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10.1371/journal.pcbi.1004701 | Evolutionary and Functional Relationships in the Truncated Hemoglobin Family | Predicting function from sequence is an important goal in current biological research, and although, broad functional assignment is possible when a protein is assigned to a family, predicting functional specificity with accuracy is not straightforward. If function is provided by key structural properties and the releva... | Globins are a superfamily of widely studied and diverse globular proteins whose function is tightly related to their oxygen affinity and reactivity. Two prominent members are the well-known tetrameric hemoglobin and the monomeric myoglobin, both involved in reversible oxygen storage and transport in mammals. Truncated ... | Predicting function from sequence and/or structure is one of the most important goals of structural biology, especially considering the increasing number of available sequences derived from multiple sequencing projects [1]. General function assignment or annotation, typically based on similarity with sequences with kno... |
10.1371/journal.ppat.1005161 | Intrinsic MyD88-Akt1-mTOR Signaling Coordinates Disparate Tc17 and Tc1 Responses during Vaccine Immunity against Fungal Pneumonia | Fungal infections have skyrocketed in immune-compromised patients lacking CD4+ T cells, underscoring the need for vaccine prevention. An understanding of the elements that promote vaccine immunity in this setting is essential. We previously demonstrated that vaccine-induced IL-17A+ CD8+ T cells (Tc17) are required for ... | Patients with AIDS, cancer or immune suppressive treatments are vulnerable to infection with invasive fungi. We have found that even when helper CD4 T cells are profoundly reduced in a mouse model that mimics this defect in AIDS, other remaining T cells are capable of mounting vaccine immunity against a deadly fungal i... | The rising incidence rate of life threatening fungal infections in immune-deficient hosts requires preventive measure in at risk individuals. CD4+ T cells are the primary effector cells that control fungal infections in healthy hosts, and their loss in lymphopenic patients necessitates targeting residual immune subsets... |
10.1371/journal.pcbi.0030215 | A Nucleosome-Guided Map of Transcription Factor Binding Sites in Yeast | Finding functional DNA binding sites of transcription factors (TFs) throughout the genome is a crucial step in understanding transcriptional regulation. Unfortunately, these binding sites are typically short and degenerate, posing a significant statistical challenge: many more matches to known TF motifs occur in the ge... | Identifying transcription factor (TF) binding sites across the genome is an important problem in molecular biology. Large-scale discovery of TF binding sites is usually carried out by searching for short DNA patterns that appear often within promoter regions of genes that are known to be co-bound by a TF. In such probl... | Finding functional DNA binding sites of transcription factors (TFs) throughout the genome is a necessary step in understanding transcriptional regulation. However, despite an explosion of TF binding data from high-throughput technologies like ChIP-chip ([1,2], and many more), DIP-chip [3], PBM [4], and gene expression ... |
10.1371/journal.pntd.0002394 | Venom of the Brazilian Spider Sicarius ornatus (Araneae, Sicariidae) Contains Active Sphingomyelinase D: Potential for Toxicity after Envenomation | The spider family Sicariidae includes two genera, Sicarius and Loxosceles. Bites by Sicarius are uncommon in humans and, in Brazil, a single report is known of a 17-year old man bitten by a Sicarius species that developed a necrotic lesion similar to that caused by Loxosceles. Envenomation by Loxosceles spiders can res... | The spider family Sicariidae includes two genera, Sicarius and Loxosceles. These spiders' venoms share a common characteristic, i.e., the presence of Sphingomyelinases D (SMase D). This toxin is the main component responsible for the local and systemic effects observed in loxoscelism. In the present study, we have inve... | The spider family Sicariidae includes two genera, Sicarius and Loxosceles. Sicarius species (six-eyed crab spiders, six-eyed sand spiders) live in dry forests and deserts throughout Southern Africa, South America and Central America. The genus Sicarius is composed of robust flattened spiders, 9–19 mm long and a leg spa... |
10.1371/journal.pntd.0004595 | Severe Fever with Thrombocytopenia Syndrome Virus Antigen Detection Using Monoclonal Antibodies to the Nucleocapsid Protein | Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne infectious disease with a high case fatality rate, and is caused by the SFTS virus (SFTSV). SFTS is endemic to China, South Korea, and Japan. The viral RNA level in sera of patients with SFTS is known to be strongly associated with outcomes. Virological... | Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne emerging infectious disease caused by a novel bunyavirus, SFTS virus (SFTSV). Since first discovered in China in 2011, SFTSV has been detected from SFTS patients and ticks with expanding geographic ranges from China to Japan and South Korea. The potenti... | Between 2007 and 2010, a severe febrile illness associated with gastrointestinal symptoms, thrombocytopenia, and leukocytopenia caused by an unknown etiological agent was reported in rural areas of Hubei and Henan provinces in Central China [1]. The case-fatality rate of the disease was reported to be between 12%–30% a... |
10.1371/journal.ppat.1007942 | Symbiotic microbiota may reflect host adaptation by resident to invasive ant species | Exotic invasive species can influence the behavior and ecology of native and resident species, but these changes are often overlooked. Here we hypothesize that the ghost ant, Tapinoma melanocephalum, living in areas that have been invaded by the red imported fire ant, Solenopsis invicta, displays behavioral differences... | Insects display a wide range of dependence on symbiotic bacteria for basic functions. Responses by resident species to selective pressures imposed by invasive species, as well as specific underlying mechanisms that give rise to these responses are still poorly understood. Here we investigate the role of the symbiotic b... | Rapid development of global trade and travel have created conditions for long-distance migration and concomitantly increased the threat of biological invasion by exotic species [1]. Invasive species can affect the distribution, abundance and reproduction of native taxa [2,3] and disturb the structure and function of ec... |
10.1371/journal.pcbi.1002651 | Maintaining a Cognitive Map in Darkness: The Need to Fuse Boundary Knowledge with Path Integration | Spatial navigation requires the processing of complex, disparate and often ambiguous sensory data. The neurocomputations underpinning this vital ability remain poorly understood. Controversy remains as to whether multimodal sensory information must be combined into a unified representation, consistent with Tolman's “co... | Do animals need “cognitive maps“? One of the main difficulties in answering this question is finding a definitive scenario where having and not having a “cognitive map“ result in measurably different outcomes. Many key predictions made by models involving some sort of “cognitive map“ can also be replicated by models wi... | In 1948, Tolman employed two analogies to describe the prevailing classes of models used to explain the experimental data on maze navigation and learning obtained from rats [1]. Tolman likened the stimulus-response class of models to an old fashioned telephone exchange, where incoming calls are linked via connecting sw... |
10.1371/journal.pntd.0001479 | A Multicenter Evaluation of Diagnostic Tools to Define Endpoints for Programs to Eliminate Bancroftian Filariasis | Successful mass drug administration (MDA) campaigns have brought several countries near the point of Lymphatic Filariasis (LF) elimination. A diagnostic tool is needed to determine when the prevalence levels have decreased to a point that MDA campaigns can be discontinued without the threat of recrudescence. A six-coun... | Lymphatic filariasis (LF), a mosquito-borne parasitic disease, is a candidate for elimination largely because of the success of mass drug administration (MDA) campaigns, in which entire at-risk populations are given a once-yearly regimen of single-dose treatment with two medications. As a result, a diagnostic tool is n... | In 2000 the Global Programme to Eliminate Lymphatic Filariasis (GPELF) was launched, providing antifilarial drugs to millions of people through mass drug administration (MDA) programs. During the GPELF's first nine years over 2.6 billion treatments of antifilarial drugs were given to people in 48 countries through MDA ... |
10.1371/journal.pgen.1002705 | Genome-Wide Association of Pericardial Fat Identifies a Unique Locus for Ectopic Fat | Pericardial fat is a localized fat depot associated with coronary artery calcium and myocardial infarction. We hypothesized that genetic loci would be associated with pericardial fat independent of other body fat depots. Pericardial fat was quantified in 5,487 individuals of European ancestry from the Framingham Heart ... | Pericardial fat is a localized fat depot associated with coronary artery calcium and myocardial infarction. To test whether genetic loci are associated with pericardial fat independent of other body fat depots, we measured pericardial fat in 5,487 individuals of European ancestry. After performing an unbiased screen us... | Obesity is a heterogeneous condition, and its attendant metabolic sequelae may not be adequately captured by using traditional metrics of generalized adiposity [1]. In part, this is because different fat depots may be associated with differential metabolic risk. For example, visceral abdominal fat is thought to be a un... |
10.1371/journal.pgen.1002177 | Gene-Based Tests of Association | Genome-wide association studies (GWAS) are now used routinely to identify SNPs associated with complex human phenotypes. In several cases, multiple variants within a gene contribute independently to disease risk. Here we introduce a novel Gene-Wide Significance (GWiS) test that uses greedy Bayesian model selection to i... | Genome-wide association studies (GWAS) have successfully identified genetic variants associated with complex human phenotypes. Despite a proliferation of analysis methods, most studies rely on simple, robust SNP–by–SNP univariate tests with ever-larger population sizes. Here we introduce a new test motivated by the bio... | Traditional single-SNP GWAS methods have been remarkably successful in identifying genetic associations, including those for various ECG parameters in recent studies of PR interval (the beginning of the P wave to the beginning of the QRS interval) [1], QRS interval (depolarization of both ventricles) [2] and QT interva... |
10.1371/journal.pcbi.1007060 | Foraging as an evidence accumulation process | The patch-leaving problem is a canonical foraging task, in which a forager must decide to leave a current resource in search for another. Theoretical work has derived optimal strategies for when to leave a patch, and experiments have tested for conditions where animals do or do not follow an optimal strategy. Neverthel... | Foraging is a ubiquitous animal behavior, performed by organisms as different as worms, birds, rats, and humans. Although the behavior has been extensively studied, it is not known how the brain processes information obtained during foraging activity to make subsequent foraging decisions. We form an evidence accumulati... | In systems and cognitive neuroscience, decision-making has been extensively studied using the concept of evidence accumulation [1, 2, 3, 4, 5, 6, 7]. Evidence accumulation has been implicated for example in social decisions [8], sensory decisions [9, 10], economic decisions [11], memory decisions [12], visual search de... |
10.1371/journal.pntd.0002823 | Dicer-2-Dependent Activation of Culex Vago Occurs via the TRAF-Rel2 Signaling Pathway | Despite their importance as vectors of human and livestock diseases, relatively little is known about innate antiviral immune pathways in mosquitoes and other insects. Previous work has shown that Culex Vago (CxVago), which is induced and secreted from West Nile virus (WNV)-infected mosquito cells, acts as a functional... | Viruses like West Nile, dengue and Japanese encephalitis are responsible for large number of human and livestock diseases worldwide. These viruses, transmitted by female mosquitoes via saliva during blood-feeding, elicit an immune response in these mosquitoes. The details of this immune response are still being investi... | Hematophagous insects (mosquitoes, sand flies and midges) serve as vectors of many important viral diseases of humans and livestock. Arthropod-borne viruses are endemic or seasonally epidemic through most regions of the world, accounting for inestimable numbers of human infections, significant rates of mortality, and m... |
10.1371/journal.pgen.1007114 | ciRS-7 exonic sequence is embedded in a long non-coding RNA locus | ciRS-7 is an intensely studied, highly expressed and conserved circRNA. Essentially nothing is known about its biogenesis, including the location of its promoter. A prevailing assumption has been that ciRS-7 is an exceptional circRNA because it is transcribed from a locus lacking any mature linear RNA transcripts of th... | circRNAs were recently discovered to be a significant product of ‘host’ gene expression programs but little is known about their transcriptional regulation. Here, we have studied the expression of a functional and highly expressed circRNA named ciRS-7. ciRS-7 has an unusual function for a circRNA; it is believed to be ... | Until recently, the expression of circRNA was almost completely uncharacterized, with a few important exceptions [1–4]. It is now appreciated that circRNAs are a ubiquitous feature of eukaryotic gene expression [1,3,5,6]. While many functions have been posited for circRNAs, few have been supported with experimental evi... |
10.1371/journal.pntd.0004646 | Symptoms and Immune Markers in Plasmodium/Dengue Virus Co-infection Compared with Mono-infection with Either in Peru | Malaria and dengue are two of the most common vector-borne diseases in the world, but co-infection is rarely described, and immunologic comparisons of co-infection with mono-infection are lacking.
We collected symptom histories and blood specimens from subjects in a febrile illness surveillance study conducted in Iquit... | Dengue and malaria are two of the most important diseases spread by mosquitoes. Clinical manifestations of both febrile diseases overlap considerably, and either can be fatal. In addition, they are co-endemic in many places throughout the world. Despite this, only a handful of reports of co-infection with dengue virus ... | Malaria and dengue fever are two of the most important mosquito-borne infections affecting humans. Annually, approximately 584,000 and 12,000 people die and another 198 million and 96 million are estimated to fall ill from malaria and dengue, respectively [1, 2]. Although Anopheles, the mosquito vector of malaria, and ... |
10.1371/journal.ppat.1001111 | SRFR1 Negatively Regulates Plant NB-LRR Resistance Protein Accumulation to Prevent Autoimmunity | Plant defense responses need to be tightly regulated to prevent auto-immunity, which is detrimental to growth and development. To identify negative regulators of Resistance (R) protein-mediated resistance, we screened for mutants with constitutive defense responses in the npr1-1 background. Map-based cloning revealed t... | The nucleotide-binding domain and leucine-rich repeats-containing (NLR) proteins are structurally conserved immune receptors found in both animals and plants. Correct folding of NLR proteins requires two conserved proteins, SGT1 and HSP90. We showed that another evolutionarily conserved protein, SRFR1, interacts with S... | To protect themselves from infections by microbial pathogens, plants have evolved a large number of immune receptors to sense pathogen-derived molecules and trigger defense responses [1]. Resistance (R) proteins with nucleotide-binding (NB) and Leucine-rich repeat (LRR) domains constitute the main type of intracellular... |
10.1371/journal.pntd.0001992 | Evaluation of rK39 Rapid Diagnostic Tests for Canine Visceral Leishmaniasis: Longitudinal Study and Meta-Analysis | There is a need for sensitive and specific rapid diagnostic tests (RDT) for canine visceral leishmaniasis. The aims of this study were to evaluate the diagnostic performance of immunochromatographic dipstick RDTs using rK39 antigen for canine visceral leishmaniasis by (i) investigating the sensitivity of RDTs to detect... | Canine visceral leishmaniasis is a vector-borne disease caused by the intracellular parasite Leishmania infantum. It is an important veterinary disease, and dogs are also the main animal reservoir for human infection. The disease is widespread in the Mediterranean area, and parts of Asia and South and Central America, ... | Zoonotic visceral leishmaniasis (ZVL) is a potentially fatal disease caused by the intracellular protozoan parasite Leishmania infantum, which is endemic in South and Central America, the Mediterranean basin and parts of Asia. The domestic dog is the most important reservoir host, and infection is maintained by transmi... |
10.1371/journal.pntd.0002146 | Elimination of Iron Deficiency Anemia and Soil Transmitted Helminth Infection: Evidence from a Fifty-four Month Iron-Folic Acid and De-worming Program | Intermittent iron-folic acid supplementation and regular de-worming are effective initiatives to reduce anemia, iron deficiency, iron deficiency anemia, and soil transmitted helminth infections in women of reproductive age. However, few studies have assessed the long-term effectiveness of population-based interventions... | Nutritional deficiencies are common in women in rural and disadvantaged regions, and, in particular, iron and folate deficiencies may impact their health and that of their offspring. Weekly iron-folic acid supplementation and regular deworming help to prevent these deficiencies, yet many women in developing countries d... | Iron deficiency is one of the most common nutritional deficiencies affecting women of reproductive age and children [1]. The increased demand for iron in these groups is often exacerbated by limited intake of heme iron, and hookworm infection with associated gastrointestinal blood loss. Globally, 42% of pregnant women ... |
10.1371/journal.pbio.1001612 | Two-Tiered Control of Epithelial Growth and Autophagy by the Insulin Receptor and the Ret-Like Receptor, Stitcher | Body size in Drosophila larvae, like in other animals, is controlled by nutrition. Nutrient restriction leads to catabolic responses in the majority of tissues, but the Drosophila mitotic imaginal discs continue growing. The nature of these differential control mechanisms that spare distinct tissues from starvation are... | Growth of organs, or anabolism, is tightly controlled by nutritional and hormonal cues such as insulin-like peptides that also suppress autophagy through their receptors and downstream growth pathway. Starvation conditions induce growth arrest and catabolism (involving autophagy) in some tissues while sparing the growt... | Cellular and organ growth (anabolism) in animals is regulated by complex interactions of nutritional and hormonal cues. As accumulation of cell mass usually precedes cell division, cellular growth is intimately coupled to proliferation and net organ growth. In all eukaryotes studied, the evolutionarily conserved protei... |
10.1371/journal.pgen.1005016 | The Contribution of Alu Elements to Mutagenic DNA Double-Strand Break Repair | Alu elements make up the largest family of human mobile elements, numbering 1.1 million copies and comprising 11% of the human genome. As a consequence of evolution and genetic drift, Alu elements of various sequence divergence exist throughout the human genome. Alu/Alu recombination has been shown to cause approximate... | DNA double-strand breaks (DSBs) are a highly mutagenic form of DNA damage that can be repaired through one of several pathways with varied degrees of sequence preservation. Faithful repair of DSBs often occurs through gene conversion in which a sister chromatid is used as a repair template. Unfaithful repair of DSBs ca... | DNA double-strand breaks (DSBs) are the most dangerous type of DNA damage due to their tendency to lead to chromosomal rearrangements, a hallmark of tumorigenesis, when they are repaired [1]. One way in which chromosomal rearrangements occur in DSB repair is the use of non-allelic recombination between repetitive eleme... |
10.1371/journal.pgen.1005564 | Large-Scale Analysis of Kinase Signaling in Yeast Pseudohyphal Development Identifies Regulation of Ribonucleoprotein Granules | Yeast pseudohyphal filamentation is a stress-responsive growth transition relevant to processes required for virulence in pathogenic fungi. Pseudohyphal growth is controlled through a regulatory network encompassing conserved MAPK (Ste20p, Ste11p, Ste7p, Kss1p, and Fus3p), protein kinase A (Tpk2p), Elm1p, and Snf1p kin... | Eukaryotic cells affect precise changes in shape and growth in response to environmental and nutritional stress, enabling cell survival and wild-type function. The single-celled budding yeast provides a striking example, undergoing a set of changes under conditions of nitrogen or glucose limitation resulting in the for... | The pseudohyphal growth response is a complex morphogenetic program in which fungal cells transition from a yeast-like growth form to a filamentous state, with cells remaining physically connected after cytokinesis in elongated structures [1–3]. This growth transition is evident in several strains of S. cerevisiae (e.g... |
10.1371/journal.pntd.0001725 | Breeding Sites of Phlebotomus sergenti, the Sand Fly Vector of Cutaneous Leishmaniasis in the Judean Desert | Phlebotomine sand flies transmit Leishmania, phlebo-viruses and Bartonella to humans. A prominent gap in our knowledge of sand fly biology remains the ecology of their immature stages. Sand flies, unlike mosquitoes do not breed in water and only small numbers of larvae have been recovered from diverse habitats that pro... | Sand flies are small blood sucking flies that transmit Leishmania, the etiologic agent of leishmaniasis - a prevalent disease over large areas of the World. Unlike mosquitoes, sand flies do not breed in water. Their larvae develop in humid habitats containing decaying organic matter (e.g. habitats such as burrows, tree... | The leishmaniases are a group of diseases endangering some 350 million people in 88 countries, most of them in the poorer regions of the globe. The two major clinical forms are cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL). CL manifests as a sore at the bite site of the infected sand fly and is usually s... |
10.1371/journal.pcbi.1004456 | Explaining the Timing of Natural Scene Understanding with a Computational Model of Perceptual Categorization | Observers can rapidly perform a variety of visual tasks such as categorizing a scene as open, as outdoor, or as a beach. Although we know that different tasks are typically associated with systematic differences in behavioral responses, to date, little is known about the underlying mechanisms. Here, we implemented a si... | The speed of sight has fascinated scientists and philosophers for centuries. In the blink of an eye, observers can rapidly and effortlessly perform a variety of categorization tasks such as categorizing a scene as open, as natural, or as a beach. The past decade of work has shown that there exist systematic differences... | Categorization is perhaps one of our most critical visual functions as it allowed our ancestors to distinguish friend from foe and the edible from the inedible. Observers can rapidly extract meaning from brief presentations of complex visual scenes [1]—far exceeding the best existing engineered artificial systems [2].
... |
10.1371/journal.pntd.0000284 | Spatial Distribution of Taenia solium Porcine Cysticercosis within a Rural Area of Mexico | Cysticercosis is caused by Taenia solium, a parasitic disease that affects humans and rurally bred pigs in developing countries. The cysticercus may localize in the central nervous system of the human, causing neurocysticercosis, the most severe and frequent form of the disease. There appears to be an association betwe... | Taenia solium cysticercosis is a parasitic disease that severely affects human health in underdeveloped countries and has re-emerged in North America. The adult parasite lives in the intestines of humans, where it thrives and sheds packages (proglottids) loaded with thousands of eggs that are, in turn, expelled upon de... | Cysticercosis is caused by Taenia solium, a parasitic disease that affects humans and freely roaming pigs in developing countries [1]. In Mexico, cysticercosis persists because conditions ideal for the parasite's life cycle remain prevalent in many rural areas [2]. The most severe manifestation of the disease occurs wh... |
10.1371/journal.pntd.0001536 | Dengue Virus Infection-Enhancing Activity in Serum Samples with Neutralizing Activity as Determined by Using FcγR-Expressing Cells | Progress in dengue vaccine development has been hampered by limited understanding of protective immunity against dengue virus infection. Conventional neutralizing antibody titration assays that use FcγR-negative cells do not consider possible infection-enhancement activity. We reasoned that as FcγR-expressing cells are... | Dengue has become a major international public health concern in recent decades. There are four dengue virus serotypes. Recovery from infection with one serotype confers life-long protection to the homologous serotype but only partial protection to subsequent infection with other serotypes. Secondary infection with a s... | Dengue fever (DF) and dengue hemorrhagic fever (DHF) is caused by infection with dengue virus (DENV), a flavivirus, which consists of four serotypes (DENV-1, DENV-2, DENV-3 and DENV-4). DENV affects up to 100 million people annually living in the tropics and sub-tropical areas. Clinical manifestations of DENV infection... |
10.1371/journal.ppat.1007355 | Microevolution in response to transient heme-iron restriction enhances intracellular bacterial community development and persistence | Bacterial pathogens must sense, respond and adapt to a myriad of dynamic microenvironmental stressors to survive. Adaptation is key for colonization and long-term ability to endure fluctuations in nutrient availability and inflammatory processes. We hypothesize that strains adapted to survive nutrient deprivation are m... | Nontypeable Haemophilus influenzae (NTHI) inhabits diverse niches in the host. The ability to adapt to new microenvironments is consistent with the predominance of NTHI as a causative agent of otitis media (OM) in children. We evaluated the microevolution of NTHI associated with adaptation and persistence in response t... | The host sequesters essential micronutrients (i.e. metals) as a mechanism to limit bacterial infection [1]. Bacteria that require exogenous nutrients for growth are subjected to stresses that necessitate adaptation for survival. Bacteria can adapt to these stresses through transcriptional, epigenetic and genetic mechan... |
10.1371/journal.pcbi.1005922 | Robust and efficient coding with grid cells | The neuronal code arising from the coordinated activity of grid cells in the rodent entorhinal cortex can uniquely represent space across a large range of distances, but the precise conditions for optimal coding capacity are known only for environments with finite size. Here we consider a coding scheme that is suitable... | Navigation in natural, open environments poses serious challenges to animals as the distances to be represented may span several orders of magnitudes and are potentially unbounded. The recently discovered grid cells in the rodent brain are though to play a crucial role in generating unique representations for a large n... | Optimising neuronal systems for efficient processing and representation of information is a key principle for both understanding and designing neuronal circuits [1], but deciding whether a particular neuronal phenomenon reflects an optimisation process is often difficult. Grid cells in the medial entorhinal cortex have... |
10.1371/journal.pntd.0000790 | FMRFamide-Like Peptides (FLPs) Enhance Voltage-Gated Calcium Currents to Elicit Muscle Contraction in the Human Parasite Schistosoma mansoni | Schistosomes are amongst the most important and neglected pathogens in the world, and schistosomiasis control relies almost exclusively on a single drug. The neuromuscular system of schistosomes is fertile ground for therapeutic intervention, yet the details of physiological events involved in neuromuscular function re... | Schistosomiasis (bilharzia) is caused by infection with trematodes of the genus Schistosoma. The disease afflicts over 200 million people, with the bulk of the disease burden focused in some of the world's poorest countries. Schistosomiasis control rests largely on chemotherapy with a single drug, praziquantel, a preca... | Schistosomes continue to inflict widespread suffering, infecting over 200 million worldwide, yet a proportional lack of scientific attention leaves schistosomiasis as one of the most prevalent neglected tropical diseases [1], [2]. Significant advances in schistosomiasis control have been achieved in the past few years,... |
10.1371/journal.ppat.1006861 | Switching and loss of cellular cytokine producing capacity characterize in vivo viral infection and malignant transformation in human T- lymphotropic virus type 1 infection | Adult T-cell leukaemia/lymphoma (ATL) arises from chronic non-malignant human T lymphotropic virus type-1 (HTLV-1) infection which is characterized by high plasma pro-inflammatory cytokines whereas ATL is characterized by high plasma anti-inflammatory (IL-10) concentrations. The poor prognosis of ATL is partly ascribed... | Human T-cell lymphotropic virus type-1 (HTLV-1) infection of CD4+ T cells is associated with a change in their cytokine producing capacity and is responsible for the different plasma cytokine profiles in patients with adult T-cell leukaemia/Lymphoma (ATL) and non-malignant HTLV-1 infection. Dominant malignant clonal gr... | Human T- lymphotropic virus type-1 (HTLV-1) is a complex delta retrovirus infecting an estimated 10 million individuals worldwide [1]. In the majority, infection leads to a chronic asymptomatic carrier state (AC) but 2% to 6% develop adult T-cell leukaemia/lymphoma (ATL) and another 3% inflammatory disorders e.g. HTLV-... |
10.1371/journal.pcbi.1006744 | Synchrony is more than its top-down and climatic parts: interacting Moran effects on phytoplankton in British seas | Large-scale spatial synchrony is ubiquitous in ecology. We examined 56 years of data representing chlorophyll density in 26 areas in British seas monitored by the Continuous Plankton Recorder survey. We used wavelet methods to disaggregate synchronous fluctuations by timescale and determine that drivers of synchrony in... | The size of the annual bloom in phytoplankton can vary similarly from year to year in different parts of the same oceanic region, a phenomenon called spatial synchrony. The growth of phytoplankton near the ocean surface is the foundation of marine food webs, which include numerous commercially exploited species. And sp... | Many ecosystems are subject to large spatially synchronous fluctuations, with serious consequences for ecosystem services and stability across space and time. Spatial synchrony is the tendency for spatially separated populations to undergo correlated fluctuations. Spatial synchrony is a fundamental and nearly ubiquitou... |
10.1371/journal.pntd.0002075 | Rabies in Iraq: Trends in Human Cases 2001–2010 and Characterisation of Animal Rabies Strains from Baghdad | Control of rabies requires a consistent supply of dependable resources, constructive cooperation between veterinary and public health authorities, and systematic surveillance. These are challenging in any circumstances, but particularly during conflict. Here we describe available human rabies surveillance data from Ira... | Control of rabies requires cooperation between government departments, consistent funding, and an understanding of the epidemiology of the disease obtained through surveillance. Here we describe human rabies surveillance data from Iraq and the results of renewed sampling for rabies in animals. In Iraq, it is obligatory... | The first written record of disease consistent with rabies is in the Laws of Eshunna, a Sumerian city in ancient Mesopotamia. Largely corresponding to the region of what is now the Republic of Iraq, Mesopotamia encompassed the Euphrates and Tigris river systems and is considered by many to be the birthplace of civilisa... |
10.1371/journal.ppat.1001242 | Compartmentation of Redox Metabolism in Malaria Parasites | Malaria, caused by the apicomplexan parasite Plasmodium, still represents a major threat to human health and welfare and leads to about one million human deaths annually. Plasmodium is a rapidly multiplying unicellular organism undergoing a complex developmental cycle in man and mosquito – a life style that requires ra... | The unicellular parasite Plasmodium falciparum is the causative agent of tropical malaria, which represents a global health burden. In order to survive in its human host and the malaria vector Anopheles, malaria parasites depend on adequate antioxidant defense and efficient redox regulation. Furthermore, as shown by gl... | Malaria threatens more than 40% of the world's population. Current estimations point to 200–300 million clinical episodes and about 1 million human deaths each year [1]. The unicellular parasite Plasmodium falciparum causes the most dangerous form of this tropical disease including the development of cerebral malaria. ... |
10.1371/journal.ppat.1003188 | Macrophage-expressed IFN-β Contributes to Apoptotic Alveolar Epithelial Cell Injury in Severe Influenza Virus Pneumonia | Influenza viruses (IV) cause pneumonia in humans with progression to lung failure and fatal outcome. Dysregulated release of cytokines including type I interferons (IFNs) has been attributed a crucial role in immune-mediated pulmonary injury during severe IV infection. Using ex vivo and in vivo IV infection models, we ... | Acute lung injury induced by influenza virus (IV) infection has been linked to an unbalanced release of pro-inflammatory cytokines including type I interferons (IFN) causing immune-mediated organ damage. Using ex vivo and in vivo IV infection models, we demonstrate that alveolar macrophage-expressed IFN-β induces alveo... | Influenza viruses (IV) can cause primary viral pneumonia in humans with rapid progression to lung failure and fatal outcome [1]. Histopathologic and clinical features of IV-induced lung injury in humans resemble those of other forms of ARDS (acute respiratory distress syndrome), characterized by apoptotic and necrotic ... |
10.1371/journal.pcbi.1000539 | A Model of Cardiovascular Disease Giving a Plausible Mechanism for the Effect of Fractionated Low-Dose Ionizing Radiation Exposure | Atherosclerosis is the main cause of coronary heart disease and stroke, the two major causes of death in developed society. There is emerging evidence of excess risk of cardiovascular disease at low radiation doses in various occupationally exposed groups receiving small daily radiation doses. Assuming that they are ca... | Atherosclerosis is the main cause of coronary heart disease and stroke, the two major causes of death in developed society. There is emerging evidence of excess risk of cardiovascular disease in various occupationally exposed groups, exposed to fractionated radiation doses with small doses/fraction. The mechanisms for ... | Atherosclerosis is the main cause of coronary heart disease and stroke, the two major causes of death in developed society [1]. Though previously initiation of atherosclerosis was attributed mainly to lipid accumulation within the arterial walls, it is now widely accepted that inflammation plays a vital role in the ini... |
10.1371/journal.pcbi.1001007 | Using Sequence-Specific Chemical and Structural Properties of DNA to Predict Transcription Factor Binding Sites | An important step in understanding gene regulation is to identify the DNA binding sites recognized by each transcription factor (TF). Conventional approaches to prediction of TF binding sites involve the definition of consensus sequences or position-specific weight matrices and rely on statistical analysis of DNA seque... | An important step in characterizing the genetic regulatory network of a cell is to identify the DNA binding sites recognized by each transcription factor (TF) protein encoded in the genome. Current computational approaches to TF binding site prediction rely exclusively on DNA sequence analysis. In this manuscript, we p... | An important step in characterizing the genetic regulatory network of a cell is to identify the DNA binding sites recognized by each transcription factor (TF) protein encoded in the genome. A TF typically activates and/or represses genes by associating with specific DNA sequences. Although other factors, such as metabo... |
10.1371/journal.pmed.1002287 | Identification of genes associated with dissociation of cognitive performance and neuropathological burden: Multistep analysis of genetic, epigenetic, and transcriptional data | The molecular underpinnings of the dissociation of cognitive performance and neuropathological burden are poorly understood, and there are currently no known genetic or epigenetic determinants of the dissociation.
“Residual cognition” was quantified by regressing out the effects of cerebral pathologies and demographic ... | Only a part of cognitive impairment in older adults is explained by common neuropathologies such as amyloid plaques, neurofibrillary tangles, stroke, or Lewy bodies found in Parkinson disease and some forms of dementia.
Understanding the molecular basis of dissociation between cognitive outcomes and neuropathological b... | It is well known that cognitive impairment in older adults is only partially explained by common neuropathologies such as Alzheimer disease (AD), stroke, and Lewy body disease [1–4]. Previous studies have shown that the majority of the variability in cognitive decline is unexplained, even when quantitative indices of c... |
10.1371/journal.pcbi.1004795 | A Predictive Model for Yeast Cell Polarization in Pheromone Gradients | Budding yeast cells exist in two mating types, a and α, which use peptide pheromones to communicate with each other during mating. Mating depends on the ability of cells to polarize up pheromone gradients, but cells also respond to spatially uniform fields of pheromone by polarizing along a single axis. We used quantit... | Budding yeast cells exist in two mating types, a and α, which use peptide pheromones to communicate with each other during mating. Mating depends on the ability of cells to polarize up pheromone gradients, but cells also respond to spatially uniform fields of pheromone by polarizing along a single axis. We used quantit... | Many events in plant and animal development depend on the ability of cells to interact with only one of many potential partners. Examples include the interaction of neuronal growth cones with target cells [1], myotube fusion and vascular guidance [2, 3], the growth of pollen tubes to reach ovules [4], and the mating of... |
10.1371/journal.pcbi.1000331 | Cross-Over between Discrete and Continuous Protein Structure Space: Insights into Automatic Classification and Networks of Protein Structures | Structural classifications of proteins assume the existence of the fold, which is an intrinsic equivalence class of protein domains. Here, we test in which conditions such an equivalence class is compatible with objective similarity measures. We base our analysis on the transitive property of the equivalence relationsh... | Making order of the fast-growing information on proteins is essential for gaining evolutionary and functional knowledge. The most successful approaches to this task are based on classifications of protein structures, such as SCOP and CATH, which assume a discrete view of the protein structure space as a collection of s... | Structural genomics projects [1] aim at an exhaustive exploration of the space of protein structures realized in evolution [2],[3], speeding up considerably the rate at which new protein structures are resolved. In this context, structural classification of proteins [4]–[9] has become essential for uncovering remote ev... |
10.1371/journal.pntd.0004441 | Illuminating the Prevalence of Trypanosoma brucei s.l. in Glossina Using LAMP as a Tool for Xenomonitoring | As the reality of eliminating human African trypanosomiasis (HAT) by 2020 draws closer, the need to detect and identify the remaining areas of transmission increases. Here, we have explored the feasibility of using commercially available LAMP kits, designed to detect the Trypanozoon group of trypanosomes, as a xenomoni... | Recent control efforts have reduced the global incidence of Gambiense human African trypanosomiasis (HAT) to <5,000 cases per year, strengthening the prospect of eliminating the disease as a public health problem by 2020. To meet this goal, new methods for identifying transmission must be explored to provide a cost-eff... | Human African trypanosomiasis (HAT), commonly known as sleeping sickness, is a parasitic disease caused by two sub-species of trypanosome, Trypanosoma brucei gambiense in West and Central Africa, which causes a chronic disease and T.b. rhodesiense in East and southern Africa which causes an acute disease. These pathoge... |
10.1371/journal.pntd.0000352 | Human Helminth Co-Infection: Analysis of Spatial Patterns and Risk Factors in a Brazilian Community | Individuals living in areas endemic for helminths are commonly infected with multiple species. Despite increasing emphasis given to the potential health impacts of polyparasitism, few studies have investigated the relative importance of household and environmental factors on the risk of helminth co-infection. Here, we ... | Helminth species such as Necator americanus and Schistosoma mansoni are among the most prevalent of chronic human infections in the developing world. Individuals living in endemic areas are commonly infected with both species. Although the implications of being co-infected with helminths are increasingly recognized, fa... | People living in poor areas of the tropics commonly harbour multiple parasitic infections, including infection with multiple helminth species [1],[2]. An increasing number of studies demonstrate that individuals infected with multiple helminth species tend to harbour the most intense infections [3]–[11] and can be at a... |
10.1371/journal.pntd.0001832 | Whole Genome Sequence of Treponema pallidum ssp. pallidum, Strain Mexico A, Suggests Recombination between Yaws and Syphilis Strains | Treponema pallidum ssp. pallidum (TPA), the causative agent of syphilis, and Treponema pallidum ssp. pertenue (TPE), the causative agent of yaws, are closely related spirochetes causing diseases with distinct clinical manifestations. The TPA Mexico A strain was isolated in 1953 from male, with primary syphilis, living ... | Treponema pallidum is a Gram-negative spirochete that causes diseases with distinct clinical manifestations and uses different transmission strategies. While syphilis (caused by subspecies pallidum) is a worldwide venereal and congenital disease, yaws (caused by subspecies pertenue) is a tropical disease transmitted by... | Treponema pallidum ssp. pallidum (TPA) and Treponema pallidum ssp. pertenue (TPE) strains, the causative agents of syphilis [1] and yaws [2], infect more than 12 and 2 million people annually, respectively [3]. Whereas syphilis is a sexually transmitted and congenital disease affecting adults and newborns worldwide, ya... |
10.1371/journal.pgen.1002906 | Stromal Liver Kinase B1 [STK11] Signaling Loss Induces Oviductal Adenomas and Endometrial Cancer by Activating Mammalian Target of Rapamycin Complex 1 | Germline mutations of the Liver Kinase b1 (LKB1/STK11) tumor suppressor gene have been linked to Peutz-Jeghers Syndrome (PJS), an autosomal-dominant, cancer-prone disorder in which patients develop neoplasms in several organs, including the oviduct, ovary, and cervix. We have conditionally deleted Lkb1 in Müllerian duc... | Peutz-Jeghers Syndrome patients have autosomal dominant mutations in the LKB1/STK11 gene and are prone to developing cancer, predominantly in the intestinal tract but also in other tissues, including the reproductive tracts and gonads. To elucidate the mechanisms disrupted by the loss of LKB1 in the reproductive tract,... | The embryonic Müllerian ducts, which are composed of a simple columnar epithelium surrounded by mesenchymal cells, differentiate into the oviducts, uterus, cervix, and anterior portion of the vagina [1]. During differentiation, epithelial-mesenchymal communication plays an important role in specification of the Mülleri... |
10.1371/journal.ppat.1002296 | The Role of Sialyl Glycan Recognition in Host Tissue Tropism of the Avian Parasite Eimeria tenella | Eimeria spp. are a highly successful group of intracellular protozoan parasites that develop within intestinal epithelial cells of poultry, causing coccidiosis. As a result of resistance against anticoccidial drugs and the expense of manufacturing live vaccines, it is necessary to understand the relationship between Ei... | Eimeria spp. are highly successful protozoan parasites of the intestine of birds and one of the most important diseases in modern poultry farming. The economic impact is significant causing billion dollar losses to the industry and as a result there is pressing need for new therapeutic approaches. Anticoccidial drugs a... | The phylum Apicomplexa contains some of the most widespread protozoan parasites of humans and animals. Key members include Plasmodium spp., Eimeria spp., Neospora caninum and Toxoplasma gondii. Eimeria spp. are a highly successful group of host-specific, intracellular protozoan parasites that develop within intestinal ... |
10.1371/journal.pcbi.1002505 | Insights into the Fold Organization of TIM Barrel from Interaction Energy Based Structure Networks | There are many well-known examples of proteins with low sequence similarity, adopting the same structural fold. This aspect of sequence-structure relationship has been extensively studied both experimentally and theoretically, however with limited success. Most of the studies consider remote homology or “sequence conse... | Proteins are polymers of amino-acids that fold into unique three-dimensional structures to perform cellular functions. This structure formation has been shown to depend on the amino-acid sequences. But examples of proteins with diverse sequences retaining a similar structural fold are quite substantial that we can no l... | Proteins are amino–acid polymers capable of folding into unique three–dimensional functional states. The information for the structure formation is contained within their amino–acid sequence [1]. With an enormous amount of data available on genomic sequences in organisms and the structures of the proteins they encode, ... |
10.1371/journal.pgen.1007313 | Actin organization and endocytic trafficking are controlled by a network linking NIMA-related kinases to the CDC-42-SID-3/ACK1 pathway | Molting is an essential process in the nematode Caenorhabditis elegans during which the epidermal apical extracellular matrix, termed the cuticle, is detached and replaced at each larval stage. The conserved NIMA-related kinases NEKL-2/NEK8/NEK9 and NEKL-3/NEK6/NEK7, together with their ankyrin repeat partners, MLT-2/A... | Protein kinases are key molecular regulators that act by modifying the structures and activities of proteins within the cell. Members of the NEK family of protein kinases regulate cell division and the formation of specialized organelles called cilia. Accordingly, mutations in the human NEK genes have been implicated i... | Members of the NIMA-related kinase (NEK) family are conserved serine/threonine kinases found in fungi, plants, and animals. The original member of the family, Never in Mitosis A (NIMA), was discovered in the filamentous fungus Aspergillus nidulans, where it promotes cell cycle progression [1, 2]. More recent analysis h... |
10.1371/journal.pcbi.1004629 | The Role of Symmetric Stem Cell Divisions in Tissue Homeostasis | Successful maintenance of cellular lineages critically depends on the fate decision dynamics of stem cells (SCs) upon division. There are three possible strategies with respect to SC fate decision symmetry: (a) asymmetric mode, when each and every SC division produces one SC and one non-SC progeny; (b) symmetric mode, ... | Stem cells have long been associated with their ability to divide asymmetrically, when one daughter cell retains stem cell properties of the parent cell, while the other daughter cell becomes more mature and loses its stemness. Recent findings, however, point at the existence of an alternative, symmetric division strat... | All cells within the body organize into distinct phylogenetic lineages. At the end of each lineage are the non-dividing, terminally differentiated cells. Usually these cells, such as neurons, adipocytes or muscle fibers, are highly specialized and endow tissues with their respective functions. The origin of all differe... |
10.1371/journal.ppat.1004262 | The Semen Microbiome and Its Relationship with Local Immunology and Viral Load in HIV Infection | Semen is a major vector for HIV transmission, but the semen HIV RNA viral load (VL) only correlates moderately with the blood VL. Viral shedding can be enhanced by genital infections and associated inflammation, but it can also occur in the absence of classical pathogens. Thus, we hypothesized that a dysregulated semen... | The classical paradigm of HIV infectivity centers on the blood HIV RNA viral load. However, while other fluid compartments such as semen and cerebrospinal fluid can have distinct viral loads from blood, the causes of localized HIV shedding are not fully understood. Since the semen viral load is an independent predictor... | Semen is an important vector in the sexual transmission of HIV [1], and the risk of transmission increases with the semen HIV RNA viral load (VL) [2], [3]. The semen VL is more variable over time than that of blood, and the two are only moderately correlated [4]–[8]. Therefore, since the semen HIV VL is an independent ... |
10.1371/journal.pntd.0002063 | Standardizing Visual Control Devices for Tsetse Flies: East African Species Glossina swynnertoni | Here we set out to standardize long-lasting, visually-attractive devices for Glossina swynnertoni, a vector of both human and animal trypanosomiasis in open savannah in Tanzania and Kenya, and in neighbouring conservation areas used by pastoralists. The goal was to determine the most practical device/material that woul... | Glossina swynnertoni is restricted to open savannah in north-western Tanzania and south-western Kenya, where it is a vector of both human and animal trypanosomiasis in wildlife reserves and in neighbouring conservation areas used by pastoralists. Despite the challenge to minimize disease transmission through effective ... | Glossina swynnertoni Austen (Diptera, Glossinidae) is restricted to open savannah in north-western Tanzania and south-western Kenya, extending from Tarangire in the south through Manyara to the Serengeti plains, and into the Maasai Mara in the north [1]. Swynnerton [2] found it at 900–1800 m above sea level and conside... |
10.1371/journal.pntd.0000694 | Burkholderia pseudomallei Is Spatially Distributed in Soil in Northeast Thailand | Melioidosis is a frequently fatal infectious disease caused by the soil dwelling Gram-negative bacterium Burkholderia pseudomallei. Environmental sampling is important to identify geographical distribution of the organism and related risk of infection to humans and livestock. The aim of this study was to evaluate spati... | Melioidosis is a severe infection caused by the environmental bacterium Burkholderia pseudomallei. Soil sampling is important to identify geographic regions where humans and animals are at risk of exposure. The purpose of this study was to examine a factor that has a major bearing on the accuracy of soil sampling: the ... | The Gram-negative bacterium Burkholderia pseudomallei is the cause of melioidosis and a category B select agent. This organism is present in soil and water across much of southeast Asia and in northern Australia and is increasingly being detected elsewhere, including areas of South America [1]. Melioidosis occurs as a ... |
10.1371/journal.ppat.1001249 | Molecular Architectures of Trimeric SIV and HIV-1 Envelope Glycoproteins on Intact Viruses: Strain-Dependent Variation in Quaternary Structure | The initial step in target cell infection by human, and the closely related simian immunodeficiency viruses (HIV and SIV, respectively) occurs with the binding of trimeric envelope glycoproteins (Env), composed of heterodimers of the viral transmembrane glycoprotein (gp41) and surface glycoprotein (gp120) to target T-c... | HIV and SIV contact and infect target T-cells following the binding of trimeric Env spikes displayed on the viral membrane with cellular receptors. The conformational changes in trimeric Env that are triggered by the interaction between trimeric Env and cell surface receptors lead ultimately to fusion of the viral and ... | About 2.5 million individuals are newly infected with human immunodeficiency virus (HIV) each year, and over 2 million deaths result annually from HIV/AIDS (http://www.unaids.org). HIV-1 and the closely related simian immunodeficiency virus (SIV) bind to target cells by the interaction of trimeric envelope glycoprotein... |
10.1371/journal.pgen.1000506 | Genome-Wide uH2A Localization Analysis Highlights Bmi1-Dependent Deposition of the Mark at Repressed Genes | Polycomb group (PcG) proteins control organism development by regulating the expression of developmental genes. Transcriptional regulation by PcG proteins is achieved, at least partly, through the PRC2-mediated methylation on lysine 27 of histone H3 (H3K27) and PRC1-mediated ubiquitylation on lysine 119 of histone H2A ... | A wealth of recent studies has demonstrated the role of Bmi1-stimulated histone ubiquitylation in the repression of transcription at targeted genetic loci. However, the repressive function of this mark has never been extrapolated genome-wide. We have used deep sequencing technology to explore the global deposition of B... | In higher eukaryotes, DNA is organized in the form of chromatin. The basic repeating unit of chromatin is called the nucleosome, which consists of 146 bp of DNA wrapped around a core histone octamer. One unique feature of core histones is their proclivity for covalent modification including acetylation, methylation, ub... |
10.1371/journal.ppat.1002577 | Human Cytomegalovirus Clinical Strain-Specific microRNA miR-UL148D Targets the Human Chemokine RANTES during Infection | The human cytomegalovirus (HCMV) clinical strain Toledo and the attenuated strain AD169 exhibit a striking difference in pathogenic potential and cell tropism. The virulent Toledo genome contains a 15-kb segment, which is present in all virulent strains but is absent from the AD169 genome. The pathogenic differences be... | Unlike the attenuated HCMV strain AD169, the clinical isolates of HCMV, including the Toledo strain, are virulent and can cause disease in healthy adults. Toledo differs from AD169 in that Toledo contains a 15-kb DNA segment, encoding at least 19 ORFs and a single microRNA known as miR-UL148D. This 15-kb segment is bel... | Human cytomegalovirus (HCMV) is a member of the β-herpesvirus family and a ubiquitous human pathogen. After a primary infection, HCMV establishes lifelong latency, which seldom causes illness in an immunocompetent host [1], [2]. However, HCMV is an infectious pathogen that induces morbidity and mortality in immunocompr... |
10.1371/journal.pbio.1001346 | Small Heat Shock Proteins Potentiate Amyloid Dissolution by Protein Disaggregases from Yeast and Humans | How small heat shock proteins (sHsps) might empower proteostasis networks to control beneficial prions or disassemble pathological amyloid is unknown. Here, we establish that yeast sHsps, Hsp26 and Hsp42, inhibit prionogenesis by the [PSI+] prion protein, Sup35, via distinct and synergistic mechanisms. Hsp42 prevents c... | Amyloid fibers are protein aggregates that are associated with numerous neurodegenerative diseases, including Parkinson's disease, for which there are no effective treatments. They can also play beneficial roles; in yeast, for example, they are associated with increased survival and the evolution of new traits. Amyloid... | Amyloid fibers are thread-like protein polymers with cross-β structure. These unusually stable, self-templating structures were first identified in various systemic amyloidoses and neurodegenerative disorders such as Alzheimer's disease [1]. In isolation, many proteins can form amyloid fibers, suggesting that amyloidog... |
10.1371/journal.pgen.1006568 | Two Paralogous Tetraspanins TSP-12 and TSP-14 Function with the ADAM10 Metalloprotease SUP-17 to Promote BMP Signaling in Caenorhabditis elegans | The highly conserved bone morphogenetic protein (BMP) signaling pathway regulates many developmental and homeostatic processes. While the core components of the BMP pathway have been well studied, much research is needed for understanding the mechanisms involved in the precise spatiotemporal control of BMP signaling in... | Bone morphogenetic protein (BMP) signaling regulates multiple developmental and homeostatic processes. Misregulation of this pathway can cause various diseases, including cancers. Thus, it is essential to understand how BMP signaling is tightly regulated spatiotemporally in vivo. We have identified a highly conserved A... | The highly conserved bone morphogenetic protein (BMP) pathway is repeatedly used in metazoan development to regulate multiple distinct processes in different cellular contexts. In canonical BMP signaling, secreted BMP ligands bind to the heteromeric type I/type II receptor complexes and induce the phosphorylation of ty... |
10.1371/journal.pgen.1006840 | Temporal dynamics of neurogenomic plasticity in response to social interactions in male threespined sticklebacks | Animals exhibit dramatic immediate behavioral plasticity in response to social interactions, and brief social interactions can shape the future social landscape. However, the molecular mechanisms contributing to behavioral plasticity are unclear. Here, we show that the genome dynamically responds to social interactions... | Social interactions provoke changes in the brain and behavior but their underlying molecular mechanisms remain obscure. Male sticklebacks are small fish whose fitness depends on their ability to defend a territory. Here, by measuring the time course of gene expression in response to a territorial challenge in two brain... | Animals exhibit remarkable behavioral plasticity. Social interactions in particular can provoke moment-to-moment changes in behavior. These changes are coordinated at the neural level, but social interactions also elicit transcriptional changes within the brains of behaving animals [1]. For example, genome-wide transcr... |
10.1371/journal.pgen.1004594 | Nephronophthisis-Associated CEP164 Regulates Cell Cycle Progression, Apoptosis and Epithelial-to-Mesenchymal Transition | We recently reported that centrosomal protein 164 (CEP164) regulates both cilia and the DNA damage response in the autosomal recessive polycystic kidney disease nephronophthisis. Here we examine the functional role of CEP164 in nephronophthisis-related ciliopathies and concomitant fibrosis. Live cell imaging of RPE-FUC... | Nephronophthisis is a leading inherited cause of renal failure in children and young adults. This work contributes to understanding of the disease mechanism of nephronophthisis, which is characterized by multi-cystic and fibrotic kidneys. The genes mutated in patients with nephronophthisis all seem to encode proteins i... | Nephronophthisis (NPHP) is an autosomal recessive polycystic kidney disease (PKD) attributed to dysfunction of the primary cilia [1], antennae-like structures projecting from the cell surface which have sensory or mechanical functions [2]. To date, mutations in seventeen genes have been identified as causing NPHP, yet ... |
10.1371/journal.ppat.1003427 | The Xanthomonas campestris Type III Effector XopJ Targets the Host Cell Proteasome to Suppress Salicylic-Acid Mediated Plant Defence | The phytopathogenic bacterium Xanthomonas campestris pv. vesicatoria (Xcv) requires type III effector proteins (T3Es) for virulence. After translocation into the host cell, T3Es are thought to interact with components of host immunity to suppress defence responses. XopJ is a T3E protein from Xcv that interferes with pl... | Many bacteria that are pathogens for mammals, insects or plants use a specialized apparatus called the type III secretion system to inject a diverse set of effector proteins into the cytoplasm of their eukaryotic host cells in order to alter cellular processes in favour of the pathogen's lifestyle. However, direct cell... | Plants have to protect themselves from a plethora of microbial enemies. In a first layer of defence, conserved microbial molecules called PAMPs/MAMPs (pathogen/microbe-associated molecular patterns) are recognized on the cell surface which then leads to the induction of a number of defence responses, including the gene... |
10.1371/journal.pgen.1004516 | An Essential Nonredundant Role for Mycobacterial DnaK in Native Protein Folding | Protein chaperones are essential in all domains of life to prevent and resolve protein misfolding during translation and proteotoxic stress. HSP70 family chaperones, including E. coli DnaK, function in stress induced protein refolding and degradation, but are dispensable for cellular viability due to redundant chaperon... | All living organisms use protein chaperones to prevent proteins from becoming insoluble either spontaneously or during cellular stress that can damage proteins. The HSP70 chaperone DnaK has been well characterized in E. coli and is important for that bacterium to resist protein denaturation from heat, but is dispensabl... | Proper protein folding is essential for all organisms and assures that the primary sequence of the polypeptide forms its functional tertiary and quaternary structures. Protein chaperones are present in all domains of life and serve multiple functions in protein homeostasis. During translation, chaperones are required t... |
10.1371/journal.pgen.1004592 | Systematic Dissection of Coding Exons at Single Nucleotide Resolution Supports an Additional Role in Cell-Specific Transcriptional Regulation | In addition to their protein coding function, exons can also serve as transcriptional enhancers. Mutations in these exonic-enhancers (eExons) could alter both protein function and transcription. However, the functional consequence of eExon mutations is not well known. Here, using massively parallel reporter assays, we ... | Exons that code for protein can also have additional functions, such as regulating gene transcription through enhancer activity. Here, we changed every nucleotide in three different exons that also function as enhancers, and examined their enhancer activity to test whether nucleotide changes in these exons can affect b... | Protein coding sequences have been shown to contain additional functional information such as splicing [1], [2], mRNA stability [3], microRNA target sites [4], and transcriptional enhancer activity [5]–[10]. Furthermore, by analyzing various genomic datasets, numerous exons were shown to interact with promoter and enha... |
10.1371/journal.ppat.1002890 | ADCC Develops Over Time during Persistent Infection with Live-Attenuated SIV and Is Associated with Complete Protection against SIVmac251 Challenge | Live-attenuated strains of simian immunodeficiency virus (SIV) routinely confer apparent sterilizing immunity against pathogenic SIV challenge in rhesus macaques. Understanding the mechanisms of protection by live-attenuated SIV may provide important insights into the immune responses needed for protection against HIV-... | Live-attenuated vaccines can prevent simian immunodeficiency virus (SIV) infection upon experimental challenge of rhesus macaques. Although safety considerations preclude vaccinating humans with live-attenuated HIV-1, it may be possible to replicate the types of immunity induced by live-attenuated SIV through an altern... | The development of a vaccine against HIV-1 continues to be hampered by our limited understanding of the types of immune responses needed for protection. Although safety considerations preclude the use of live-attenuated HIV-1 in people [1]–[5], live-attenuated strains of simian immunodeficiency virus (SIV) afford the m... |
10.1371/journal.ppat.1004270 | Independent Bottlenecks Characterize Colonization of Systemic Compartments and Gut Lymphoid Tissue by Salmonella | Vaccination represents an important instrument to control typhoid fever in humans and protects mice from lethal infection with mouse pathogenic serovars of Salmonella species. Mixed infections with tagged Salmonella can be used in combination with probabilistic models to describe the dynamics of the infection process. ... | Pathogens have evolved strategies to invade, replicate and spread within their hosts. On the contrary, vertebrates have developed sophisticated immune defence mechanisms that limit, and ideally clear, the infection. This dynamic interplay between host and pathogens determines the course of the infection and the develop... | While infections with Salmonella enterica serovar Typhi and Paratyphi are estimated to affect some 27 million individuals each year [1] nontyphoidal strains of Salmonella can also cause life-threatening invasive disease, in particular in immunocompromised patients and by selected Salmonella lineages in African countrie... |
10.1371/journal.pntd.0004146 | Serological Evidence of Chikungunya Virus among Acute Febrile Patients in Southern Mozambique | In the last two decades, chikungunya virus (CHIKV) has rapidly expanded to several geographical areas, causing frequent outbreaks in sub-Saharan Africa, South East Asia, South America, and Europe. Therefore, the disease remains heavily neglected in Mozambique, and no recent study has been conducted.
Between January and... | Chikungunya virus (CHIKV) is an emerging arbovirus that remains heavily neglected in Mozambique, and no recent study has been conducted. Between January and September 2013, four hundred acute febrile patients with no other evident cause of fever and attending a health center in a suburban area of Maputo city, Mozambiqu... | Chikungunya virus (CHIKV) is an arthropod borne virus (arbovirus) transmitted by Aedes mosquitoes and belonging to the Togaviridae family and alphavirus genus. Clinical presentation of CHIKV disease ranges from a self-limiting and undifferentiated febrile illness accompanied by exanthema, myalgia and headache to severe... |
10.1371/journal.pgen.1007636 | Components of Brachypodium distachyon resistance to nonadapted wheat stripe rust pathogens are simply inherited | Phytopathogens have a limited range of host plant species that they can successfully parasitise ie. that they are adapted for. Infection of plants by nonadapted pathogens often results in an active resistance response that is relatively poorly characterised because phenotypic variation in this response often does not e... | Plant pathogens are specialists and can colonise only a limited number of plant species (hosts). Pathogen infection of a plant that is not a host of the disease often results in an active plant defense response. This poorly characterised defense response is durable as phytopathogens rarely successfully colonise new hos... | Only a limited number of phytopathogen species are adapted to paracitise a given plant species. The numerous phyopathogens unable of colonising a plant species (nonadapted) are often suppressed by an active plant resistance response upon challenge [1, 2, 3, 4]. Plant resistance against nonadapted pathogens is considere... |
10.1371/journal.pcbi.1005244 | Utility and Limitations of Using Gene Expression Data to Identify Functional Associations | Gene co-expression has been widely used to hypothesize gene function through guilt-by association. However, it is not clear to what degree co-expression is informative, whether it can be applied to genes involved in different biological processes, and how the type of dataset impacts inferences about gene functions. Her... | There remain genes with no known function even in the most well studied, model species. One common way to hypothesize gene function is based on the assumption that genes with similar expression profiles tend to have similar functions. However, using datasets and biological pathway information from the model plant Arabi... | With the ease of sequencing, an ever increasing number of genomes from a wide range of species are available. One major challenge is to ascribe functions to genomic features. For example, while ~70% of Arabidopsis thaliana genes have annotated functions [1], only ~40% of these annotations are supported by experimental ... |
10.1371/journal.pbio.3000123 | Structural basis of DSF recognition by its receptor RpfR and its regulatory interaction with the DSF synthase RpfF | The diffusible signal factors (DSFs) are a family of quorum-sensing autoinducers (AIs) produced and detected by numerous gram-negative bacteria. The DSF family AIs are fatty acids, differing in their acyl chain length, branching, and substitution but having in common a cis-2 double bond that is required for their activ... | Communication between many species of gram-negative bacteria is mediated by a family of cell–cell signaling autoinducers (AIs) known as the diffusible signal factors (DSFs). DSFs are fatty acids, containing a signature cis-2 double bond critical for their activity. The DSFs differ from one another by their acyl chain l... | Quorum sensing is a form of bacterial cell–cell communication that enables populations of bacteria to synchronize their gene expression in order to coordinate group behaviors such as bioluminescence, sporulation, genetic competence, biofilm formation, motility, and virulence factor expression (reviewed in [1,2]). Quoru... |
10.1371/journal.pcbi.1003509 | An In-Silico Model of Lipoprotein Metabolism and Kinetics for the Evaluation of Targets and Biomarkers in the Reverse Cholesterol Transport Pathway | High-density lipoprotein (HDL) is believed to play an important role in lowering cardiovascular disease (CVD) risk by mediating the process of reverse cholesterol transport (RCT). Via RCT, excess cholesterol from peripheral tissues is carried back to the liver and hence should lead to the reduction of atherosclerotic p... | Epidemiological studies have shown a strong inverse association between HDL-C and cardiovascular risk and led to the formulation of the “HDL cholesterol hypothesis”: under this hypothesis, interventions raising HDL-C should decrease risk. However, the recent failures of HDL-C raising therapies in improving cardiovascul... | Epidemiological studies have shown that high levels of low-density lipoprotein cholesterol (LDL-C) as well as low levels of high-density lipoprotein cholesterol (HDL-C) are associated with increased cardiovascular disease (CVD) risk [1], [2]. While LDL-C lowering therapies have been shown consistently to reduce CVD ris... |
10.1371/journal.pgen.1004466 | Hypoxia Adaptations in the Grey Wolf (Canis lupus chanco) from Qinghai-Tibet Plateau | The Tibetan grey wolf (Canis lupus chanco) occupies habitats on the Qinghai-Tibet Plateau, a high altitude (>3000 m) environment where low oxygen tension exerts unique selection pressure on individuals to adapt to hypoxic conditions. To identify genes involved in hypoxia adaptation, we generated complete genome sequenc... | Understanding the genetic mechanisms that allow some individuals to live at high altitudes under hypoxic conditions can provide insight into the evolutionary constraints of adaptation to extreme conditions and the development of hypoxia-related disease in humans. The Tibetan grey wolf (Canis lupus chanco) has long exis... | Species inhabiting the Qinghai-Tibet Plateau exist in low oxygen tension environments and must adapt to low oxygen tension [1]. Documenting the genetic mechanisms for adaptation to hypoxia can provide insights into the process of evolution under extreme conditions and hypoxia-related disease in humans. Compared with th... |
10.1371/journal.ppat.1004232 | HopW1 from Pseudomonas syringae Disrupts the Actin Cytoskeleton to Promote Virulence in Arabidopsis | A central mechanism of virulence of extracellular bacterial pathogens is the injection into host cells of effector proteins that modify host cellular functions. HopW1 is an effector injected by the type III secretion system that increases the growth of the plant pathogen Pseudomonas syringae on the Columbia accession o... | Eukaryotic cells require a dynamic actin cytoskeleton for basic functions, some of which are important for immune responses. Such functions include the transport of cellular material to and from different cellular compartments. The plant pathogen Pseudomonas syringae is extracellular and causes disease by injecting eff... | Plants that are infected with foliar bacterial pathogens can mount a multilayered response, the success of which is shaped by the perception of pathogen-derived molecules and the ability of the pathogen to disrupt host responses. Essential for understanding dynamic host-pathogen interactions is the identification of cr... |
10.1371/journal.ppat.1000296 | Transcriptional Profiling in Pathogenic and Non-Pathogenic SIV Infections Reveals Significant Distinctions in Kinetics and Tissue Compartmentalization | Simian immunodeficiency virus (SIV) infection leads to AIDS in experimentally infected macaques, whereas natural reservoir hosts exhibit limited disease and pathology. It is, however, unclear how natural hosts can sustain high viral loads, comparable to those observed in the pathogenic model, without developing severe ... | Simian immunodeficiency virus (SIV) does not cause disease in African green monkeys (a natural host for the virus), whereas experimentally infected Asian macaques (a non-natural host) develop a progressive disease that is similar to that which occurs in HIV-infected humans. Insight into how HIV causes disease and leads... | Natural reservoir hosts of simian immunodeficiency virus (SIV) do not develop AIDS in response to infection and live a normal lifespan. This is in contrast to non-natural hosts, such as Asian pig-tailed macaques (PTs), which, when experimentally infected with SIV, develop AIDS in a similar manner to HIV-infected humans... |
10.1371/journal.pcbi.1004524 | The Mass-Longevity Triangle: Pareto Optimality and the Geometry of Life-History Trait Space | When organisms need to perform multiple tasks they face a fundamental tradeoff: no phenotype can be optimal at all tasks. This situation was recently analyzed using Pareto optimality, showing that tradeoffs between tasks lead to phenotypes distributed on low dimensional polygons in trait space. The vertices of these po... | Understanding why some mammals live longer than others is of crucial interest. Here we study how longevity relates to other life-history traits, using data on about 2000 species of mammals and birds. In contrast to the tradition in which traits fall on a line in logarithmic coordinates, called allometric lines. We find... | Mammals can have very different lifespans, and it is of great interest to understand why longevity differs between species. Recent studies use comparative approaches to understand mechanisms for longevity in diverse mammalian species, especially species which are long lived [1–3]. In order to expand such studies to a w... |
10.1371/journal.pgen.1002937 | Reduced Prostasin (CAP1/PRSS8) Activity Eliminates HAI-1 and HAI-2 Deficiency–Associated Developmental Defects by Preventing Matriptase Activation | Loss of either hepatocyte growth factor activator inhibitor (HAI)-1 or -2 is associated with embryonic lethality in mice, which can be rescued by the simultaneous inactivation of the membrane-anchored serine protease, matriptase, thereby demonstrating that a matriptase-dependent proteolytic pathway is a critical develo... | Vertebrate embryogenesis is dependent upon a series of precisely coordinated cell proliferation, migration, and differentiation events. Recently, the execution of these events was shown to be guided in part by extracellular cues provided by focal pericellular proteolysis by a newly identified family of membrane-anchore... | Studies conducted within the past two decades have uncovered a large family of membrane-anchored serine proteases that regulates vertebrate development, tissue homeostasis, and tissue repair by providing focal proteolysis essential for cytokine and growth factor maturation, extracellular matrix remodeling, signaling re... |
10.1371/journal.pcbi.1005780 | A theoretical framework for analyzing coupled neuronal networks: Application to the olfactory system | Determining how synaptic coupling within and between regions is modulated during sensory processing is an important topic in neuroscience. Electrophysiological recordings provide detailed information about neural spiking but have traditionally been confined to a particular region or layer of cortex. Here we develop new... | Sensory processing is known to span multiple regions of the nervous system. However, electrophysiological recordings during sensory processing have traditionally been limited to a single region or brain layer. With recent advances in experimental techniques, recorded spiking activity from multiple regions simultaneousl... | As experimental tools advance, measuring whole-brain dynamics with single-neuron resolution becomes closer to reality [1–4]. However, a task that remains technically elusive is to measure the interactions within and across brain regions that govern such system-wide dynamics. Here we develop a theoretical approach to el... |
10.1371/journal.ppat.1004022 | Crk Adaptors Negatively Regulate Actin Polymerization in Pedestals Formed by Enteropathogenic Escherichia coli (EPEC) by Binding to Tir Effector | Infections by enteropathogenic Escherichia coli (EPEC) cause diarrhea linked to high infant mortality in developing countries. EPEC adheres to epithelial cells and induces the formation of actin pedestals. Actin polymerization is driven fundamentally through signaling mediated by Tir bacterial effector protein, which i... | Infections by enteropathogenic Escherichia coli are an important cause of diarrhea linked to high infant mortality. Such bacteria attach to cells and form actin-rich structures called pedestals, which contain many proteins that play unknown functions during pedestal formation. Here we studied two nearly identical forms... | Enteropathogenic Escherichia coli (EPEC) causes infant diarrhea worldwide and is a leading cause of death in developing countries. EPEC adheres to intestinal epithelial cells, causing local disappearance of microvilli and altering cell permeability, giving rise to what are classically known as attaching and effacing (A... |
10.1371/journal.pntd.0001797 | Open Release of Male Mosquitoes Infected with a Wolbachia Biopesticide: Field Performance and Infection Containment | Lymphatic filariasis (LF) is a globally significant disease, with 1.3 billion persons in 83 countries at risk. A coordinated effort of administering annual macrofilaricidal prophylactics to the entire at-risk population has succeeded in impacting and eliminating LF transmission in multiple regions. However, some areas ... | Additional tools are required to mitigate mosquito borne disease in the South Pacific, including human lymphatic filariasis (LF). Wolbachia are obligate intracellular bacteria that occur in a majority of insect species and that cause a form of conditional sterility in mosquitoes. Prior work demonstrates that male Aedes... | Lymphatic filariasis (LF) is a disfiguring and socioeconomically burdensome disease estimated to affect over 120 million people worldwide, with 1.3 billion people at risk [1]. An ongoing global strategy for eliminating this mosquito borne disease is to interrupt transmission by administering annual macrofilaricidal pro... |
10.1371/journal.pcbi.1002825 | How Evolving Heterogeneity Distributions of Resource Allocation Strategies Shape Mortality Patterns | It is well established that individuals age differently. Yet the nature of these inter-individual differences is still largely unknown. For humans, two main hypotheses have been recently formulated: individuals may experience differences in aging rate or aging timing. This issue is central because it directly influence... | Aging is a widespread phenomenon across the tree of life. From yeast to humans, mortality changes over age have been widely documented. Interestingly, all individuals are not equal with respect to the aging process: large variability in individual life span has been reported, even in clonal populations. Understanding t... | Aging can be generally defined as age-related changes in a set of variables, from growth rate to reproductive effort, which influence the fitness of an organism. Aging is a multiscale process which can be measured at almost every level of the individual organism. Individual metrics of aging include a broad range of pro... |
10.1371/journal.ppat.1002346 | Murid Herpesvirus-4 Exploits Dendritic Cells to Infect B Cells | Dendritic cells (DCs) play a central role in initiating immune responses. Some persistent viruses infect DCs and can disrupt their functions in vitro. However, these viruses remain strongly immunogenic in vivo. Thus what role DC infection plays in the pathogenesis of persistent infections is unclear. Here we show that ... | We detect invading viruses with dendritic cells and eliminate them with lymphocytes. A key interaction is lymphocyte activation by dendritic cells presenting viral antigens. Not all viruses can be eliminated, and some that persist deliberately colonize lymphocytes and dendritic cells, such that parasitism and host defe... | Dendritic cells (DCs) act as sentinels against infection: they encode pathogen-responsive receptors, abound at pathogen entry sites, and orchestrate both innate and adaptiveimmune responses [1], [2]. Virus-infected DCs are generally immunogenic [3]–[5], and DC infection may be important for optimal T cell priming [6]. ... |
10.1371/journal.pbio.2001493 | FSP1-positive fibroblasts are adipogenic niche and regulate adipose homeostasis | Adipocyte progenitors reside in the stromal vascular fraction (SVF) of adipose tissues that are composed of fibroblasts, immune cells, and endothelial cells. It remains to be elucidated how the SVF regulates adipocyte progenitor fate determination and adipose homeostasis. Here, we report that fibroblast-specific protei... | White adipose tissue (WAT), which consists mostly of adipocytes, is not only a passive energy storage but also an active metabolic and endocrine organ in the body. The importance of maintaining proper adipose mass is emphasized by the fact that both adipose tissue excess—in obese individuals—and deficiency have adverse... | Adult adipose tissue contains adipocyte progenitors that are critical to adipose homeostatic turnover as well as adaptive hyperplastic expansion and regeneration [1–4]. Peroxisome proliferator-activated receptor-γ (PPARγ)+ adipocyte progenitors and preadipocytes—characteristic of cell surface markers, e.g., cluster of ... |
10.1371/journal.ppat.1003315 | Differential Adaptation of Candida albicans In Vivo Modulates Immune Recognition by Dectin-1 | The β-glucan receptor Dectin-1 is a member of the C-type lectin family and functions as an innate pattern recognition receptor in antifungal immunity. In both mouse and man, Dectin-1 has been found to play an essential role in controlling infections with Candida albicans, a normally commensal fungus in man which can ca... | Dectin-1 is a pattern recognition receptor recognising the fungal cell-wall component, β-glucan, and plays an essential role in controlling C. albicans infections in both mouse and man. Candida albicans is part of the normal human microflora, yet is capable of causing superficial mucosal infections as well as life-thre... | The immune system of healthy individuals has effective mechanisms for preventing fungal infection, yet immunosuppressive infections, such as HIV/AIDS, and modern immunosuppressive and invasive medical interventions can substantially increase the risk of infection with numerous fungal pathogens. Candida albicans is one ... |
10.1371/journal.pntd.0002731 | Dynamics of the Force of Infection: Insights from Echinococcus multilocularis Infection in Foxes | Characterizing the force of infection (FOI) is an essential part of planning cost effective control strategies for zoonotic diseases. Echinococcus multilocularis is the causative agent of alveolar echinococcosis in humans, a serious disease with a high fatality rate and an increasing global spread. Red foxes are high p... | Human alveolar echinococcosis (AE) is caused by the fox tapeworm E. multilocularis and has a high fatality rate if untreated. The frequency of the tapeworm in foxes can be reduced through the regular distribution of anthelmintic baits and thus decrease the risk of zoonotic transmission. Here, we estimate the force of i... | The force of infection (FOI) is a crucial epidemiological parameter and characterizing its dynamics is an essential part of planning cost effective control strategies for infectious diseases [1]. Mechanistically, disease intervention strategies are typically targeted at decreasing the per capita infection rate. If succ... |
10.1371/journal.pgen.1000558 | The Ups and Downs of Mutation Frequencies during Aging Can Account for the Apert Syndrome Paternal Age Effect | Apert syndrome is almost always caused by a spontaneous mutation of paternal origin in one of two nucleotides in the fibroblast growth factor receptor 2 gene (FGFR2). The incidence of this disease increases with the age of the father (paternal age effect), and this increase is greater than what would be expected based ... | Epidemiological studies show that the incidence of some genetic diseases increases with the age of the father. This “paternal age effect” is traditionally explained by the fact that, as men age, the male germ-line cells continue to divide, and each division presents an additional chance for mutation. Apert syndrome is ... | The paternal age effect (PAE), e.g. [1]–[5], is the phenomenon whereby the incidence of sporadic cases of certain genetic diseases increases with the age of the father. The most common explanation for this effect is that replication of premeiotic cells throughout a male's life results in the accumulation of more mutati... |
10.1371/journal.pgen.1006413 | Bottom-up Assembly of the Phytochrome Network | Plants have developed sophisticated systems to monitor and rapidly acclimate to environmental fluctuations. Light is an essential source of environmental information throughout the plant’s life cycle. The model plant Arabidopsis thaliana possesses five phytochromes (phyA-phyE) with important roles in germination, seedl... | As sessile organisms, plants respond to and integrate environmental information. An intriguing aspect is how plants integrate this information. We studied the interactions among members of the phytochrome family of photoreceptors, which detect the changes in light quality that occur upon shading by other plants, as wel... | Plant photoreceptor signaling networks are sensitive to a large dynamic range of light inputs. Plant light signaling systems are sensitive enough to induce germination in response to extremely short exposures of light, as encountered during soil tillage, and very low light intensities, as experienced under soil litter,... |
10.1371/journal.ppat.1004384 | Molecular Insights Into the Evolutionary Pathway of Vibrio cholerae O1 Atypical El Tor Variants | Pandemic V. cholerae strains in the O1 serogroup have 2 biotypes: classical and El Tor. The classical biotype strains of the sixth pandemic, which encode the classical type cholera toxin (CT), have been replaced by El Tor biotype strains of the seventh pandemic. The prototype El Tor strains that produce biotype-specifi... | In this report, we suggest a genetic mechanism of how the V. cholerae atypical El Tor variants were generated from classical and prototype El Tor biotype strains. An intermediary strain, containing the CTX-1 and CTX-2 prophages, was identified among the clinical isolates that were collected in 1991, when the atypical s... | Vibrio cholerae O1 serogroup strains have been categorized into 2 biotypes - classical and El Tor -based on microbiological properties and the CTX prophage that they harbor [1], [2]. Classical biotype strains contain the classical CTX prophage (CTXcla), and El Tor strains are believed to contain the El Tor CTX prophage... |
10.1371/journal.ppat.1002508 | Identification of Genetic Determinants and Enzymes Involved with the Amidation of Glutamic Acid Residues in the Peptidoglycan of Staphylococcus aureus | The glutamic acid residues of the peptidoglycan of Staphylococcus aureus and many other bacteria become amidated by an as yet unknown mechanism. In this communication we describe the identification, in the genome of S. aureus strain COL, of two co-transcribed genes, murT and gatD, which are responsible for peptidoglyca... | Genetic determinants and enzymes that catalyze the multiple steps in the assembly of bacterial cell wall peptidoglycan have been known for some time. On the other hand, the mechanism by which glutamic acid residues of this structure undergo modification to glutamine has remained unknown. In this communication, we descr... | Peptidoglycan forms an essential stress-bearing and shape-maintaining layer in the bacterial cell envelope. Its biosynthetic pathway is the target of important classes of antimicrobials such as beta-lactams and glycopeptides, and the polymerized cell wall is targeted by antimicrobial enzymes like lysozyme. The biosynth... |
10.1371/journal.pcbi.1006049 | The importance of geometry in the corneal micropocket angiogenesis assay | The corneal micropocket angiogenesis assay is an experimental protocol for studying vessel network formation, or neovascularization, in vivo. The assay is attractive due to the ease with which the developing vessel network can be observed in the same animal over time. Measurements from the assay have been used in combi... | Neovascularization, or the formation of new blood vessels, is an important process in development, wound healing and cancer. The corneal micropocket assay is used to better understand the process and, in the case of cancer, how it can be controlled with drug therapies for improved patient outcomes. In the assay, the he... | Neovascularization, or new blood vessel formation, is an important process in development, wound healing, cancer and other diseases. The corneal micropocket angiogenesis assay, shown in Fig 1, is widely used for studying neovascularization in vivo [1–3]. The assay involves the implantation of a pellet containing pro-an... |
10.1371/journal.ppat.1005164 | Antigen-Specific Th17 Cells Are Primed by Distinct and Complementary Dendritic Cell Subsets in Oropharyngeal Candidiasis | Candida spp. can cause severe and chronic mucocutaneous and systemic infections in immunocompromised individuals. Protection from mucocutaneous candidiasis depends on T helper cells, in particular those secreting IL-17. The events regulating T cell activation and differentiation toward effector fates in response to fun... | Candida spp. are present in the normal microbiota without causing damage to the host. They can become pathogenic and bear a serious health hazard for individuals with a weakened immune system. The continuous incidence of fungal infections and the increase in resistance against available antifungal drugs urge the develo... | Opportunistic fungal infections cause an increasing medical problem due to the progression in immunosuppression worldwide [1]. Candida spp. present in the normal human microbiota can cause mucocutaneous infections when cellular immune barriers of the host are breached. As such, HIV+ individuals with low T cells counts ... |
10.1371/journal.pcbi.1002477 | Computational Design of a PDZ Domain Peptide Inhibitor that Rescues CFTR Activity | The cystic fibrosis transmembrane conductance regulator (CFTR) is an epithelial chloride channel mutated in patients with cystic fibrosis (CF). The most prevalent CFTR mutation, ΔF508, blocks folding in the endoplasmic reticulum. Recent work has shown that some ΔF508-CFTR channel activity can be recovered by pharmaceut... | Cystic fibrosis (CF) is an inherited disease that causes the body to produce thick mucus that clogs the lungs and obstructs the breakdown and absorption of food. The cystic fibrosis transmembrane conductance regulator (CFTR) is mutated in CF patients, and the most common mutation causes three defects in CFTR: misfoldin... | Protein-peptide interactions (PPIs) are vital for cell signaling, protein trafficking and localization, gene expression, and many other biological functions. The PDZ (PSD-95, discs large, zonula occludens-1) family of proteins forms PPIs that play crucial physiological roles, including synapse formation [1] and epithel... |
10.1371/journal.pcbi.0030182 | Structure-Templated Predictions of Novel Protein Interactions from Sequence Information | The multitude of functions performed in the cell are largely controlled by a set of carefully orchestrated protein interactions often facilitated by specific binding of conserved domains in the interacting proteins. Interacting domains commonly exhibit distinct binding specificity to short and conserved recognition pep... | Many functions performed within a living cell are mediated by specific interactions between proteins. Precise geometric and chemical matches between segments of the protein structures facilitate those interactions. Such binding surfaces are often evolutionarily conserved elements of protein structures known as conserve... | The interaction between two proteins is a geometric and electrostatic match between two polypeptide surfaces that results in a stable set of bonds between amino acid side chains or backbone atoms. The interacting amino acids are often part of conserved sequence features such as domains or short linear motifs that const... |
10.1371/journal.pbio.2001878 | Egocentric and allocentric representations in auditory cortex | A key function of the brain is to provide a stable representation of an object’s location in the world. In hearing, sound azimuth and elevation are encoded by neurons throughout the auditory system, and auditory cortex is necessary for sound localization. However, the coordinate frame in which neurons represent sound s... | When we hear a sound, we can describe its location relative to ourselves (e.g., “the phone is on my right”) or relative to the world (e.g., “the phone is in the corner”). These descriptions of space are known as egocentric and allocentric, respectively, and illustrate the representation of sound location in reference f... | A central role of the brain is to build a model of the world and objects within it that remains stable across changes in sensory input when we move. In hearing, this requires that an observer maintains the identification of an auditory object as they move through an environment. Movement is a critical aspect of sensing... |
10.1371/journal.pntd.0002003 | Syndromic Algorithms for Detection of Gambiense Human African Trypanosomiasis in South Sudan | Active screening by mobile teams is considered the best method for detecting human African trypanosomiasis (HAT) caused by Trypanosoma brucei gambiense but the current funding context in many post-conflict countries limits this approach. As an alternative, non-specialist health care workers (HCWs) in peripheral health ... | Human African trypanosomiasis (HAT or sleeping sickness) is an almost always fatal disease affecting poor people in rural, conflict-affected areas of sub-Saharan Africa. It is difficult to diagnose. Effective treatment exists, but because diagnostic and treatment services are usually based only in hospitals, many HAT p... | Found in remote sub-Saharan areas where health systems are often weak and/or destabilised by armed conflict, human African trypanosomiasis (HAT, or sleeping sickness) is one of the world's most neglected tropical diseases (NTDs). It is caused by trypanosome parasites that are transmitted primarily through the bites of ... |
10.1371/journal.ppat.0030183 | Secreted NS1 of Dengue Virus Attaches to the Surface of Cells via Interactions with Heparan Sulfate and Chondroitin Sulfate E | Dengue virus (DENV) nonstructural protein-1 (NS1) is a secreted glycoprotein that is absent from viral particles but accumulates in the supernatant and on the plasma membrane of cells during infection. Immune recognition of cell surface NS1 on endothelial cells has been hypothesized as a mechanism for the vascular leak... | Dengue virus (DENV) is a mosquito-transmitted virus that infects humans and has become a global emerging infectious disease threat. Four serotypes of DENV exist, and the most severe cases are associated with secondary infection with a different virus serotype. Clinical deterioration is characterized by bleeding and sel... | Dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS) are severe and potentially fatal complications of infection by dengue virus (DENV), a mosquito-borne RNA virus of the Flaviviridae family. Globally, DENV infects 25 to 100 million people per year, but the life-threatening complications primarily occur in scho... |
10.1371/journal.pntd.0002431 | Meta-analysis of Urine Heme Dipstick Diagnosis of Schistosoma haematobium Infection, Including Low-Prevalence and Previously-Treated Populations | Urogenital schistosomiasis remains highly endemic in Africa. Current control is based on drug administration, targeted either to school-age children or to high-risk communities at-large. Urine dipsticks for detection of microhematuria offer an inexpensive means for estimating infection prevalence. However, their diagno... | Schistosomiasis is a chronic human disease caused by infection with multicellular trematode parasites of Schistosoma species. In particular, Schistosoma haematobium colonizes the veins in the pelvis, in and around the urinary tract, and causes inflammation that leads to ulceration and bleeding into the urine. One low-t... | Urogenital schistosomiasis caused by Schistosoma haematobium infection is highly endemic in many developing areas of Africa and the Middle East that lack adequate sanitation and safe water supply [1]–[5]. The urinary dipstick for detection of hematuria has long been recommended as a relatively inexpensive and potential... |
10.1371/journal.pgen.1002750 | In Vivo Control of CpG and Non-CpG DNA Methylation by DNA Methyltransferases | The enzymatic control of the setting and maintenance of symmetric and non-symmetric DNA methylation patterns in a particular genome context is not well understood. Here, we describe a comprehensive analysis of DNA methylation patterns generated by high resolution sequencing of hairpin-bisulfite amplicons of selected si... | DNA methylation is a stable covalent epigenetic modification of cytosines mostly confined to CpG-dinucleotides in mammals. In general, it is associated with silencing of genomic DNA regions. Three catalytically active DNA methyltransferases (Dnmts) set and maintain CpG methylation in cooperation with other (co-)factors... | DNA methylation at the C-5 positions of cytosine (5mC) is a key epigenetic modification in mammals essential for normal development [1], [2]. Cytosine methylation is predominantly found in CpG dinucleotide context and about 70 to 80% of all CpGs are methylated. These methylated CpGs are usually located in CpG poor regi... |
10.1371/journal.ppat.1007003 | Loss of CXCR6 coreceptor usage characterizes pathogenic lentiviruses | Pandemic HIV-1 originated from the cross-species transmission of SIVcpz, which infects chimpanzees, while SIVcpz itself emerged following the cross-species transmission and recombination of monkey SIVs, with env contributed by the SIVgsn/mus/mon lineage that infects greater spot-nosed, mustached and mona monkeys. SIVcp... | Use of an entry coreceptor, in conjunction with CD4, is the main determinant of HIV/SIV cell targeting, which in turn may be a central factor determining pathogenicity of infection. Two SIVs that generally do not cause AIDS in their natural hosts, SIVsmm of sooty mangabeys and SIVagm of African green monkeys, express l... | Pandemic HIV-1 resulted from the cross-species transmission of SIVcpz, which infects chimpanzees (Pan troglodytes), into humans [1, 2]. SIVcpz itself emerged in chimpanzees following the cross-species transmission and recombination of SIVs infecting monkeys on which chimpanzees prey [3, 4]. The 5’ half of SIVcpz, which... |
10.1371/journal.pntd.0000543 | Anti-schistosomal Intervention Targets Identified by Lifecycle Transcriptomic Analyses | Novel methods to identify anthelmintic drug and vaccine targets are urgently needed, especially for those parasite species currently being controlled by singular, often limited strategies. A clearer understanding of the transcriptional components underpinning helminth development will enable identification of exploitab... | Despite the implementation of focused and well-funded chemotherapeutic control initiatives over the last decade, schistosomiasis remains a significant cause of morbidity and mortality within countries of the developing world. There is, therefore, an urgent need for the rapid translation of genomic information into viab... | Parasitic helminths constitute the most important group of metazoan pathogens affecting the global health and wellbeing of human and animal populations. While most infected individuals live within subtropical and tropical countries of the developing world, distribution of favourable habitats for helminth transmission w... |
10.1371/journal.pmed.1002744 | Maternal body mass index, gestational weight gain, and the risk of overweight and obesity across childhood: An individual participant data meta-analysis | Maternal obesity and excessive gestational weight gain may have persistent effects on offspring fat development. However, it remains unclear whether these effects differ by severity of obesity, and whether these effects are restricted to the extremes of maternal body mass index (BMI) and gestational weight gain. We aim... | Maternal pre-pregnancy obesity and excessive gestational weight gain are important risk factors of various pregnancy and birth complications.
An accumulating body of evidence suggests that maternal obesity and excessive gestational weight gain also have persistent effects on offspring fat development.
It is not clear w... | Maternal pre-pregnancy obesity and excessive gestational weight gain are major public health problems. Maternal obesity is an important risk factor of gestational hypertensive and diabetic disorders, fetal death, pre-term birth, and macrosomia [1,2]. An accumulating body of evidence suggests that maternal obesity also ... |
10.1371/journal.pbio.3000132 | Feather arrays are patterned by interacting signalling and cell density waves | Feathers are arranged in a precise pattern in avian skin. They first arise during development in a row along the dorsal midline, with rows of new feather buds added sequentially in a spreading wave. We show that the patterning of feathers relies on coupled fibroblast growth factor (FGF) and bone morphogenetic protein (... | Feathers are a defining feature of birds. In flighted birds, the feathers are arranged in a highly ordered pattern that arises during embryonic development. Feather rudiments are produced in rows, with these rows appearing one after another in a spreading wave. We show that the formation of highly regular feather patte... | Feathers evolved before birds but today are their primary diagnostic character. Feathers are arranged in clusters called tracts [1], apparent as well-defined feather-bearing areas of skin at specific body sites. Each tract is a contiguous set of feathers initially laid out with a regular spacing between neighbouring fe... |
10.1371/journal.pbio.2006859 | Prophylactic TLR9 stimulation reduces brain metastasis through microglia activation | Brain metastases are prevalent in various types of cancer and are often terminal, given the low efficacy of available therapies. Therefore, preventing them is of utmost clinical relevance, and prophylactic treatments are perhaps the most efficient strategy. Here, we show that systemic prophylactic administration of a t... | Brain metastases are prevalent and often terminal. Thus, reducing their occurrence could markedly improve cancer outcome. We show that systemic prophylactic and perioperative administration of a TLR9 agonist, CpG-C, reduced metastatic growth in experimental and spontaneous brain metastasis models, employing mouse and h... | Ten to twenty percent of cancer patients develop brain metastases, commonly as the final stage of cancer progression, with lung and melanoma cancers having the highest incidence (40%–50% and 30%–50%, respectively) [1]. Therapies include surgery and radiation; however, both treatments result in only a modest survival ad... |
10.1371/journal.pgen.1004387 | Genes That Bias Mendelian Segregation | Mendel laws of inheritance can be cheated by Meiotic Drive Elements (MDs), complex nuclear genetic loci found in various eukaryotic genomes and distorting segregation in their favor. Here, we identify and characterize in the model fungus Podospora anserina Spok1 and Spok2, two MDs known as Spore Killers. We show that t... | Chromosome segregation during meiosis ensures that paternal and maternal chromosomes are equally transmitted to the progeny. Meiotic Drive Elements (MDs) are known to distort this 1∶1 ratio in many animal, plant, and fungal species by killing the gametes not carrying them. Most of the known MDs are complex genetic loci... | In many organisms, genetic factors, called Meiotic Drive Elements (MDs), have found ways to break Mendel's laws of heredity. MDs skew the expected 1∶1 ratio in their favor and are thus overrepresented in the progeny after meiosis. They have been observed in metazoans, plants and fungi [1]. They may play a critical role... |
10.1371/journal.pntd.0006364 | The effectiveness of water treatment processes against schistosome cercariae: A systematic review | Schistosomiasis is one of the most disabling neglected tropical diseases, ranking second in terms of years lived with disability. While treatment with the drug praziquantel can have immediate beneficial effects, reinfection can occur rapidly if people are in contact with cercaria-infested water. Water treatment for sch... | Schistosomiasis control currently focuses on preventive chemotherapy (PC) with praziquantel, which is effective, safe, and inexpensive. However, this treatment does not prevent subsequent reinfection. As schistosomiasis control targets become more ambitious and move towards elimination, interest is increasing in the po... | Schistosomiasis is a water-borne helminthic disease caused by schistosomes, which are parasitic worms. Infection occurs through dermal-contact with cercaria-infested freshwater. Cercariae are released by snails infected with miracidia which hatch from the eggs in human urine and feces. Despite efforts to control the di... |
10.1371/journal.pcbi.1003573 | The Self-Limiting Dynamics of TGF-β Signaling In Silico and In Vitro, with Negative Feedback through PPM1A Upregulation | The TGF-β/Smad signaling system decreases its activity through strong negative regulation. Several molecular mechanisms of negative regulation have been published, but the relative impact of each mechanism on the overall system is unknown. In this work, we used computational and experimental methods to assess multiple ... | TGF-β signaling pathway regulates a variety of cellular responses, such as differentiation, migration and apoptosis. Phosphorylated R-Smad, the central signaling protein in this pathway, exhibits self-limiting behaviors: it not only decreases quickly after TGF-β is removed, but it also decreases slowly when TGF-β remai... | Transforming Growth Factor-β (TGF-β), a regulator of cell migration and cell fate, is a pharmaceutical target for the treatment of metastatic cancer and fibrotic diseases [1]. Signal transduction from extracellular TGF-β to the cell nucleus through the Smad pathway is well documented [2]–[7]. The TGF-β ligand binds seq... |
10.1371/journal.ppat.1003195 | Cytotoxic Capacity of SIV-Specific CD8+ T Cells against Primary Autologous Targets Correlates with Immune Control in SIV-Infected Rhesus Macaques | Although the study of non-human primates has resulted in important advances for understanding HIV-specific immunity, a clear correlate of immune control over simian immunodeficiency virus (SIV) replication has not been found to date. In this study, CD8+ T-cell cytotoxic capacity was examined to determine whether this f... | Clues regarding the features of effective immunity against lentiviruses have come from the study of non-human primates. We evaluated rhesus macaques infected with Simian Immunodeficiency Virus (SIV), a lentivirus closely related to Human Immunodeficiency Virus (HIV). In contrast to most SIV-infected rhesus macaques tha... | Clues regarding the features of an effective cellular immune response capable of controlling a chronic lentiviral infection have come from humans who naturally restrict HIV replication referred to as long-term nonprogressors/elite controllers (LTNP/EC) [1]–[4]. LTNP/EC show an enrichment of some MHC class I alleles, pa... |
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