) molecules present antigenic peptides to CD8+ T cells, and are also important for natural killer (NK) cell immune surveillance against infections and cancers. MHC-I molecules are assembled via a complex assembly pathway in the endoplasmic reticulum (ER) of cells. Peptides... | Human leukocyte antigen (HLA) class I molecules present pathogen-derived components (peptides) to cytotoxic T cells, thereby inducing the T cells to kill virus-infected cells. A complex cellular pathway involving the transporter associated with antigen processing (TAP) is typically required for the loading of peptides ... | MHC-I molecules play a pivotal role in immune surveillance of intracellular pathogens by presenting antigenic peptides to cytotoxic T cells (CTL). They also function to regulate natural killer (NK) cell activity by engaging NK cell receptors including KIR3DL1 [1], KIR2DL1/2/3 [2], CD94-NKG2A [3] and KIR3DS1 [4, 5]. MHC... |
10.1371/journal.pbio.0060208 | Evolution of Genomic Imprinting with Biparental Care: Implications for Prader-Willi and Angelman Syndromes | The term “imprinted gene” refers to genes whose expression is conditioned by their parental origin. Among theories to unravel the evolution of genomic imprinting, the kinship theory prevails as the most widely accepted, because it sheds light on many aspects of the biology of imprinted genes. While most assumptions und... | Genomic imprinting refers to genes that are silent when maternally inherited but expressed when paternally inherited, or vice versa. Hailed as the most successful evolutionary explanation for genomic imprinting, the kinship theory contends that the paternally inherited copy of a gene, which determines the allocation of... | Imprinted genes violate Mendel's laws by exhibiting an expression conditioned by their parental origin [1]. Either they are silent when maternally inherited (MI) and expressed when paternally inherited (PI), or vice versa [1].
This form of genetic memory captivated the interest of biologists early on. Since its ... |
10.1371/journal.pcbi.0030192 | Metabolic Reconstruction and Modeling of Nitrogen Fixation in Rhizobium etli | Rhizobiaceas are bacteria that fix nitrogen during symbiosis with plants. This symbiotic relationship is crucial for the nitrogen cycle, and understanding symbiotic mechanisms is a scientific challenge with direct applications in agronomy and plant development. Rhizobium etli is a bacteria which provides legumes with a... | Nitrogen fixation is an important process for improving plant development in crops. Overall, it constitutes a central role in the nitrogen cycle which is essential to life. In this work we were interested in understanding nitrogen fixation in Rhizobium etli from a genome-scale perspective. Using the genome annotation a... | Free-living bacteria belonging to the Rhizobium genera are often symbiots associated with plants of the family leguminosae. These bacteria differentiate and have the ability to fix atmospheric nitrogen into ammonium when some compounds are exchanged between the bacteroid and its plant host [1–3]. Establishment of effec... |
10.1371/journal.ppat.1003562 | Francisella tularensis Harvests Nutrients Derived via ATG5-Independent Autophagy to Support Intracellular Growth | Francisella tularensis is a highly virulent intracellular pathogen that invades and replicates within numerous host cell types including macrophages, hepatocytes and pneumocytes. By 24 hours post invasion, F. tularensis replicates up to 1000-fold in the cytoplasm of infected cells. To achieve such rapid intracellular p... | Francisella tularensis is a highly virulent bacterial pathogen that infects hundreds of different animal species including humans. During infection, F. tularensis bacteria invade and rapidly multiply inside host cells. Within the host cell environment, basic nutrients that bacteria require for growth are in limited sup... | When intracellular bacterial pathogens invade host cells, the bacteria must scavenge energy sources and anabolic substrates from the nutrient-limited intracellular environment. Most of the potential nutrient sources inside a host cell are stored within complex structures such as lipid droplets, glycogen and proteins, w... |
10.1371/journal.pbio.1001381 | Clade Age and Species Richness Are Decoupled Across the Eukaryotic Tree of Life | Explaining the dramatic variation in species richness across the tree of life remains a key challenge in evolutionary biology. At the largest phylogenetic scales, the extreme heterogeneity in species richness observed among different groups of organisms is almost certainly a function of many complex and interdependent ... | Species richness varies by many orders of magnitude across the evolutionary "tree of life." Some groups, like beetles and flowering plants, contain nearly incomprehensible species diversity, but the overwhelming majority of groups contain far fewer species. Many processes presumably contribute to this variati... | One of the most striking large-scale patterns in biology is the uneven distribution of species richness across the tree of life. Some groups are characterized by nearly incomprehensible species diversity (beetles, grasses), yet many other groups are species-poor (tuataras, ginkgoes). Evolutionary biologists have long b... |
10.1371/journal.pntd.0005502 | The novel nematicide wact-86 interacts with aldicarb to kill nematodes | Parasitic nematodes negatively impact human and animal health worldwide. The market withdrawal of nematicidal agents due to unfavourable toxicities has limited the available treatment options. In principle, co-administering nematicides at lower doses along with molecules that potentiate their activity could mitigate ad... | Many nematicides that have been used to kill plant and animal parasitic nematodes are being phased out over concerns of toxicity to humans. One potential solution to reduce toxicity is to use the nematicide at a lower concentration in combination with a second compound that together will produce a synergistic killing e... | Parasitic nematodes infect more than one billion people worldwide, negatively impacting human health and productivity [1,2]. Dramatic worldwide economic losses are incurred from nematode infections of commercially vital crops and livestock [3–5]. As a result of the growing resistance of nematodes to all of the major an... |
10.1371/journal.pntd.0003160 | Achieving Population-Level Immunity to Rabies in Free-Roaming Dogs in Africa and Asia | Canine rabies can be effectively controlled by vaccination with readily available, high-quality vaccines. These vaccines should provide protection from challenge in healthy dogs, for the claimed period, for duration of immunity, which is often two or three years. It has been suggested that, in free-roaming dog populati... | Canine-mediated rabies is a horrific disease that claims tens of thousands of human lives every year, particularly in Asia and Africa. The disease can be effectively controlled through mass vaccination of dogs with high-quality vaccines; however, questions remain over the effectiveness of vaccination where the health s... | Canine-mediated rabies is a viral zoonosis, causing at least 55,000 human deaths every year [1]. Mortality from rabies is highest in less developed communities in Asia and Africa, where domestic dogs are free-roaming [2]–[8]; with increasing evidence that the majority are owned [2], [3], [6], [9], [10] and, thus, gener... |
10.1371/journal.pcbi.1007061 | The ability of transcription factors to differentially regulate gene expression is a crucial component of the mechanism underlying inversion, a frequently observed genetic interaction pattern | Genetic interactions, a phenomenon whereby combinations of mutations lead to unexpected effects, reflect how cellular processes are wired and play an important role in complex genetic diseases. Understanding the molecular basis of genetic interactions is crucial for deciphering pathway organization as well as understan... | The relationship between genotype and phenotype is one of the major challenges in biology. While many previous studies have identified genes involved in complex genetic diseases, there is still a gap between genotype and phenotype. One of the difficulties in filling this gap has been attributed to genetic interactions.... | Understanding the relationship between genotype and phenotype of an organism is a major challenge [1,2]. One of the difficulties for unravelling genotype-phenotype relationship has been genetic interactions, when combinations of mutations lead to phenotypic effects that are unexpected based on the phenotypes of the ind... |
10.1371/journal.ppat.1007107 | Methyl-CpG-binding (SmMBD2/3) and chromobox (SmCBX) proteins are required for neoblast proliferation and oviposition in the parasitic blood fluke Schistosoma mansoni | While schistosomiasis remains a significant health problem in low to middle income countries, it also represents a recently recognised threat to more economically-developed regions. Until a vaccine is developed, this neglected infectious disease is primarily controlled by praziquantel, a drug with a currently unknown m... | Schistosomiasis, caused by infection with blood fluke worms, is responsible for chronic disability and debilitating pathology in millions of infected individuals living in deprived regions of the developing world. Currently, schistosomiasis is primarily controlled by administration of a single drug (praziquantel) with ... | Characterised by a complex lifecycle alternating between two different hosts (snail and mammal) and a fresh water ecosystem, schistosomes are highly evolved human pathogens responsible for the neglected infectious disease schistosomiasis. Predominantly found in sub-tropical and tropical regions of resource-poor communi... |
10.1371/journal.pcbi.1005095 | Inhomogeneity Based Characterization of Distribution Patterns on the Plasma Membrane | Cell surface protein and lipid molecules are organized in various patterns: randomly, along gradients, or clustered when segregated into discrete micro- and nano-domains. Their distribution is tightly coupled to events such as polarization, endocytosis, and intracellular signaling, but challenging to quantify using tra... | Plasma membrane organization is fundamental to cellular signaling, transport of molecules, and cell adhesion. To achieve this, plasma membrane proteins and lipids are spatially organized: they form clusters, aggregate in signaling platforms, distribute into gradients on polarized cells, or randomly distribute across th... | The function of cell surface proteins and lipids is tightly coupled to their spatial organization [1–3]. Membrane constituents cluster in nano- and micro-domains originating from lipid affinity (e.g., lipid rafts) [4], protein-protein interactions (e.g., tetraspanin domains) [5], and constraints imposed by the cytoskel... |
10.1371/journal.pbio.2000737 | Four simple rules that are sufficient to generate the mammalian blastocyst | Early mammalian development is both highly regulative and self-organizing. It involves the interplay of cell position, predetermined gene regulatory networks, and environmental interactions to generate the physical arrangement of the blastocyst with precise timing. However, this process occurs in the absence of materna... | The first 4.5 days of mammalian embryo development proceeds without maternal information and is remarkably robust to perturbations. For example, if an early embryo is cut in half, it produces 2 perfectly patterned, smaller embryos. Where does the information guiding this development come from? Here, we explore this iss... | Early mammalian development is a fascinating example of how deterministic spatiotemporal patterns emerge at the level of cell populations from highly stochastic regulatory components. During mouse preimplantation development, 2 sequential lineage decisions take place [1] (Fig 1), and these decisions are marked by the e... |
10.1371/journal.pmed.1002920 | Risk and protective factors for child development: An observational South African birth cohort | Approximately 250 million (43%) children under the age of 5 years in low- and middle-income countries (LMICs) are failing to meet their developmental potential. Risk factors are recognised to contribute to this loss of human potential. Expanding understanding of the risks that lead to poor outcomes and which protective... | Child development in early childhood lays a foundation for lifelong learning.
Risk and protective factors for child development are known to include many issues faced by children growing up in low- and middle-income countries.
Studies indicate a difference between boys and girls in terms of impact of factors influencin... | Approximately 250 million (43%) of children under the age of 5 years in low- and middle-income countries (LMICs) are at risk of poor developmental outcomes [1]. Child development takes place as an ongoing biological and psychological process influenced by the environment, caregivers, community, and society. Key risk fa... |
10.1371/journal.ppat.1002012 | Metabolite Cross-Feeding Enhances Virulence in a Model Polymicrobial Infection | Microbes within polymicrobial infections often display synergistic interactions resulting in enhanced pathogenesis; however, the molecular mechanisms governing these interactions are not well understood. Development of model systems that allow detailed mechanistic studies of polymicrobial synergy is a critical step tow... | Many bacterial infections are not the result of colonization and persistence of a single pathogenic microbe in an infection site but instead the result of colonization by several. Although the importance of polymicrobial interactions and pathogenesis has been noted by many prominent microbiologists including Louis Past... | The survival of pathogens in the human body has been rigorously studied for well over a century. The ability of bacteria to colonize, persist and thrive in vivo is due to an array of capabilities including the ability to attach to host tissues, produce extracellular virulence factors, and evade the immune system. Invad... |
10.1371/journal.ppat.1005853 | Overexpression of Differentially Expressed Genes Identified in Non-pathogenic and Pathogenic Entamoeba histolytica Clones Allow Identification of New Pathogenicity Factors Involved in Amoebic Liver Abscess Formation | We here compared pathogenic (p) and non-pathogenic (np) isolates of Entamoeba histolytica to identify molecules involved in the ability of this parasite to induce amoebic liver abscess (ALA)-like lesions in two rodent models for the disease. We performed a comprehensive analysis of 12 clones (A1–A12) derived from a non... | The pathogen Entamoeba histolytica can live asymptomatically in the human gut, or it can disrupt the intestinal barrier and induce life-threatening abscesses in different organs, most often in the liver. The molecular framework that enables this invasive, highly pathogenic phenotype is still not well understood. In ord... | The protozoan parasite Entamoeba histolytica is responsible for approximately 50 million cases of invasive amoebiasis per year, resulting in an annual death toll of 40,000–100,000 [1]. The parasite life cycle is relatively simple, comprising infectious cysts that can survive outside the host and vegetative trophozoites... |
10.1371/journal.pntd.0000987 | Evaluation of Mammalian and Intermediate Host Surveillance Methods for Detecting Schistosomiasis Reemergence in Southwest China | Schistosomiasis has reemerged in China, threatening schistosomiasis elimination efforts. Surveillance methods that can identify locations where schistosomiasis has reemerged are needed to prevent the further spread of infections.
We tested humans, cows, water buffalo and the intermediate host snail, Oncomelania hupensi... | Schistosomiasis has reemerged in China in regions where it was previously controlled. As reductions in schistosomiasis, a water-born parasitic infection, prompt consideration of schistosomiasis elimination, surveillance strategies that can signal reemergence and prevent further lapses in control are needed. We examined... | The success of disease control programs in reducing schistosomiasis infections and morbidity have prompted consideration of the elimination of human schistosomiasis [1], [2]. Dramatic declines in Schistosoma haematobium and S. mansoni have been observed following widespread distribution of the antihelminthic drug, praz... |
10.1371/journal.pcbi.1003005 | Sparse Coding Can Predict Primary Visual Cortex Receptive Field Changes Induced by Abnormal Visual Input | Receptive fields acquired through unsupervised learning of sparse representations of natural scenes have similar properties to primary visual cortex (V1) simple cell receptive fields. However, what drives in vivo development of receptive fields remains controversial. The strongest evidence for the importance of sensory... | The responses of neurons in the primary visual cortex (V1), a region of the brain involved in encoding visual input, are modified by the visual experience of the animal during development. For example, most neurons in animals reared viewing stripes of a particular orientation only respond to the orientation that the an... | Simple cells in the mammalian primary visual cortex (V1) are among the cells in the brain that are best functionally characterised [1]–[3]. They have also been used as a key model system for studying the complex interplay of intrinsic and extrinsic factors, i.e., nature and nurture, in controlling development. For inst... |
10.1371/journal.pntd.0003192 | Physician Survey to Determine How Dengue Is Diagnosed, Treated and Reported in Puerto Rico | Dengue is a major cause of morbidity in Puerto Rico and is well-known to its physicians. Early case identification and timely initiation of treatment for patients with severe dengue can reduce medical complications and mortality. To determine clinical management and reporting practices, and assess knowledge of dengue a... | Dengue is a major cause of morbidity in Puerto Rico and is well-known to its physicians. Early case identification and timely initiation of treatment for patients with severe dengue can reduce medical complications and mortality. We conducted a survey among physicians who practice in Puerto Rico to determine clinical m... | Dengue is a mosquito-borne disease caused by any one of four dengue virus (DENV) types -1, -2, -3, and -4. Each DENV is capable of causing the full spectrum of disease from an asymptomatic infection to severe, life-threatening illness including dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) [1]. Dengue ... |
10.1371/journal.pntd.0001183 | The Use of a Mobile Laboratory Unit in Support of Patient Management and Epidemiological Surveillance during the 2005 Marburg Outbreak in Angola | Marburg virus (MARV), a zoonotic pathogen causing severe hemorrhagic fever in man, has emerged in Angola resulting in the largest outbreak of Marburg hemorrhagic fever (MHF) with the highest case fatality rate to date.
A mobile laboratory unit (MLU) was deployed as part of the World Health Organization outbreak respons... | A mobile laboratory unit (MLU) was deployed to Uige, Angola as part of the World Health Organization response to an outbreak of viral hemorrhagic fever caused by Marburg virus (MARV). Utilizing mainly quantitative real-time PCR assays, this laboratory provided specific MARV diagnostics in the field. The MLU operated fo... | Marburg virus (MARV) is classified as members of the family Filoviridae, genus Marburgvirus, type species Lake Victoria marburgvirus. A single species has been described which includes several virus strains [1]. Today, the geographic distribution of MARV seems to primarily involve areas in East Africa within 500 miles ... |
10.1371/journal.ppat.1003830 | Lysine Acetyltransferase GCN5b Interacts with AP2 Factors and Is Required for Toxoplasma gondii Proliferation | Histone acetylation has been linked to developmental changes in gene expression and is a validated drug target of apicomplexan parasites, but little is known about the roles of individual histone modifying enzymes and how they are recruited to target genes. The protozoan parasite Toxoplasma gondii (phylum Apicomplexa) ... | Toxoplasma gondii is a protozoan parasite that causes significant opportunistic infection in AIDS and other immunocompromised patients. Acute episodes of toxoplasmosis stem from tissue destruction caused by the rapidly growing form of the parasite, the tachyzoite. In this study, we identify a lysine acetyltransferase (... | Lysine acetylation of histones is a well-characterized post-translational modification linked to the activation of gene expression. Initially identified in the free-living protozoan Tetrahymena thermophila, the first histone acetyltransferase (HAT) was homologous to a transcriptional adaptor protein in yeast known as G... |
10.1371/journal.pgen.1007874 | Allele-specific RNA imaging shows that allelic imbalances can arise in tissues through transcriptional bursting | Extensive cell-to-cell variation exists even among putatively identical cells, and there is great interest in understanding how the properties of transcription relate to this heterogeneity. Differential expression from the two gene copies in diploid cells could potentially contribute, yet our ability to measure from wh... | In mammals, most cells of the body contain two genetic datasets: one from the mother and one from the father, and—in theory—these two sets of information could contribute equally to produce the molecules in a given cell. In practice, however, this is not always the case, which can have dramatic implications for many tr... | Gene expression in genetically identical individual cells often deviates from that of the cell population average [1], which in mammals can impact cell fate and development [2–5], response to environmental stimuli [6–9] and disease [10–13]. Over the past few years, it has emerged that at least some of this variability ... |
10.1371/journal.pgen.1000178 | Stability and Dynamics of Polycomb Target Sites in Drosophila Development | Polycomb-group (PcG) and Trithorax-group proteins together form a maintenance machinery that is responsible for stable heritable states of gene activity. While the best-studied target genes are the Hox genes of the Antennapedia and Bithorax complexes, a large number of key developmental genes are also Polycomb (Pc) tar... | Cells make fate decisions as they progressively differentiate into specific cell types during development. The stability of these decisions is important and is achieved, in part, by changes to the chromatin that packages DNA in the nucleus. A key set of protein complexes that together constitute the Polycomb-group/Trit... | As the cells of the embryo progress along developmental pathways they make fate decisions, becoming committed to particular lineages and ultimately to a specific differentiated cell state. Although cell fate decisions may be triggered by transient signals, the resultant cell states are generally stable and are maintain... |
10.1371/journal.pgen.1004128 | Extreme Population Differences in the Human Zinc Transporter ZIP4 (SLC39A4) Are Explained by Positive Selection in Sub-Saharan Africa | Extreme differences in allele frequency between West Africans and Eurasians were observed for a leucine-to-valine substitution (Leu372Val) in the human intestinal zinc uptake transporter, ZIP4, yet no further evidence was found for a selective sweep around the ZIP4 gene (SLC39A4). By interrogating allele frequencies in... | Zinc is an essential trace element with many biological functions in the body, whose concentrations are tightly regulated by different membrane transporters. Here we report an unusual case of positive natural selection for an amino acid replacement in the human intestinal zinc uptake transporter ZIP4. This substitution... | Zinc homeostasis is critically important for human health. Similarly to iron, zinc has manifold functions in the body, such as in the immune system [1], aging [2], DNA repair [3], signaling [4] and in diseases such as diabetes [5] and cancer [6]. On the molecular level, zinc acts as a co-factor in hundreds of metallo-e... |
10.1371/journal.pmed.1002815 | Malaria morbidity and mortality following introduction of a universal policy of artemisinin-based treatment for malaria in Papua, Indonesia: A longitudinal surveillance study | Malaria control activities can have a disproportionately greater impact on Plasmodium falciparum than on P. vivax in areas where both species are coendemic. We investigated temporal trends in malaria-related morbidity and mortality in Papua, Indonesia, before and after introduction of a universal, artemisinin-based ant... | Multidrug-resistant malaria results in recurrent parasitaemia, a cumulative risk of anaemia, and progression to severe and fatal disease.
Whilst artemisinin combination therapies (ACTs) and intravenous (IV) artesunate can reduce morbidity and mortality associated with P. falciparum malaria, they have no activity on the... | Prompt and effective treatment of malaria reduces morbidity and limits onward transmission of the Plasmodium parasite [1,2]. Large-scale use of highly efficacious antimalarial treatment regimens has contributed to significant reductions in P. falciparum malaria in many malaria-endemic regions [3,4]. P. vivax is more di... |
10.1371/journal.pntd.0003321 | Th1-Biased Immunomodulation and Therapeutic Potential of Artemisia annua in Murine Visceral Leishmaniasis | In the absence of vaccines and limitations of currently available chemotherapy, development of safe and efficacious drugs is urgently needed for visceral leishmaniasis (VL) that is fatal, if left untreated. Earlier we reported in vitro apoptotic antileishmanial activity of n-hexane fractions of Artemisia annua leaves (... | Visceral leishmaniasis (VL) is a fatal, vector-borne tropical disease that affects the poorest sections of the society. The currently available drugs are toxic, expensive and have severe side effects. The problem is further compounded by emergence of VL-HIV co-infection and occurence of PKDL after apparent cure. Thus, ... | Protozoal infections are a worldwide health problem, particularly in the third world countries [1]–[2], and account for approximately 14% of the world's population, who are at risk of infection. Leishmaniasis is considered by the WHO as one of the six major infectious diseases, with a high incidence and ability to prod... |
10.1371/journal.pcbi.1005471 | The preferred nucleotide contexts of the AID/APOBEC cytidine deaminases have differential effects when mutating retrotransposon and virus sequences compared to host genes | The AID / APOBEC genes are a family of cytidine deaminases that have evolved in vertebrates, and particularly mammals, to mutate RNA and DNA at distinct preferred nucleotide contexts (or “hotspots”) on foreign genomes such as viruses and retrotransposons. These enzymes play a pivotal role in intrinsic immunity defense ... | The APOBEC family of cytidine deaminases are important enzymes in most vertebrates. The ancestral member of this gene family is activation induced deaminase (AID), which mutates the Immunoglobulin loci in B Cells during antibody affinity maturation in jawed vertebrates. The APOBEC family has expanded particularly in th... | The AID/APOBEC family of cytidine deaminases have important functions in both intrinsic and adaptive immunity. AID is expressed primarily in germinal center B cells as part of the adaptive immune response [1], whereas the APOBECs act primarily in the intrinsic immune response in various cell types (reviewed in [2]). Th... |
10.1371/journal.pgen.1000307 | A Simple Screen to Identify Promoters Conferring High Levels of Phenotypic Noise | Genetically identical populations of unicellular organisms often show marked variation in some phenotypic traits. To investigate the molecular causes and possible biological functions of this phenotypic noise, it would be useful to have a method to identify genes whose expression varies stochastically on a certain time... | According to the conventional view, the characteristics of an organism are determined by nature and nurture—by its genes and by the environment it lives in. Consequently, one would expect that two organisms that share the same genes and live in the same environment have identical characteristics. Recently it has become... | Clonal populations of unicellular organisms growing under constant conditions often show substantial variation in phenotypic traits. The rate at which some of these traits vary is so high that it cannot result from mutational change. Rather, this phenotypic noise has been shown to result from chance events in the cells... |
10.1371/journal.pcbi.1003642 | The Natural History of Biocatalytic Mechanisms | Phylogenomic analysis of the occurrence and abundance of protein domains in proteomes has recently showed that the α/β architecture is probably the oldest fold design. This holds important implications for the origins of biochemistry. Here we explore structure-function relationships addressing the use of chemical mecha... | Structural phylogenomics enables one to construct a historical timeline of the structural scaffolds known as protein folds and of the biocatalytic mechanisms that are embedded in them. This timeline defines a natural history of biocatalysis through its most granular components, the mechanistic steps. This history revea... | The three-dimensional (3D) atomic structures of contemporary proteins provide clues about how both structure and function unfolded in the course of billions of years of evolution [1]. The phylogenomic analysis of protein domain occurrence and abundance in modern proteomes [2], [3] enables retrodictive views of protein ... |
10.1371/journal.ppat.1007508 | The Vaccinia virion: Filling the gap between atomic and ultrastructure | We have investigated the molecular-level structure of the Vaccinia virion in situ by protein-protein chemical crosslinking, identifying 4609 unique-mass crosslink ions at an effective FDR of 0.33%, covering 2534 unique pairs of crosslinked protein positions, 625 of which were inter-protein. The data were statistically ... | Vaccinia is one of the most complex virions among the animal viruses, containing 70+ distinct gene products. Although virion ultrastructure has been apparent, at least in outline by electron microscopy since the year 1961 or earlier, its molecular architecture is largely unknown: Vaccinia is resistant to classical stru... | The virion of Vaccinia, the prototypical poxvirus, is one of the largest among the animal viruses. While its ultrastructural characterization is the beneficiary of 60+ years of electron microscopic examination [1–3] and references therein, attempts to better understand its molecular and atomic architecture have fallen ... |
10.1371/journal.pcbi.1000500 | Parallel Computational Subunits in Dentate Granule Cells Generate Multiple Place Fields | A fundamental question in understanding neuronal computations is how dendritic events influence the output of the neuron. Different forms of integration of neighbouring and distributed synaptic inputs, isolated dendritic spikes and local regulation of synaptic efficacy suggest that individual dendritic branches may fun... | Neurons were originally divided into three morphologically distinct compartments: the dendrites receive the synaptic input, the soma integrates it and communicates the output of the cell to other neurons via the axon. Although several lines of evidence challenged this oversimplified view, neurons are still considered t... | Neurons possess highly branched, complex dendritic trees, but the relationship between the structure of the dendritic arbor and underlying neural function is poorly understood [1]. Recent studies suggest that dendritic branches form independent computational subunits: Individual branches function as single integrative ... |
10.1371/journal.pbio.1001525 | White-Opaque Switching in Natural MTLa/α Isolates of Candida albicans: Evolutionary Implications for Roles in Host Adaptation, Pathogenesis, and Sex | Phenotypic transitions play critical roles in host adaptation, virulence, and sexual reproduction in pathogenic fungi. A minority of natural isolates of Candida albicans, which are homozygous at the mating type locus (MTL, a/a or α/α), are known to be able to switch between two distinct cell types: white and opaque. It... | Phenotypic transitions enable fungal pathogens to better adapt to their ever-changing environments. Approximately 10% of natural Candida albicans strains, which are homozygous at the mating type locus (MTL, a/a and α/α), can switch between two distinguishable morphological forms: white and opaque. The two cell types di... | Phenotypic plasticity is critical for microorganisms to survive under fluctuating environments. For fungal pathogens, phenotypic switching is a common strategy to rapidly adapt to different host niches and facilitate colonization and infection [1]. A specific phenotype can also confer the fungus a growth advantage over... |
10.1371/journal.pbio.2006571 | Organic cation transporter 3 (Oct3) is a distinct catecholamines clearance route in adipocytes mediating the beiging of white adipose tissue | Beiging of white adipose tissue (WAT) is a particularly appealing target for therapeutics in the treatment of metabolic diseases through norepinephrine (NE)-mediated signaling pathways. Although previous studies report NE clearance mechanisms via SLC6A2 on sympathetic neurons or proinflammatory macrophages in adipose t... | Adipose tissues (ATs) can be divided into three distinct types: white fat (or white AT [WAT]), brown fat, and beige fat. Growing evidence suggests that the development of beige fat cells in WAT, also called browning or beiging of WAT, might protect against obesity and improve systemic metabolism. Norepinephrine (NE)-in... | Obesity, a disease characterized by excess body fat, is a major risk factor for many human diseases, including type 2 diabetes, cardiovascular disease, and hepatic steatosis [1]. In mammals, fat is stored primarily in adipose tissue (AT), and three distinct types of ATs have been characterized: white AT (WAT), brown AT... |
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