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10.1371/journal.pcbi.1004176 | Extensive Decoupling of Metabolic Genes in Cancer | Tumorigenesis requires the re-organization of metabolism to support malignant proliferation. We examine how the altered metabolism of cancer cells is reflected in the rewiring of co-expression patterns among metabolic genes. Focusing on breast and clear-cell kidney tumors, we report the existence of key metabolic genes... | The metabolism of malignant tumors is deranged. The transition from healthy to cancerous state involves, among other factors, the transcriptional coordination of genes spread throughout the cell’s metabolic pathways. An examination of this multivariate regulatory effort can offer insights which may remain hidden from a... | All cellular events, from the transduction of signals to the translation of nucleic acids, rely on the interaction of molecular entities. Indeed, one may argue that the fundamental unit of a biological network is not its constituent components (e.g. proteins or genes), but rather the edges representing the interactions... |
10.1371/journal.pbio.1002333 | Reproducible Research Practices and Transparency across the Biomedical Literature | There is a growing movement to encourage reproducibility and transparency practices in the scientific community, including public access to raw data and protocols, the conduct of replication studies, systematic integration of evidence in systematic reviews, and the documentation of funding and potential conflicts of in... | There is increasing interest in the scientific community about whether published research is transparent and reproducible. Lack of replication and non-transparency decreases the value of research. Several biomedical journals have started to encourage or require authors to submit detailed protocols, full datasets, and d... | The inability to replicate published research has been an ongoing concern in the scientific community [1]. There is clear evidence from basic molecular and animal modeling research that a large portion of published articles lack reproducibility [2], which could potentially be related to the increase in lack of efficacy... |
10.1371/journal.pgen.1005149 | Spastin Binds to Lipid Droplets and Affects Lipid Metabolism | Mutations in SPAST, encoding spastin, are the most common cause of autosomal dominant hereditary spastic paraplegia (HSP). HSP is characterized by weakness and spasticity of the lower limbs, owing to progressive retrograde degeneration of the long corticospinal axons. Spastin is a conserved microtubule (MT)-severing pr... | Hereditary spastic paraplegia (HSP) is a genetically heterogeneous neurological disease characterized by weakness and spasticity of the lower limbs, caused by progressive retrograde degeneration of the corticospinal axons, the longest in the central nervous system. The most commonly mutated gene in autosomal dominant f... | Lipid droplets (LDs) are complex and dynamic organelles whose function is to assemble, store, and supply neutral lipids, mainly sterol esters and triacylglycerols (TAGs) [1, 2]. Initially recognized in specialized cells, such as adipocytes, it is now clear that any cell has the ability to form LDs. Current models consi... |
10.1371/journal.pcbi.1003727 | Memory Capacity of Networks with Stochastic Binary Synapses | In standard attractor neural network models, specific patterns of activity are stored in the synaptic matrix, so that they become fixed point attractors of the network dynamics. The storage capacity of such networks has been quantified in two ways: the maximal number of patterns that can be stored, and the stored infor... | Two central hypotheses in neuroscience are that long-term memory is sustained by modifications of the connectivity of neural circuits, while short-term memory is sustained by persistent neuronal activity following the presentation of a stimulus. These two hypotheses have been substantiated by several decades of electro... | Attractor neural networks have been proposed as long-term memory storage devices [1], [2], [3]. In such networks, a pattern of activity (the set of firing rates of all neurons in the network) is said to be memorized if it is one of the stable states of the network dynamics. Specific patterns of activity become stable s... |
10.1371/journal.pntd.0000365 | Molecular and Behavioral Differentiation among Brazilian Populations of Lutzomyia longipalpis (Diptera: Psychodidae: Phlebotominae) | Lutzomyia longipalpis is the primary vector of American visceral leishmaniasis. There is strong evidence that L. longipalpis is a species complex, but until recently the existence of sibling species among Brazilian populations was considered a controversial issue. In addition, there is still no consensus regarding the ... | Lutzomyia longipalpis is the main vector of visceral leishmaniasis in the Americas. There is strong evidence that L. longipalpis is a species complex, but there is still no consensus regarding the number of species occurring in Brazil. We combined molecular and behavioral analyses of a number of L. longipalpis populati... | Cryptic speciation is an interesting and important issue to evolutionary biologists as organisms that are distinct in several ways can look the same even to specialist taxonomists, leading to false conclusions about their biology. Moreover, it also has practical implications for conservation management and in the ident... |
10.1371/journal.pntd.0001523 | A Novel G Protein-Coupled Receptor of Schistosoma mansoni (SmGPR-3) Is Activated by Dopamine and Is Widely Expressed in the Nervous System | Schistosomes have a well developed nervous system that coordinates virtually every activity of the parasite and therefore is considered to be a promising target for chemotherapeutic intervention. Neurotransmitter receptors, in particular those involved in neuromuscular control, are proven drug targets in other helminth... | Bloodflukes of the genus Schistosoma are the causative agents of human schistosomiasis, a debilitating disease that afflicts over 200 million people worldwide. There is no vaccine for schistosomiasis and treatment relies heavily on a single drug, praziquantel. Recent reports of praziquantel resistance raise concerns ab... | The bloodfluke Schistosoma mansoni is one of three species of schistosomes that cause significant disease in humans. Approximately 200 million people are infected and another 600 million are at risk of infection. Over 90% of all human schistosomiasis is due to S. mansoni. This species exists in Africa, the Middle East,... |
10.1371/journal.pcbi.1000713 | Estimating the Stoichiometry of HIV Neutralization | HIV-1 virions infect target cells by first establishing contact between envelope glycoprotein trimers on the virion's surface and CD4 receptors on a target cell, recruiting co-receptors, fusing with the cell membrane and finally releasing the genetic material into the target cell. Specific experimental setups allow the... | A large part of the research on the Human Immunodeficiency Virus focuses on how virus particles attach and enter their target cells, and how entry can be inhibited by antibodies or antiretroviral drugs. Because virus particles are too small to be observed in action the inference of the details of HIV entry has to be in... | Virions of human immunodeficiency virus (HIV) are coated by a lipid bilayer. Trimers of the dimeric envelope proteins (Envs) gp120 and gp41 are inserted into this membrane [3]–[5]. These trimers, often also referred to with the more general term spikes, can bind to CD4 receptors [6],[7]. After successful engagement of ... |
10.1371/journal.pcbi.1003311 | Stochastic Computations in Cortical Microcircuit Models | Experimental data from neuroscience suggest that a substantial amount of knowledge is stored in the brain in the form of probability distributions over network states and trajectories of network states. We provide a theoretical foundation for this hypothesis by showing that even very detailed models for cortical microc... | The brain has not only the capability to process sensory input, but it can also produce predictions, imaginations, and solve problems that combine learned knowledge with information about a new scenario. But although these more complex information processing capabilities lie at the heart of human intelligence, we still... | The question whether brain computations are inherently deterministic or inherently stochastic is obviously of fundamental importance. Numerous experimental data highlight inherently stochastic aspects of neurons, synapses and networks of neurons on virtually all spatial and temporal scales that have been examined [1]–[... |
10.1371/journal.pgen.1004467 | MDRL lncRNA Regulates the Processing of miR-484 Primary Transcript by Targeting miR-361 | Long noncoding RNAs (lncRNAs) are emerging as new players in gene regulation, but whether lncRNAs operate in the processing of miRNA primary transcript is unclear. Also, whether lncRNAs are involved in the regulation of the mitochondrial network remains to be elucidated. Here, we report that a long noncoding RNA, named... | Long non-coding RNAs (lncRNAs) have been shown to be involved in a wide range of biological functions. However, studies linking individual lncRNA to the mitochondrial fission program remain scarce. Also, it remains unknown whether lncRNAs can operate in the processing of miRNA primary transcript. Here, we provide causa... | Long non-coding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides. A number of lncRNAs have been shown to be involved in a wide range of biological functions including RNA processing [1], gene transcription regulation [2], miRNAs' host genes [3], modulation of apoptosis and invasion [4], mar... |
10.1371/journal.pgen.1002042 | DNA Damage, Somatic Aneuploidy, and Malignant Sarcoma Susceptibility in Muscular Dystrophies | Albeit genetically highly heterogeneous, muscular dystrophies (MDs) share a convergent pathology leading to muscle wasting accompanied by proliferation of fibrous and fatty tissue, suggesting a common MD–pathomechanism. Here we show that mutations in muscular dystrophy genes (Dmd, Dysf, Capn3, Large) lead to the sponta... | All kinds of muscular dystrophies (MDs) are characterized by progressive muscle wasting due to life-long proliferation of precursor cells of myo- (muscle), fibro- (connective tissue), and lipogenic (fat) origin. Despite discovery of many MD genes over the past 25 years, MDs still represent debilitating, incurable disea... | Muscular dystrophies (MDs) comprise a group of inherited disorders, characterized by progressive muscle wasting and weakness, frequently causing premature death due to lack of effective therapies. More than 150 years ago, Edward Meryon was the first to characterize the detrimental “fatty degeneration of the voluntary m... |
10.1371/journal.ppat.1001282 | The C-Terminus of Toxoplasma RON2 Provides the Crucial Link between AMA1 and the Host-Associated Invasion Complex | Host cell invasion by apicomplexan parasites requires formation of the moving junction (MJ), a ring-like apposition between the parasite and host plasma membranes that the parasite migrates through during entry. The Toxoplasma MJ is a secreted complex including TgAMA1, a transmembrane protein on the parasite surface, a... | Invasion by the obligate intracellular parasites, Toxoplasma and Plasmodium, requires the formation of a ring of contact between parasite and host plasma membranes, the so-called moving junction (MJ), that the parasite migrates through during entry. The MJ is a complex of secreted parasite proteins including AMA1, on t... | Protozoan parasites are a significant cause of morbidity and mortality in humans worldwide. Among the most devastating and globally prevalent parasites are the members of the phylum Apicomplexa, which includes the etiological agents of malaria, cryptosporidiosis, and toxoplasmosis. Apicomplexans are related by an anter... |
10.1371/journal.pcbi.1000134 | Predicting Human Nucleosome Occupancy from Primary Sequence | Nucleosomes are the fundamental repeating unit of chromatin and comprise the structural building blocks of the living eukaryotic genome. Micrococcal nuclease (MNase) has long been used to delineate nucleosomal organization. Microarray-based nucleosome mapping experiments in yeast chromatin have revealed regularly-space... | Inside the nucleus, DNA is wrapped into a complex molecular structure called chromatin, whose fundamental unit is ∼150 bp of DNA organized around the eight-histone protein complex known as the nucleosome. Understanding the local organization of nucleosomes is critical for understanding how chromatin impacts gene regula... | Nucleosomes are the fundamental repeating unit of chromatin, and the positioning of nucleosomes along the genome has been a topic of long-standing interest. The prevailing “statistical positioning” theory of nucleosome organization was first proposed by Kornberg more than 25 years ago [1]. This theory, for which consid... |
10.1371/journal.pgen.1000152 | The Identification of Zebrafish Mutants Showing Alterations in Senescence-Associated Biomarkers | There is an interesting overlap of function in a wide range of organisms between genes that modulate the stress responses and those that regulate aging phenotypes and, in some cases, lifespan. We have therefore screened mutagenized zebrafish embryos for the altered expression of a stress biomarker, senescence-associate... | By performing genetic mutant screens using senescence-associated biomarkers, we show that the zebrafish is a tractable model system for the study of aging. In vertebrate organisms, it has not previously been possible to carry out systematic screens for genes that are important for stress responses and aging in an unbia... | Chronic oxidative stress has been shown to reduce lifespan in many species and lead to accelerated aging [1]–[3]. It has also been reported that oxidative stress is involved in neurodegeneration, sarcopenia and other muscle wasting conditions, which are accompanied by multiple aging symptoms [4]–[6]. Reactive oxygen sp... |
10.1371/journal.ppat.1003669 | Cross-Serotype Immunity Induced by Immunization with a Conserved Rhinovirus Capsid Protein | Human rhinovirus (RV) infections are the principle cause of common colds and precipitate asthma and COPD exacerbations. There is currently no RV vaccine, largely due to the existence of ∼150 strains. We aimed to define highly conserved areas of the RV proteome and test their usefulness as candidate antigens for a broad... | Human rhinovirus infections cause the majority of common colds as well as asthma and chronic obstructive pulmonary disease (COPD) exacerbations. The disease burden attributable to rhinoviruses is therefore huge. Despite this and the fact that human rhinoviruses were discovered over 50 years ago, there are currently no ... | Human rhinovirus (RV) infections are the most frequent cause of the common cold [1] and are highly associated with exacerbations of asthma and COPD [2], [3], [4]. Despite the great disease burden and healthcare costs therefore attributable to RV infections, there is currently neither a vaccine nor specific anti-viral t... |
10.1371/journal.pgen.1002322 | A Phenomics-Based Strategy Identifies Loci on APOC1, BRAP, and PLCG1 Associated with Metabolic Syndrome Phenotype Domains | Despite evidence of the clustering of metabolic syndrome components, current approaches for identifying unifying genetic mechanisms typically evaluate clinical categories that do not provide adequate etiological information. Here, we used data from 19,486 European American and 6,287 African American Candidate Gene Asso... | The metabolic syndrome represents a clustering of metabolic phenotypes (e.g. elevated blood pressure, cholesterol levels, and plasma glucose, as well as abdominal obesity) and is associated with an increased risk of atherosclerosis and type 2 diabetes. Although multiple genes influencing the specific metabolic syndrome... | The metabolic syndrome represents metabolic dysregulation expressed as the clustering of several physiologic risk factors and is associated with an increased risk of atherosclerosis and type 2 diabetes [1]. The core metabolic syndrome domains are abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, ele... |
10.1371/journal.ppat.1006284 | Arabidopsis leucine-rich repeat receptor–like kinase NILR1 is required for induction of innate immunity to parasitic nematodes | Plant-parasitic nematodes are destructive pests causing losses of billions of dollars annually. An effective plant defence against pathogens relies on the recognition of pathogen-associated molecular patterns (PAMPs) by surface-localised receptors leading to the activation of PAMP-triggered immunity (PTI). Extensive st... | Host perception of pathogens via receptors leads to the activation of antimicrobial defence responses in all multicellular organisms, including plants. Plant-parasitic nematodes cause significant yield losses in agriculture; therefore resistance is an important trait in crop breeding. However, not much is known about t... | Plant-parasitic nematodes attack the majority of economically significant crops, as shown by international surveys indicating an overall yield loss of 12%. In some crops, such as banana, a loss of up to 30% has been reported. Losses amount to $100 billion annually worldwide [1]. The economically most important nematode... |
10.1371/journal.pntd.0001395 | Ebola Virus Glycoprotein Needs an Additional Trigger, beyond Proteolytic Priming for Membrane Fusion | Ebolavirus belongs to the family filoviridae and causes severe hemorrhagic fever in humans with 50–90% lethality. Detailed understanding of how the viruses attach to and enter new host cells is critical to development of medical interventions. The virus displays a trimeric glycoprotein (GP1,2) on its surface that is so... | Ebolavirus causes often fatal hemorrhagic fever in humans and nonhuman primates. During infection, the virus is internalized into the low pH endosomes prior to the delivery of viral RNA to the infected cell. Cleavage by endosomal cathepsins of the heavily glycosylated mucin-like domain and glycan cap from the ebolaviru... | Ebolaviruses cause severe hemorrhagic fever in humans and non-human primates with 50–90% lethality. No specific vaccines or treatments for ebolavirus infection have yet approved for human use [1]–[5]. Among the five different members of the ebolavirus genus, Zaire ebolavirus (ZEBOV) and Sudan ebolavirus (SEBOV) are the... |
10.1371/journal.pntd.0001411 | Targeting the Wolbachia Cell Division Protein FtsZ as a New Approach for Antifilarial Therapy | The use of antibiotics targeting the obligate bacterial endosymbiont Wolbachia of filarial parasites has been validated as an approach for controlling filarial infection in animals and humans. Availability of genomic sequences for the Wolbachia (wBm) present in the human filarial parasite Brugia malayi has enabled geno... | Filarial nematode parasites are responsible for a number of devastating diseases in humans and animals. These include lymphatic filariasis and onchocerciasis that afflict 150 million people in the tropics and threaten the health of over one billion. The parasites possess intracellular bacteria, Wolbachia, which are nee... | Filarial nematode parasites are responsible for a number of devastating diseases in humans and animals. These include lymphatic filariasis and onchocerciasis that afflict 150 million people in the tropics and threaten the health of over one billion. Unlike other nematodes, the majority of filarial species are infected ... |
10.1371/journal.pgen.1000727 | The Rts1 Regulatory Subunit of Protein Phosphatase 2A Is Required for Control of G1 Cyclin Transcription and Nutrient Modulation of Cell Size | The key molecular event that marks entry into the cell cycle is transcription of G1 cyclins, which bind and activate cyclin-dependent kinases. In yeast cells, initiation of G1 cyclin transcription is linked to achievement of a critical cell size, which contributes to cell-size homeostasis. The critical cell size is mod... | A critical point in the cell cycle occurs in G1 phase, when cells must decide whether to enter a new round of cell division. At this time, cells assess nutrient availability to ensure that they have sufficient resources to complete cell growth and division. Vertebrate cells also assess growth factors that control cell ... | Entry into the cell cycle is initiated by G1 cyclins, which bind and activate cyclin-dependent kinases [1]. There are two cyclin-dependent kinases in budding yeast that function during G1, called Cdk1 and Pho85, which are activated by numerous different G1 cyclins [1]. Cdk1 is activated by the cyclins Cln1, Cln2, and C... |
10.1371/journal.pcbi.1003966 | Evolution of Integrated Causal Structures in Animats Exposed to Environments of Increasing Complexity | Natural selection favors the evolution of brains that can capture fitness-relevant features of the environment's causal structure. We investigated the evolution of small, adaptive logic-gate networks (“animats”) in task environments where falling blocks of different sizes have to be caught or avoided in a ‘Tetris-like’... | The capacity to integrate information is a prominent feature of biological brains and has been related to cognitive flexibility as well as consciousness. To investigate how environment complexity affects the capacity for information integration, we simulated the evolution of artificial organisms (“animats”) controlled ... | Many studies have sought to elucidate the role of information in evolution [1]–[4], its relation to fitness [5]–[7], and how information about the environment is acquired and inherited by an organism [8], [9]. Common to most current approaches to characterize and quantify information in biology is the notion that biolo... |
10.1371/journal.ppat.1006918 | Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues | The malaria-causing blood stage of Plasmodium falciparum requires extracellular pantothenate for proliferation. The parasite converts pantothenate into coenzyme A (CoA) via five enzymes, the first being a pantothenate kinase (PfPanK). Multiple antiplasmodial pantothenate analogues, including pantothenol and CJ-15,801, ... | The coenzyme A (CoA) biosynthetic pathway is under investigation as a target for the development of drugs aimed at several infectious agents, including malaria parasites. To synthesise CoA, the parasite scavenges the essential precursor pantothenate (vitamin B5). Several pantothenate analogues possess potent (nM) activ... | In recent years, the effort to roll back malaria has shown encouraging progress through the increased use of insecticide-treated mosquito nets, improved diagnostics and artemisinin-based combination chemotherapies (ACTs) [1]. Evidence of this includes the decreasing worldwide malaria incidence (266 million cases in 200... |
10.1371/journal.ppat.1003231 | Enterovirus 71 Protease 2Apro Targets MAVS to Inhibit Anti-Viral Type I Interferon Responses | Enterovirus 71 (EV71) is the major causative pathogen of hand, foot, and mouth disease (HFMD). Its pathogenicity is not fully understood, but innate immune evasion is likely a key factor. Strategies to circumvent the initiation and effector phases of anti-viral innate immunity are well known; less well known is whether... | Enterovirus 71 (EV71) is the causative pathogen of hand, foot, and mouth disease (HFMD). Since the 2008 outbreak of HFMD in Fuyang, Anhui province, China, HFMD has been a severe public health concern affecting children. The major obstacle hindering HFMD prevention and control efforts is the lack of targeted anti-viral ... | When viruses infect host cells, the innate immune response is activated as the first line of defense against viral invasion. Pathogen associated molecular patterns (PAMPs) are sensed by host pattern recognition receptors (PRRs), resulting the expression of type I interferon and proinflammatory cytokines [1], [2]. These... |
10.1371/journal.pgen.1004574 | Dopamine Signaling Leads to Loss of Polycomb Repression and Aberrant Gene Activation in Experimental Parkinsonism | Polycomb group (PcG) proteins bind to and repress genes in embryonic stem cells through lineage commitment to the terminal differentiated state. PcG repressed genes are commonly characterized by the presence of the epigenetic histone mark H3K27me3, catalyzed by the Polycomb repressive complex 2. Here, we present in viv... | In Parkinson's disease (PD) the motor impairment produced by the progressive death of midbrain dopaminergic neurons is commonly treated with the dopamine precursor, L-DOPA. Utilizing a mouse model of PD, we show that L-DOPA, via activation of dopamine D1 receptors, promotes the expression of genes normally repressed by... | An emerging concept in neurobiology is that many mechanisms implicated in chromatin remodeling and developmental processes retain their plasticity in the adult brain. Indeed, a number of environmental stimuli are known to generate chromatin modifications that have been causally linked to synaptic plasticity and associa... |
10.1371/journal.pcbi.1003556 | Sensing Membrane Stresses by Protein Insertions | Protein domains shallowly inserting into the membrane matrix are ubiquitous in peripheral membrane proteins involved in various processes of intracellular membrane shaping and remodeling. It has been suggested that these domains sense membrane curvature through their preferable binding to strongly curved membranes, the... | Selective targeting of soluble proteins to cellular membranes relies on different mechanisms such as receptor-mediated recruitment or direct binding to specific lipids. A new paradigm has been recently proposed, according to which membrane binding of some proteins is driven by the geometrical and physical properties of... | Lipid bilayers serving as matrices of biological membranes bear internal elastic stresses. These stresses can be generated by external forces applied to the membrane surface and driving overall membrane deformations such as generation of membrane curvature and stretching-compression of the membrane area [1], and/or by ... |
10.1371/journal.pntd.0001645 | Dengue-1 Envelope Protein Domain III along with PELC and CpG Oligodeoxynucleotides Synergistically Enhances Immune Responses | The major weaknesses of subunit vaccines are their low immunogenicity and poor efficacy. Adjuvants can help to overcome some of these inherent defects with subunit vaccines. Here, we evaluated the efficacy of the newly developed water-in-oil-in-water multiphase emulsion system, termed PELC, in potentiating the protecti... | Dengue is a mosquito-borne disease. Infection of dengue virus can cause clinical manifestations ranging from self-limiting dengue fever to potentially life-threatening dengue hemorrhagic fever or dengue shock syndrome. In recent years, dengue has spread to most tropical and subtropical areas, making it a global health ... | Dengue is the most important mosquito-borne flavivirus disease. People living in the tropical and subtropical areas are at risk of dengue virus infection, and more than 50 million dengue infected cases occur worldwide each year [1], [2]. Vaccine inoculation is a cost-effective way of combating the threat of infectious ... |
10.1371/journal.ppat.1006705 | Membrane alterations induced by nonstructural proteins of human norovirus | Human noroviruses (huNoV) are the most frequent cause of non-bacterial acute gastroenteritis worldwide, particularly genogroup II genotype 4 (GII.4) variants. The viral nonstructural (NS) proteins encoded by the ORF1 polyprotein induce vesical clusters harboring the viral replication sites. Little is known so far about... | Positive-strand RNA viruses induce membrane alterations harboring the viral replication complexes. In the case of human noroviruses (huNoV), the major cause of acute viral gastroenteritis, these are induced by the ORF1 polyprotein, which is post-translationally processed into the functional nonstructural (NS) proteins.... | Human noroviruses (huNoV) are the most frequent causative agent of acute gastroenteritis worldwide, responsible for over 30% of all cases, subsequently resulting in over 200,000 deaths per annum [1]. Still, no vaccine or specific antiviral therapy is available to counteract huNoV infections. Noroviruses are divided int... |
10.1371/journal.ppat.1006808 | Biogenesis of the mitochondrial DNA inheritance machinery in the mitochondrial outer membrane of Trypanosoma brucei | Mitochondria cannot form de novo but require mechanisms that mediate their inheritance to daughter cells. The parasitic protozoan Trypanosoma brucei has a single mitochondrion with a single-unit genome that is physically connected across the two mitochondrial membranes with the basal body of the flagellum. This connect... | Trypanosoma brucei and its relatives are important human and animal pathogens. Unlike most other eukaryotes trypanosomes have a single mitochondrion with a single unit mitochondrial genome, termed the kinetoplast DNA (kDNA). During each cell cycle the kDNA is replicated and subsequently segregated into the two organell... | Mitochondria are a hallmark of eukaryotic cells [1]. They derive from an endosymbiotic event between an archaeal host cell and an α-proteobacterium. The bacterial symbiont was subsequently converted into an organelle. Continued evolution since the origin of the mitochondrion, approximately 1.5–2 billion years ago, has ... |
10.1371/journal.ppat.1008035 | Phytoplasma SAP11 effector destabilization of TCP transcription factors differentially impact development and defence of Arabidopsis versus maize | Phytoplasmas are insect-transmitted bacterial pathogens that colonize a wide range of plant species, including vegetable and cereal crops, and herbaceous and woody ornamentals. Phytoplasma-infected plants often show dramatic symptoms, including proliferation of shoots (witch’s brooms), changes in leaf shapes and produc... | Phytoplasmas are parasites of a wide range of plant species and are transmitted by sap-feeding insects, such as leafhoppers. Phytoplasma-infected plants are often easily recognized because of their dramatic symptoms, including shoot proliferations (witch’s brooms) and altered leaf shapes, leading to severe economic los... | Phytoplasmas (“Candidatus (Ca.) Phytoplasma”) are economically important plant pathogens that infect a broad range of plant species. The more than 1000 phytoplasmas described so far comprise three distinct clades within a monophyletic group of the class Mollicutes that are characterized by the lack of a bacterial cell ... |
10.1371/journal.ppat.1001238 | Interaction of c-Cbl with Myosin IIA Regulates Bleb Associated Macropinocytosis of Kaposi's Sarcoma-Associated Herpesvirus | KSHV is etiologically associated with Kaposi's sarcoma (KS), an angioproliferative endothelial cell malignancy. Macropinocytosis is the predominant mode of in vitro entry of KSHV into its natural target cells, human dermal microvascular endothelial (HMVEC-d) cells. Although macropinocytosis is known to be a major route... | KSHV is etiologically associated with Kaposi's sarcoma (KS), the most common AIDS related neoplasm. The first key step in KSHV infection is its initial contact with target cells and entry. While it is known that KSHV uses macropinocytosis for its infectious entry into its natural target cells, HMVEC-d cells, we know li... | KSHV is etiologically associated with Kaposi's sarcoma (KS), the most common AIDS related malignancy, as well as with two lymphoproliferative diseases, primary effusion lymphoma (PEL) and multicentric Castleman's disease [1], [2]. KSHV infects a variety of target cells both in vivo and in vitro. Entry into the target c... |
10.1371/journal.pntd.0004123 | Spatial Analysis of Anthropogenic Landscape Disturbance and Buruli Ulcer Disease in Benin | Land use and land cover (LULC) change is one anthropogenic disturbance linked to infectious disease emergence. Current research has focused largely on wildlife and vector-borne zoonotic diseases, neglecting to investigate landscape disturbance and environmental bacterial infections. One example is Buruli ulcer (BU) dis... | Changes in land and use and land cover can impact ecosystems in unexpected ways, including changes in habitat suitability for environmental pathogens. Several studies have investigated the impacts of human disturbance to the landscape and changes in the composition of vector, host, and reservoir species in an altered a... | Land use and land cover (LULC) change at multiple spatial and temporal scales is one anthropogenic disturbance linked to infectious disease emergence [1]. Anthropogenic activities with major impacts on LULC are land degradation, including agriculture intensification and water projects, urbanization, and deforestation [... |
10.1371/journal.pmed.1002674 | Prediction of myopia development among Chinese school-aged children using refraction data from electronic medical records: A retrospective, multicentre machine learning study | Electronic medical records provide large-scale real-world clinical data for use in developing clinical decision systems. However, sophisticated methodology and analytical skills are required to handle the large-scale datasets necessary for the optimisation of prediction accuracy. Myopia is a common cause of vision loss... | Myopia has reached epidemic levels among young adults in East and Southeast Asia, affecting an estimated 80%–90% of high school graduates, with approximately 20% of them having high myopia. Various interventions, including atropine eyedrops and orthokeratology, have been proposed to control myopia progression; however,... | Myopia, the most common visual impairment in children, has increased markedly in Chinese school-aged children in recent years. This “myopia boom” is a significant international public concern, impacting study performance and daily life [1]. The risk of children developing high myopia has become a great concern among pa... |
10.1371/journal.pgen.1004314 | Whole Exome Re-Sequencing Implicates CCDC38 and Cilia Structure and Function in Resistance to Smoking Related Airflow Obstruction | Chronic obstructive pulmonary disease (COPD) is a leading cause of global morbidity and mortality and, whilst smoking remains the single most important risk factor, COPD risk is heritable. Of 26 independent genomic regions showing association with lung function in genome-wide association studies, eleven have been repor... | Very large genome-wide association studies in general population cohorts have successfully identified at least 26 genes or gene regions associated with lung function and a number of these also show association with chronic obstructive pulmonary disease (COPD). However, these findings explain a small proportion of the h... | Chronic obstructive pulmonary disease (COPD) is a leading cause of global morbidity and mortality [1] and whilst smoking remains the single most important risk factor, it is also clear that COPD risk is heritable [2]. The genetics underlying COPD are still not fully understood although genome-wide association studies h... |
10.1371/journal.ppat.1004346 | The GAP Activity of Type III Effector YopE Triggers Killing of Yersinia in Macrophages | The mammalian immune system has the ability to discriminate between pathogens and innocuous microbes by detecting conserved molecular patterns. In addition to conserved microbial patterns, the mammalian immune system may recognize distinct pathogen-induced processes through a mechanism which is poorly understood. Previ... | The type III secretion system (T3SS) is a macromolecular protein export pathway found in gram-negative bacteria. It delivers bacterial toxins into eukaryotic cells to promote pathogenic infection. T3SSs and the bacterial toxins delivered are critical arsenals for many bacterial pathogens of clinical significance, such ... | Innate immunity provides an early and critical protection against pathogenic infection. In the dominant paradigm of innate immunity, host cells detect pathogens by recognition of “microorganism-associated molecular patterns” (MAMPs) via pattern recognition receptors (PRRs) [1]. However, MAMPs, such as flagellin or lipo... |
10.1371/journal.pgen.1003684 | A Model-Based Analysis of GC-Biased Gene Conversion in the Human and Chimpanzee Genomes | GC-biased gene conversion (gBGC) is a recombination-associated process that favors the fixation of G/C alleles over A/T alleles. In mammals, gBGC is hypothesized to contribute to variation in GC content, rapidly evolving sequences, and the fixation of deleterious mutations, but its prevalence and general functional con... | Interpreting patterns of DNA sequence variation in the genomes of closely related species is critically important for understanding the causes and functional effects of nucleotide substitutions. Classical models describe patterns of substitution in terms of the fundamental forces of mutation, recombination, neutral dri... | Gene conversion is the nonreciprocal exchange of genetic information from a ‘donor’ to an ‘acceptor’ sequence, primarily resulting from the repair of mismatched bases in heteroduplex recombination intermediates during meiosis [1]. In many cases, the process of resolving mismatches between G/C (guanine or cytosine; deno... |
10.1371/journal.pntd.0004322 | Intradermal Immunization of Leishmania donovani Centrin Knock-Out Parasites in Combination with Salivary Protein LJM19 from Sand Fly Vector Induces a Durable Protective Immune Response in Hamsters | Visceral leishmaniasis (VL) is a neglected tropical disease and is fatal if untreated. There is no vaccine available against leishmaniasis. The majority of patients with cutaneous leishmaniasis (CL) or VL develop a long-term protective immunity after cure from infection, which indicates that development of an effective... | Leishmaniasis is a disease with a wide spectrum of clinical manifestations caused by different species of protozoa belonging to the Leishmania genus that are transmitted by sand fly vectors. Visceral infections of Leishmania cause significant mortality and morbidity and development of a vaccine to prevent leishmaniasis... | Leishmaniasis is a disease with a wide spectrum of clinical manifestations caused by different species of protozoa belonging to the Leishmania genus that are transmitted by sand fly vectors [1]. The disease causes high morbidity and significant mortality throughout the world, where 350 million people in 98 countries ar... |
10.1371/journal.pbio.2005359 | Comparative genomics and the nature of placozoan species | Placozoans are a phylum of nonbilaterian marine animals currently represented by a single described species, Trichoplax adhaerens, Schulze 1883. Placozoans arguably show the simplest animal morphology, which is identical among isolates collected worldwide, despite an apparently sizeable genetic diversity within the phy... | Placozoans are a phylum of tiny (approximately 1 mm) marine animals that are found worldwide in temperate and tropical waters. They are characterized by morphological simplicity, with only a handful of cell types, no neurons, no tissue organization, and even no axial polarity. Since the original description of Trichopl... | Placozoans Grell, 1971, are small, benthic marine animals found worldwide in various habitats [1–6]. To date, only a single species has been described, Trichoplax adhaerens Schulze 1883. Animals are flat and have a typically disc-like morphology but have the capacity to change shape [7–9]. The lack of symmetry axes, ne... |
10.1371/journal.pntd.0006772 | Ligand binding properties of two Brugia malayi fatty acid and retinol (FAR) binding proteins and their vaccine efficacies against challenge infection in gerbils | Parasitic nematodes produce an unusual class of fatty acid and retinol (FAR)-binding proteins that may scavenge host fatty acids and retinoids. Two FARs from Brugia malayi (Bm-FAR-1 and Bm-FAR-2) were expressed as recombinant proteins, and their ligand binding, structural characteristics, and immunogenicities examined.... | Human lymphatic filariasis (LF) and river blindness (onchocerciasis) are highly debilitating neglected tropical diseases. As with all parasitic nematodes, Wuchereria bancrofti, Brugia malayi and Brugia timori, the etiological agents of LF and Onchocerca volvulus the causative agent of river blindness, possess limited l... | Human lymphatic filariasis (LF) and river blindness (onchocerciasis) are highly debilitating diseases in tropical developing countries with an estimated disease prevalence of 29.38 and 14.65 million cases that cause 1.2 and 0.96 million years lived with disability (YLD), respectively [1]. As with all parasitic nematode... |
10.1371/journal.pbio.2000410 | Selection for Mitochondrial Quality Drives Evolution of the Germline | The origin of the germline–soma distinction is a fundamental unsolved question. Plants and basal metazoans do not have a germline but generate gametes from pluripotent stem cells in somatic tissues (somatic gametogenesis). In contrast, most bilaterians sequester a dedicated germline early in development. We develop an ... | Mammalian germ cells (eggs and sperm) are immortal in the sense that they propagate successive generations. In contrast, somatic (body) cells do not persist to the next generation. Yet neither plants nor basal animals such as sponges and corals have a germline; they simply form gametes from stem cells in adult tissues.... | In distinguishing between the germline and soma, Weismann argued that the division of labour enabled the specialization of cells in somatic tissues, ultimately permitting greater organismal complexity [1]. In contrast, germline cells alone retain the capacity to provide genetic information for future generations and ne... |
10.1371/journal.pgen.1007886 | Narya, a RING finger domain-containing protein, is required for meiotic DNA double-strand break formation and crossover maturation in Drosophila melanogaster | Meiotic recombination, which is necessary to ensure that homologous chromosomes segregate properly, begins with the induction of meiotic DNA double-strand breaks (DSBs) and ends with the repair of a subset of those breaks into crossovers. Here we investigate the roles of two paralogous genes, CG12200 and CG31053, which... | Errors in chromosome segregation during meiosis are the leading cause of miscarriages and can result in genetic abnormalities like Down syndrome or Turner syndrome. For chromosomes to segregate faithfully, they must recombine with their homolog during the early steps of meiosis. An essential component of the process of... | Homologous recombination is an essential feature of meiosis and is required to ensure proper chromosome segregation. Although several core aspects of meiosis are highly conserved, many of the proteins and structures that mediate meiosis have features that are unique to each model organism. This is most apparent when co... |
10.1371/journal.pcbi.1003756 | Blind Predictions of DNA and RNA Tweezers Experiments with Force and Torque | Single-molecule tweezers measurements of double-stranded nucleic acids (dsDNA and dsRNA) provide unprecedented opportunities to dissect how these fundamental molecules respond to forces and torques analogous to those applied by topoisomerases, viral capsids, and other biological partners. However, tweezers data are sti... | DNA and RNA are fundamental molecules in the central dogma of molecular biology. Many biological behaviors of double-stranded DNA and RNA – including transcription/translation by proteins and packaging into compact structures – depend on their ability to flex and twist. Single-molecule tweezers now provide accurate mec... | Nucleic acids play central roles in biological processes including transcription, translation, catalysis and regulation of gene expression [1], [2]. Double-stranded RNA and DNA (dsRNA and dsDNA) stretch and twist when interacting with proteins [3], [4] and when forming compact structures such as nucleosomes [5] and pac... |
10.1371/journal.pbio.2006548 | Visual attention is not deployed at the endpoint of averaging saccades | The premotor theory of attention postulates that spatial attention arises from the activation of saccade areas and that the deployment of attention is the consequence of motor programming. Yet attentional and oculomotor processes have been shown to be dissociable at the neuronal level in covert attention tasks. To inve... | The premotor theory of attention postulates that spatial visual attention is a consequence of the brain activity that controls eye movement. Indeed, attention and eye movement share overlapping brain networks, and attention is deployed at the target of an eye movement (saccade) even before the eyes start to move. But i... | To process information from our rich visual environment, we evolved with attentional mechanisms allowing us to discriminate which flow to account for and which to ignore [1,2]. For example, we can extract salient saccade targets from a cluttered visual scene to later examine their contents with precise foveal vision [3... |
10.1371/journal.pcbi.1002930 | High Prevalence of Multistability of Rest States and Bursting in a Database of a Model Neuron | Flexibility in neuronal circuits has its roots in the dynamical richness of their neurons. Depending on their membrane properties single neurons can produce a plethora of activity regimes including silence, spiking and bursting. What is less appreciated is that these regimes can coexist with each other so that a transi... | It is often not appreciated that different activity regimes can coexist with each other in a given neuron so that a transient stimulus can cause a persistent change of activity. Such multistability of the neuronal dynamics has in fact been shown in a variety of neurons and can play either a functional role or present a... | Recent studies of neuronal networks of identifiable neurons have shown that the same neuron type can significantly vary in membrane properties from animal to animal. The biophysical characteristics of the single neurons performing the same task can be orders-of-magnitude different [1]–[4]. This fact testifies to the gr... |
10.1371/journal.ppat.1004311 | Early Mucosal Sensing of SIV Infection by Paneth Cells Induces IL-1β Production and Initiates Gut Epithelial Disruption | HIV causes rapid CD4+ T cell depletion in the gut mucosa, resulting in immune deficiency and defects in the intestinal epithelial barrier. Breakdown in gut barrier integrity is linked to chronic inflammation and disease progression. However, the early effects of HIV on the gut epithelium, prior to the CD4+ T cell deple... | The loss of intestinal CD4+ T cells in chronic HIV infection is associated with impaired immune responses to pathogens, aberrant immune activation, and defects in the gut epithelial barrier. While much is known about the pathogenesis of HIV in chronic disease, less is known about the defects that occur prior to gut CD4... | Chronic inflammation and disease progression in HIV infection is attributed to dysfunction in the structure of the intestinal epithelial barrier as well as impairment of the mucosal immune response resulting in increased microbial translocation [1]–[3], dysbiosis of the gut microbiome [4]–[6], and enteric opportunistic... |
10.1371/journal.ppat.1002218 | The Fecal Viral Flora of Wild Rodents | The frequent interactions of rodents with humans make them a common source of zoonotic infections. To obtain an initial unbiased measure of the viral diversity in the enteric tract of wild rodents we sequenced partially purified, randomly amplified viral RNA and DNA in the feces of 105 wild rodents (mouse, vole, and ra... | Rodents are the natural reservoir of numerous zoonotic viruses causing serious diseases in humans. We used an unbiased metagenomic approach to characterize the viral diversity in rodent feces. In addition to diet-derived insect and plant viruses mammalian viral sequences were abundant and diverse. Most notably, multipl... | The order Rodentia is the single largest group of mammalian species accounting for 40% of all mammal species [1]. There are ca 2200 living rodent species, including mice, rats, voles, squirrels, prairie dogs, beavers, chipmunks, and guinea pigs. Many rodents have mixed diets but some eat mostly seeds or green vegetatio... |
10.1371/journal.pntd.0003098 | Non-Participation during Azithromycin Mass Treatment for Trachoma in The Gambia: Heterogeneity and Risk Factors | There is concern that untreated individuals in mass drug administration (MDA) programs for neglected tropical diseases can reduce the impact of elimination efforts by maintaining a source of transmission and re-infection.
Treatment receipt was recorded against the community census during three MDAs with azithromycin fo... | As the target year for Global Elimination of Trachoma (GET2020) approaches, the scale up of mass drug administration (MDA) with azithromycin will lead to more endemic areas becoming low prevalence settings. In such areas, identification of those at highest risk of Chlamydia trachomatis infection and at highest risk of ... | Trachoma is a leading cause of preventable blindness in endemic areas [1]. Control is through the SAFE strategy [2], of which a key component is mass drug administration (MDA) with the antibiotic azithromycin. Entire communities are targeted during MDA in order to reach both pre-school and school aged children who form... |
10.1371/journal.ppat.1004071 | Histone Deacetylase Inhibitor Romidepsin Induces HIV Expression in CD4 T Cells from Patients on Suppressive Antiretroviral Therapy at Concentrations Achieved by Clinical Dosing | Persistent latent reservoir of replication-competent proviruses in memory CD4 T cells is a major obstacle to curing HIV infection. Pharmacological activation of HIV expression in latently infected cells is being explored as one of the strategies to deplete the latent HIV reservoir. In this study, we characterized the a... | Combination antiretroviral therapy has greatly improved the clinical outcome of HIV infection treatment. However, latent viral reservoirs established primarily in memory CD4 T cells persist even after long periods of suppressive antiretroviral therapy, which hinders the ability to achieve a prolonged drug-free remissio... | Combination antiretroviral therapy (cART) has dramatically improved the life expectancy and health of patients infected with HIV. In the setting of controlled clinical trials with optimal cART, up to 90% of treatment-naïve patients can achieve undetectable virus in plasma and normalization of CD4 T-cell levels [1], [2]... |
10.1371/journal.pcbi.1005641 | Classification and analysis of a large collection of in vivo bioassay descriptions | Testing potential drug treatments in animal disease models is a decisive step of all preclinical drug discovery programs. Yet, despite the importance of such experiments for translational medicine, there have been relatively few efforts to comprehensively and consistently analyze the data produced by in vivo bioassays.... | Before exposing human populations to potential drug treatments, novel compounds are tested in living non-human animals—arguably the most physiologically relevant model system known to drug discovery. Yet, high failure rates for new therapies in the clinic demonstrate a growing need for better understanding of the relev... | Testing potential therapeutic compounds in animal disease and safety models is a crucial part of preclinical drug discovery [1]. Although many in vitro methods have been developed to rapidly screen candidate molecules, no such simple assay system can recapitulate the complexities and dynamics of a living organism [2]. ... |
10.1371/journal.pntd.0005669 | Identification of antigenic Sarcoptes scabiei proteins for use in a diagnostic test and of non-antigenic proteins that may be immunomodulatory | Scabies, caused by the mite, Sarcoptes scabiei, infects millions of humans, and many wild and domestic mammals. Scabies mites burrow in the lower stratum corneum of the epidermis of the skin and are the source of substances that are antigenic or modulate aspects of the protective response of the host. Ordinary scabies ... | Scabies, caused by the mite, Sarcoptes scabiei, infects millions of humans, and many wild and domestic mammals. Scabies mites burrow in the lower stratum corneum of the epidermis of the skin and are the source of substances that are antigenic or modulate aspects of the protective response of the host. Ordinary scabies ... | Scabies is a worldwide disease that affects millions of humans, other species of primates, and many wild and domestic mammals. It is caused by the itch mite, Sarcoptes scabiei, that burrows in the lower stratum corneum of the epidermis of the skin. Scabies mites are the source of substances that modulate certain aspect... |
10.1371/journal.pgen.1008107 | Risk of spontaneous preterm birth and fetal growth associates with fetal SLIT2 | Spontaneous preterm birth (SPTB) is the leading cause of neonatal death and morbidity worldwide. Both maternal and fetal genetic factors likely contribute to SPTB. We performed a genome-wide association study (GWAS) on a population of Finnish origin that included 247 infants with SPTB (gestational age [GA] < 36 weeks) ... | Worldwide, more than 10% of babies are born prematurely without effective means of prevention. Premature birth is associated with mortality and lifelong comorbidities. Aggregation of spontaneous preterm birth in certain families suggests that there are underlying genetic factors that predispose to preterm birth. Both m... | Preterm live births that take place before 37 completed weeks of gestation and even as early as 22–24 weeks are a global problem. Up to 11.1% (15 million babies) of all births worldwide occur prematurely, and approximately 45–50% of them are idiopathic or spontaneous [1–3]. Complications caused by preterm birth are the... |
10.1371/journal.ppat.1006329 | The host ubiquitin-dependent segregase VCP/p97 is required for the onset of human cytomegalovirus replication | The human cytomegalovirus major immediate early proteins IE1 and IE2 are critical drivers of virus replication and are considered pivotal in determining the balance between productive and latent infection. IE1 and IE2 are derived from the same primary transcript by alternative splicing and regulation of their expressio... | Viruses are obligate intracellular pathogens, meaning that they are completely dependent on the host cellular machinery to replicate. Identifying which host genes are necessary for virus replication extends our understanding of how viruses replicate, how cells function and provides potential targets for novel antiviral... | Human cytomegalovirus (HCMV) is a highly prevalent herpesvirus, infecting 30 to 100% of the global population depending on the socio-economic status. Although normally asymptomatic in healthy individuals, HCMV infection is a significant cause of morbidity and mortality in immunocompromised populations, individuals with... |
10.1371/journal.pgen.1006063 | Antimicrobial Functions of Lactoferrin Promote Genetic Conflicts in Ancient Primates and Modern Humans | Lactoferrin is a multifunctional mammalian immunity protein that limits microbial growth through sequestration of nutrient iron. Additionally, lactoferrin possesses cationic protein domains that directly bind and inhibit diverse microbes. The implications for these dual functions on lactoferrin evolution and genetic co... | Immunity genes can evolve rapidly in response to antagonism by microbial pathogens, but how the emergence of new protein functions impacts such evolutionary conflicts remains unclear. Here we have traced the evolutionary history of the lactoferrin gene in primates, which in addition to an ancient iron-binding function,... | Genetic conflicts between microbes and their hosts are an important source of evolutionary innovation [1]. Selective forces imposed by these antagonistic interactions can give rise to dramatic bouts of adaptive gene evolution through positive selection. J.B.S. Haldane originally speculated on the importance of infectio... |
10.1371/journal.pgen.1002752 | Adaptive Introgression across Species Boundaries in Heliconius Butterflies | It is widely documented that hybridisation occurs between many closely related species, but the importance of introgression in adaptive evolution remains unclear, especially in animals. Here, we have examined the role of introgressive hybridisation in transferring adaptations between mimetic Heliconius butterflies, tak... | Hybridisation occurs between many animal species, however its evolutionary relevance is still a matter of great debate. While some argue that hybridisation leads to maladaptive gene combinations, and therefore to an evolutionary dead end, others consider interspecific hybridisation as a process with great potential to ... | Closely related species often hybridise through incomplete barriers to gene flow, but the evolutionary consequences of such genetic interchange remain a matter of debate [1], [2], [3], [4], [5], [6]. This is primarily because hybridisation is considered unlikely to introduce useful genetic variation [1], [4], [5], [7].... |
10.1371/journal.pgen.1005093 | Male-Biased Aganglionic Megacolon in the TashT Mouse Line Due to Perturbation of Silencer Elements in a Large Gene Desert of Chromosome 10 | Neural crest cells (NCC) are a transient migratory cell population that generates diverse cell types such as neurons and glia of the enteric nervous system (ENS). Via an insertional mutation screen for loci affecting NCC development in mice, we identified one line—named TashT—that displays a partially penetrant agangli... | Hirschsprung’s disease (also known as aganglionic megacolon) is a severe congenital defect of the enteric nervous system (ENS) resulting in complete failure to pass stools. It is characterized by the absence of neural ganglia (aganglionosis) in the distal gut due to incomplete colonization of the embryonic intestines b... | The enteric nervous system (ENS) is the intrinsic neural network of the gastrointestinal tract. One of its essential roles is to regulate intestinal motility. The ENS is made up of interconnected neural ganglia, themselves composed of neurons and supporting glial cells, forming two main parallel networks: the submucosa... |
10.1371/journal.pgen.1007581 | Cooperation, cis-interactions, versatility and evolutionary plasticity of multiple cis-acting elements underlie krox20 hindbrain regulation | Cis-regulation plays an essential role in the control of gene expression, and is particularly complex and poorly understood for developmental genes, which are subject to multiple levels of modulation. In this study, we performed a global analysis of the cis-acting elements involved in the control of the zebrafish devel... | Animal development relies on the early delimitation of specific embryonic territories that will later participate in the formation of tissues and organs. This process is governed by sets of so-called developmental genes. The activities of the genes are themselves controlled by associated DNA sequences called enhancers.... | Enhancers are short, cis-acting regulatory elements that modulate transcription of target genes, relatively independently of their orientation or distance with respect to the promoter. They act as platforms to recruit multiple transcription factors [1] that interact with the transcription machinery at the promoter via ... |
10.1371/journal.pntd.0003772 | Modeling the Geographic Spread of Rabies in China | In order to investigate how the movement of dogs affects the geographically inter-provincial spread of rabies in Mainland China, we propose a multi-patch model to describe the transmission dynamics of rabies between dogs and humans, in which each province is regarded as a patch. In each patch the submodel consists of s... | In 1999, human rabies cases were reported in about 120 counties in Mainland China, mainly in the southern provinces. Now outbreaks of human rabies have been reported in about 1000 counties and the disease has spread geographically from the south to the north. Phylogeographic analyses of rabies virus strains indicate th... | Rabies, as an acute and fatal zoonotic disease, is most often transmitted through the bite or scratch of a rabid animal. The rabies virus infects the central nervous system, ultimately causing disease in the brain and death. Once the symptoms of rabies have developed, its mortality rate is almost 100%. Rabies causes te... |
10.1371/journal.pgen.1006954 | PKA activity is essential for relieving the suppression of hyphal growth and appressorium formation by MoSfl1 in Magnaporthe oryzae | In the rice blast fungus Magnaporthe oryzae, the cAMP-PKA pathway regulates surface recognition, appressorium turgor generation, and invasive growth. However, deletion of CPKA failed to block appressorium formation and responses to exogenous cAMP. In this study, we generated and characterized the cpk2 and cpkA cpk2 mut... | The cAMP-PKA signaling pathway plays a critical role in regulating various cellular processes in eukaryotic cells in response to extracellular cues. In the rice blast fungus, this important pathway is involved in surface recognition, appressorium morphogenesis, and infection. However, the exact role of PKA is not clear... | Magnaporthe oryzae is the causal agent of rice blast, which is one of the most important rice diseases worldwide. In the past two decades, M. oryzae has been developed as a model organism to study fungal-plant interactions because of its economic importance and the experimental tractability [1–3]. For plant infection, ... |
10.1371/journal.pntd.0005288 | Emergence of Rare Species of Nontuberculous Mycobacteria as Potential Pathogens in Saudi Arabian Clinical Setting | Clinical relevance of nontuberculous mycobacteria (NTM) is increasing worldwide including in Saudi Arabia. A high species diversity of NTM’s has been noticed in a recent study. However, the identification in diagnostic laboratories is mostly limited to common species. The impact of NTM species diversity on clinical out... | Nontuberculous mycobacteria (NTM) are ubiquitous in nature and they are opportunistic pathogens. In the last decade, infections caused by NTM’s increased—around the world in immune-suppressed and immune-competent individuals and Saudi Arabia is not an exception. Developments in diagnostic technologies increased the ide... | In the last decade, the prevalence of pulmonary and extra-pulmonary diseases caused by nontuberculous mycobacteria (NTM) has been increased [1–7]. This elevation in case rates, whether it is a real emergence or due to the development of advanced diagnostic tools is still unclear. On the other hand, the elevation in imm... |
10.1371/journal.pntd.0004362 | Efficacy, Safety, and Dose of Pafuramidine, a New Oral Drug for Treatment of First Stage Sleeping Sickness, in a Phase 2a Clinical Study and Phase 2b Randomized Clinical Studies | Sleeping sickness (human African trypanosomiasis [HAT]) is caused by protozoan parasites and characterized by a chronic progressive course, which may last up to several years before death. We conducted two Phase 2 studies to determine the efficacy and safety of oral pafuramidine in African patients with first stage HAT... | Sleeping sickness (human African trypanosomiasis [HAT]) is caused by parasites, and has a chronic progressive course that may last from several months to several years before death occurs. The present studies were done to assess the effectiveness and safety of oral pafuramidine versus intramuscular pentamidine (the sta... | Sleeping sickness (human African trypanosomiasis [HAT]) is a neglected tropical disease with limited treatment options that currently requires parenteral administration. It is caused by the protozoan parasites Trypanosoma brucei (T.b.) gambiense (the West African form of the disease) and Trypanosoma brucei rhodesiense ... |
10.1371/journal.pgen.1001122 | Differentiation of Zebrafish Melanophores Depends on Transcription Factors AP2 Alpha and AP2 Epsilon | A model of the gene-regulatory-network (GRN), governing growth, survival, and differentiation of melanocytes, has emerged from studies of mouse coat color mutants and melanoma cell lines. In this model, Transcription Factor Activator Protein 2 alpha (TFAP2A) contributes to melanocyte development by activating expressio... | Neural crest-derived pigment cells, known as melanocytes, are important to an organism's survival because they protect skin cells from ultraviolet radiation, camouflage the organism from predators, and contribute to sexual selection. Networks of regulatory proteins control the steps of melanocyte development, including... | An important participant in the gene-regulatory-network (GRN) that governs the differentiation of melanocytes from neural crest precursors (i.e., the melanocyte GRN) is the class III receptor tyrosine kinase Kit. In mouse embryos, binding of this growth-factor receptor by its ligand, stem cell factor (SCF), promotes th... |
10.1371/journal.pntd.0007349 | Modelling the impact of a Schistosoma mansoni vaccine and mass drug administration to achieve morbidity control and transmission elimination | Mass drug administration (MDA) is, and has been, the principal method for the control of the schistosome helminths. Using MDA only is unlikely to eliminate the infection in areas of high transmission and the implementation of other measures such as reduced water contact improved hygiene and sanitation are required. Ide... | Nearly 258 million people are infected worldwide by schistosome parasites. The World Health Organization (WHO) has set control guidelines to combat the morbidity and mortality induced by infection, defined by reaching ≤5% and ≤1% prevalence of heavy-intensity infections in school-aged children (SAC), respectively. Mass... | Schistosomiasis inflicts significant levels of human morbidity and mortality in regions of the world with endemic infection. It is estimated that nearly 258 million people are infected worldwide with up to 700 million at risk of being infected, leading to an estimated 280000 deaths annually [1–3]. Schistosomiasis is an... |
10.1371/journal.pgen.1002366 | Arabidopsis Homologs of Retinoblastoma-Associated Protein 46/48 Associate with a Histone Deacetylase to Act Redundantly in Chromatin Silencing | RNA molecules such as small-interfering RNAs (siRNAs) and antisense RNAs (asRNAs) trigger chromatin silencing of target loci. In the model plant Arabidopsis, RNA–triggered chromatin silencing involves repressive histone modifications such as histone deacetylation, histone H3 lysine-9 methylation, and H3 lysine-27 monom... | Chromatin, made of histones and DNA, is often covalently modified in the nucleus, and modifications can regulate gene transcription. RNA molecules such as small-interfering or silencing RNAs (siRNAs) and antisense RNAs (asRNAs) can trigger silencing of gene expression in eukaryotes. We have found that in the flowering ... | Cytosine DNA methylation is critical for stable silencing of transposable elements (TE) and repetitive sequences and for epigenetic regulation of endogenous gene expression in eukaryotes [1]–[3]. DNA methylation is thought to play an ancestral role in the defense against invasive DNA elements to maintain genome stabili... |
10.1371/journal.pgen.1007588 | Numerous recursive sites contribute to accuracy of splicing in long introns in flies | Recursive splicing, a process by which a single intron is removed from pre-mRNA transcripts in multiple distinct segments, has been observed in a small subset of Drosophila melanogaster introns. However, detection of recursive splicing requires observation of splicing intermediates that are inherently unstable, making ... | The splicing of RNA transcripts is an essential step in the production of mature mRNA molecules, involving removal of intron sequences and joining of flanking exon sequences. Introns are usually removed as a single unit in a two-step catalytic reaction. However, a small subset of introns in flies are removed via splici... | RNA splicing is a crucial step in the mRNA lifecycle, during which pre-mRNA transcripts are processed into mature transcripts by the excision of intronic sequences. Introns are normally excised as a single lariat unit. However, some introns in the Drosophila melanogaster genome are known to undergo recursive splicing, ... |
10.1371/journal.pcbi.0040036 | Computational and Experimental Analysis of Redundancy in the Central Metabolism of Geobacter sulfurreducens | Previous model-based analysis of the metabolic network of Geobacter sulfurreducens suggested the existence of several redundant pathways. Here, we identified eight sets of redundant pathways that included redundancy for the assimilation of acetate, and for the conversion of pyruvate into acetyl-CoA. These equivalent pa... | Geobacter sulfurreducens is a member of the Geobacteraceae family of micro-organisms that breathe metals and have a unique mode of metabolism. Stimulation of the activity of this species in the environment has been shown to result in the removal of radioactive contaminants in groundwater. Similarly, the respiration of ... | Geobacter species are of interest because of their natural role in carbon and mineral cycling, their ability to remediate organic and metal contaminants in the subsurface, and their capacity to harvest electricity from waste organic matter [1–3]. Geobacter sulfurreducens [4] is the most commonly investigated species of... |
10.1371/journal.pcbi.1000380 | Pairwise Maximum Entropy Models for Studying Large Biological
Systems: When They Can Work and When They Can't | One of the most critical problems we face in the study of biological systems is
building accurate statistical descriptions of them. This problem has been
particularly challenging because biological systems typically contain large
numbers of interacting element... | Biological systems are exceedingly complicated: They consist of a large number of
elements, those elements interact in nonlinear and highly unpredictable ways,
and collective interactions typically play a critical role. It would seem
surprising, then, that one... | Many fundamental questions in biology are naturally treated in a probabilistic
setting. For instance, deciphering the neural code requires knowledge of the
probability of observing patterns of activity in response to stimuli [1];
determining which features of a protein ar... |
10.1371/journal.ppat.1004726 | TRIM26 Negatively Regulates Interferon-β Production and Antiviral Response through Polyubiquitination and Degradation of Nuclear IRF3 | Virus infection leads to the activation of transcription factor IRF3 and subsequent production of type I inteferons, which induce the transcription of various antiviral genes called interferon stimulated genes (ISGs) to eliminate viral infection. IRF3 activation requires phosphorylation, dimerization and nuclear transl... | Innate immunity is the first line of defense to protect host from infection of invading pathogens. Production of type I inteferons by the innate immune cells is pivotal for the cellular antiviral immune responses. After virus infection, IFN-β transcription requires IRF3, which is activated through phosphorylation, dime... | Innate immunity is essential for the host to protect from infection of invading pathogens. Activation of the innate immune response depends on the detection and recognition of pathogen-associated molecular patterns (PAMPs) by germline DNA-encoded pattern-recognition receptors (PRRs). The well studied PRRs include Toll-... |
10.1371/journal.pntd.0007411 | Deprivation of dietary fiber enhances susceptibility of mice to cryptosporidiosis | Based on our initial observations showing that mice consuming a probiotic product develop more severe cryptosporidiosis, we investigated the impact of other dietary interventions on the intracellular proliferation of Cryptosporidium parvum and C. tyzzeri in the mouse. Mice were orally infected with oocysts and parasite... | The infection with Cryptosporidium parasite, a condition known as cryptosporidiosis, is a common cause of infant diarrhea in developing countries. We have previously shown that mice infected with C. parvum, one of the main cause of human cryptosporidiosis, develop a more severe infection if given probiotics. To investi... | Protozoa of the genus Cryptosporidium are important pathogens causing diarrhea in humans, ruminants and other species of animals worldwide [1]. Various Cryptosporidium species are recognized as opportunistic pathogens in patients with AIDS, where cryptosporidiosis can lead to protracted diarrhea and wasting. Although i... |
10.1371/journal.pcbi.1002792 | Experimental Studies and Dynamics Modeling Analysis of the Swimming and Diving of Whirligig Beetles (Coleoptera: Gyrinidae) | Whirligig beetles (Coleoptera, Gyrinidae) can fly through the air, swiftly swim on the surface of water, and quickly dive across the air-water interface. The propulsive efficiency of the species is believed to be one of the highest measured for a thrust generating apparatus within the animal kingdom. The goals of this ... | The whirligig beetles belong to the family Gyrinidae, consisting of over 700 species of water beetles. They are characterized by a divided eye, ellipsoidal body, and rapidly swim in circles when alarmed. Perhaps the most interesting characteristic of whirligig beetles is their ability to rapidly swim on the surface of ... | Few organisms maintain the ability to freely crawl on land, swim in water, and fly through the air; however, the whirligig beetle (Coleoptera Gyrinidae) is able to efficiently maneuver in all three environments [1]. The whirligig beetle also has the fastest measured speed for a swimming insect, while still maintaining ... |
10.1371/journal.pgen.1001270 | Friedreich's Ataxia (GAA)n•(TTC)n Repeats Strongly Stimulate Mitotic Crossovers in Saccharomyces cerevisae | Expansions of trinucleotide GAA•TTC tracts are associated with the human disease Friedreich's ataxia, and long GAA•TTC tracts elevate genome instability in yeast. We show that tracts of (GAA)230•(TTC)230 stimulate mitotic crossovers in yeast about 10,000-fold relative to a “normal” DNA sequence; (GAA)n•(TTC)n tracts, h... | Although meiotic recombination has been much more studied than mitotic recombination, mitotic recombination is a universal property. Meiotic recombination rates are quite variable within the genome, with some chromosomal regions (hotspots) having much higher levels of exchange than other regions (coldspots). For mitoti... | Several inherited human diseases are a consequence of the expansion of trinucleotide tracts [1], [2]. Although the mechanism by which tract expansions are generated is not yet understood, most of the trinucleotide tracts prone to expansion can form secondary structures such as “hairpin-like” DNA (intrastrand pairing) o... |
10.1371/journal.pntd.0004830 | Cytokine Profile of Children Hospitalized with Virologically-Confirmed Dengue during Two Phase III Vaccine Efficacy Trials | Two large-scale efficacy studies with the recombinant yellow fever-17D–dengue virus, live-attenuated, tetravalent dengue vaccine (CYD-TDV) candidate undertaken in Asia (NCT01373281) and Latin America (NCT01374516) demonstrated significant protection against dengue disease during two years’ active surveillance (active p... | A live-attenuated, tetravalent dengue vaccine (CYD-TDV) has been shown to provide protection against dengue disease in two large-scale, placebo-controlled, phase III efficacy studies. Continued surveillance of study participants was subsequently undertaken to better define longer term vaccine efficacy and safety. A yet... | Dengue virus (DENV) is the most important mosquito-borne pathogen threatening approximately half of the world’s population, mostly in tropical and subtropical areas including Latin America and Southeast Asia [1,2]. Infection with any of the four DENV serotypes can be asymptomatic or cause a spectrum of clinical symptom... |
10.1371/journal.pbio.1001890 | A Novel Nodal Enhancer Dependent on Pluripotency Factors and Smad2/3 Signaling Conditions a Regulatory Switch During Epiblast Maturation | During early development, modulations in the expression of Nodal, a TGFβ family member, determine the specification of embryonic and extra-embryonic cell identities. Nodal has been extensively studied in the mouse, but aspects of its early expression remain unaccounted for. We identified a conserved hotspot for the bin... | In the early mouse embryo, Nodal, a member of the TGFbeta superfamily of signalling proteins, promotes the differentiation of extra-embryonic tissues, as well as tissues within the developing embryo itself. Characterising the regulation of Nodal gene expression is essential to understand how Nodal signals in diverse ti... | The gene Nodal encodes a TGFβ family member signaling via the Smad2/3-dependent Activin/Nodal pathway. Nodal is a key factor during early development, required for the specification of cell identities in embryonic and extra-embryonic lineages [1],[2]. Its re-expression in the adult has been associated with tumor progre... |
10.1371/journal.pgen.1003453 | Signatures of Diversifying Selection in European Pig Breeds | Following domestication, livestock breeds have experienced intense selection pressures for the development of desirable traits. This has resulted in a large diversity of breeds that display variation in many phenotypic traits, such as coat colour, muscle composition, early maturity, growth rate, body size, reproduction... | The domestic pig, an important source of protein worldwide, was domesticated from the ancestral wild boar in multiple locations throughout the world. In Europe, local types were developed following domestication, but phenotypically distinct breeds only arose in the eighteenth century with the advent of systematic breed... | The domestic pig is an important livestock species and an important protein source worldwide. The pig originated from the wild boar, Sus scrofa, by multiple independent domestications, mainly in Asia Minor, Europe and East Asia [1], [2]. Domestication and subsequent selective pressures altered the behaviour and phenoty... |
10.1371/journal.pntd.0000407 | Phenotypic and Functional Characterization of Human Memory T Cell Responses to Burkholderia pseudomallei | Infection with the Gram-negative bacterium Burkholderia pseudomallei is an important cause of community-acquired lethal sepsis in endemic regions in southeast Asia and northern Australia and is increasingly reported in other tropical areas. In animal models, production of interferon-gamma (IFN-γ) is critical for resist... | The Gram-negative bacterium, Burkholderia pseudomallei, is a public health problem in southeast Asia and northern Australia and a Centers for Disease Control and Prevention listed Category B potential bioterrorism agent. It is the causative agent of melioidosis, and clinical manifestations vary from acute sepsis to chr... | Melioidosis is a serious infectious disease in Southeast Asia and Northern Australia caused by the soil-dwelling Gram-negative bacterium, Burkholderia pseudomallei [1]. In Northeast Thailand, the mortality rate for acute melioidosis remains high, approximately 50%, despite recent advances in antibiotic treatments. Sero... |
10.1371/journal.pntd.0002719 | Deliberate Attenuation of Chikungunya Virus by Adaptation to Heparan Sulfate-Dependent Infectivity: A Model for Rational Arboviral Vaccine Design | Mosquito-borne chikungunya virus (CHIKV) is a positive-sense, single-stranded RNA virus from the genus Alphavirus, family Togaviridae, which causes fever, rash and severe persistent polyarthralgia in humans. Since there are currently no FDA licensed vaccines or antiviral therapies for CHIKV, the development of vaccine ... | With the adaptation of chikungunya virus (CHIKV) to transmission by the Aedes albopictus mosquito, a pandemic has occurred resulting in four to six million human infections, and the virus continues to become endemic in new regions, most recently in the Caribbean. CHIKV can cause debilitating polyarthralgia, lasting for... | In the last few years, considerable attention has been focused upon mosquito-borne chikungunya virus (CHIKV); once a relatively obscure member of the Alphavirus genus in the Togaviridae family of enveloped, positive-sense RNA viruses [1]–[3]. In 2005, an East African clade CHIKV strain emerged on the Indian Ocean islan... |
10.1371/journal.pgen.1000246 | Mutations in the SLC2A9 Gene Cause Hyperuricosuria and Hyperuricemia in the Dog | Allantoin is the end product of purine catabolism in all mammals except humans, great apes, and one breed of dog, the Dalmatian. Humans and Dalmatian dogs produce uric acid during purine degradation, which leads to elevated levels of uric acid in blood and urine and can result in significant diseases in both species. T... | Animals excrete waste products in their urine. When most mammals metabolize compounds, called purines, they produce allantoin as one waste product in their urine. Humans, great apes, and Dalmatian dogs produce a different breakdown product, uric acid. This leads to high levels of uric acid in the urine and blood. In hu... | Uric acid is the predominant product of purine metabolism in humans, great apes and one breed of dog, the Dalmatian; all other mammals excrete allantoin. During primate evolution, urate oxidase (UOX), which catalyzes the oxidation of uric acid into allantoin, accumulated several independent nonsense mutations that led ... |
10.1371/journal.ppat.1006482 | KSHV encoded ORF59 modulates histone arginine methylation of the viral genome to promote viral reactivation | Kaposi’s sarcoma associated herpesvirus (KSHV) persists in a highly-ordered chromatin structure inside latently infected cells with the majority of the viral genome having repressive marks. However, upon reactivation the viral chromatin landscape changes into ‘open’ chromatin through the involvement of lysine demethyla... | Kaposi’s sarcoma-associated herpesvirus (KSHV) must carefully regulate both phases of its lifecycle in order to persist and proliferate effectively in the infected cells. In this study, we show the importance of dynamic epigenetic modifications on the viral chromatin in dictating whether KSHV displays the latent or lyt... | Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8), is a member of the gammaherpesvirus family that is associated with Kaposi’s sarcoma (KS), Primary Effusion Lymphoma, a subset of Multicentric Castleman’s Disease, and (in HIV-co-infected patients) KSHV Inflammatory Cytokine Syndro... |
10.1371/journal.pgen.1004557 | Differential Management of the Replication Terminus Regions of the Two Vibrio cholerae Chromosomes during Cell Division | The replication terminus region (Ter) of the unique chromosome of most bacteria locates at mid-cell at the time of cell division. In several species, this localization participates in the necessary coordination between chromosome segregation and cell division, notably for the selection of the division site, the licensi... | The genome of Vibrio cholerae is divided into two circular chromosomes, chrI and chrII. ChrII is derived from a horizontally acquired mega-plasmid, which raised questions on the necessary coordination of the processes that ensure its segregation with the cell division cycle. Here, we show that the MatP/matS macrodomain... | Most bacteria harbour a single chromosome and, in the rare case in which the genetic material is divided on several chromosomes, the extra-numerous ones appear to have derived from horizontally acquired mega-plasmids that subsequently gained essential genes [1]. This is notably the case for Vibrio cholerae, the agent o... |
10.1371/journal.pgen.1004152 | Distinct Requirements for Cranial Ectoderm and Mesenchyme-Derived Wnts in Specification and Differentiation of Osteoblast and Dermal Progenitors | The cranial bones and dermis differentiate from mesenchyme beneath the surface ectoderm. Fate selection in cranial mesenchyme requires the canonical Wnt effector molecule β-catenin, but the relative contribution of Wnt ligand sources in this process remains unknown. Here we show Wnt ligands are expressed in cranial sur... | Craniofacial abnormalities are relatively common congenital birth defects, and the Wnt signaling pathway and its effectors have key roles in craniofacial development. Wntless/Gpr177 is required for the efficient secretion of all Wnt ligands and maps to a region that contains SNPs strongly associated with reduced bone m... | The bones of the skull vault develop in close contact with the embryonic skin to enclose the brain. In the mouse embryo, both bone-forming osteoblasts and skin-forming dermal fibroblasts are derived from cranial neural crest and paraxial mesoderm [1]. At E11.5, cranial dermal fibroblast progenitors undergo specificatio... |
10.1371/journal.pntd.0000815 | The OmpL37 Surface-Exposed Protein Is Expressed by Pathogenic Leptospira during Infection and Binds Skin and Vascular Elastin | Pathogenic Leptospira spp. shed in the urine of reservoir hosts into freshwater can be transmitted to a susceptible host through skin abrasions or mucous membranes causing leptospirosis. The infection process involves the ability of leptospires to adhere to cell surface and extracellular matrix components, a crucial st... | Leptospirosis is a potentially fatal disease in humans and livestock caused by Leptospira bacteria. Effective antibiotic treatment depends on timely, accurate diagnosis. However, current diagnostic and vaccine options are limited by their specificity for the lipid-sugar coat of leptospires, which varies among 200 serum... | Leptospirosis is a zoonosis caused by pathogenic Leptospira spp. transmitted from reservoir hosts (typically rodents) to humans via water contaminated by infected animals and has a significant impact on public health throughout the developing world [1]–[4]. Leptospirosis also has significant adverse effects on the agri... |
10.1371/journal.pntd.0001323 | Luciferase-Expressing Leishmania infantum Allows the Monitoring of Amastigote Population Size, In Vivo, Ex Vivo and In Vitro | Here we engineered transgenic Leishmania infantum that express luciferase, the objectives being to more easily monitor in real time their establishment either in BALB/c mice—the liver and spleen being mainly studied—or in vitro. Whatever stationary phase L. infantum promastigotes population—wild type or engineered to e... | Leishmania infantum/L. chagasi parasites are inoculated in the skin of mammals by sand flies. Though most often these L. infantum-mammal interactions are asymptomatic, they can proceed, in some individuals, to a systemic disease known as visceral leishmaniasis. If left untreated this disease is fatal. The lack of prote... | Leishmania are obligate intracellular dimorphic protozoan parasites that cause a broad spectrum of clinical diseases in mammalian hosts. Visceral leishmaniasis, due to L. infantum, is endemic in the mediterranean basin (Mediterranean Visceral Leishmaniasis, MVL) and is a fatal disease, if untreated. To date, no efficie... |
10.1371/journal.ppat.1004347 | Transgenic Analysis of the Leishmania MAP Kinase MPK10 Reveals an Auto-inhibitory Mechanism Crucial for Stage-Regulated Activity and Parasite Viability | Protozoan pathogens of the genus Leishmania have evolved unique signaling mechanisms that can sense changes in the host environment and trigger adaptive stage differentiation essential for host cell infection. The signaling mechanisms underlying parasite development remain largely elusive even though Leishmania mitogen... | Leishmaniasis is an important human disease caused by Leishmania parasites. A crucial aspect of Leishmania infectivity is its capacity to sense different environments and adapt for survival inside insect vector and vertebrate host by stage differentiation. This process is triggered by environmental changes encountered ... | Leishmaniasis is an infectious disease characterized by a variety of pathologies, affecting more than 12 million people worldwide and ranging from self-healing cutaneous lesions to fatal visceral infection [1]. This disease is caused by pathogenic protozoa of the genus Leishmania, which show two major life cycle stages... |
10.1371/journal.pcbi.1000346 | The Role of Environmental Transmission in Recurrent Avian Influenza
Epidemics | Avian influenza virus (AIV) persists in North American wild waterfowl, exhibiting
major outbreaks every 2–4 years. Attempts to explain the patterns of
periodicity and persistence using simple direct transmission models are
unsuccessful. Motivated by empirical ... | Avian influenza viruses (AIVs) in wild waterfowl constitute the historic source
of human influenza viruses, having a rich pool of genetic and antigenic
diversity that often leads to cross-species transmission. Although the emergence
of H5N1 avian influenza vir... | Many important infectious diseases persist on a knife-edge: rapid rates of
transmission coupled with brief infectious periods generate boom-and-bust epidemics
that court extinction. Such violent epidemic behavior has been observed in measles
[1]–[4], plague [5],
... |
10.1371/journal.pcbi.1003917 | Membrane Partitioning of Anionic, Ligand-Coated Nanoparticles Is Accompanied by Ligand Snorkeling, Local Disordering, and Cholesterol Depletion | Intracellular uptake of nanoparticles (NPs) may induce phase transitions, restructuring, stretching, or even complete disruption of the cell membrane. Therefore, NP cytotoxicity assessment requires a thorough understanding of the mechanisms by which these engineered nanostructures interact with the cell membrane. In th... | The increasing applications of nanotechnology in medicine rely on the fact that engineered nanomaterials, such as diagnostic and therapeutic nanoparticles, are able to translocate across the cellular membrane and reach their site of action without toxic effects. One of the first steps into assessing the NP cytotoxicity... | Understanding the interaction mechanisms between nanoparticles (NPs) and cell membranes is of critical importance for their use in medical applications [1]–[5]. In these applications, engineered nanostructures are required to contact target cells without damaging essential tissues. The ability of NPs to reach intracell... |
10.1371/journal.ppat.1002486 | Human Herpesvirus 8 (HHV8) Sequentially Shapes the NK Cell Repertoire during the Course of Asymptomatic Infection and Kaposi Sarcoma | The contribution of innate immunity to immunosurveillance of the oncogenic Human Herpes Virus 8 (HHV8) has not been studied in depth. We investigated NK cell phenotype and function in 70 HHV8-infected subjects, either asymptomatic carriers or having developed Kaposi's sarcoma (KS). Our results revealed substantial alte... | Natural Killer (NK) cells are part of the innate immune response against virus infections and tumors. Their activation is the net result of signals emanating from a panel of inhibitory and activating receptors recognizing specific ligands on target cells. Human Herpes Virus 8 (HHV8) is an oncogenic virus responsible of... | Human herpesvirus 8 (HHV8), although known as Kaposi's sarcoma-associated herpesvirus (KSHV), is a γ herpes virus able to establish a predominantly latent, life-long infection in host's monocytes, dendritic cells (DCs), B lymphocytes, and endothelial cells. HHV8 is the etiological agent of Kaposi's sarcoma (KS), a mult... |
10.1371/journal.pgen.1008226 | Profound analgesia is associated with a truncated peptide resulting from tissue specific alternative splicing of DRG CA8-204 regulated by an exon-level cis-eQTL | Carbonic anhydrase-8 (CA8) is an intracellular protein that functions as an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1) critical to intracellular Ca++ release, synaptic functions and neuronal excitability. We showed previously that murine nociception and analgesic responses are regulated by the ex... | Carbonic anhydrase-8 (CA8) inhibits IP3 binding to the inositol trisphosphate receptor-1(ITPR1), which regulates intracellular calcium signaling critical to neuronal functions. Recessive CA8-null mutants are associated with spinocerebellar ataxia and neurodegenerative disorders. We have previously demonstrated that noc... | Car8 and its human ortholog (CA8) are enzymatically inactive isoforms of carbonic anhydrase that inhibit activation of neuronal inositol 1,4,5-trisphosphate receptor type-1 (ITPR1) by phosphorylation (pITPR1), and intracellular calcium release in mice. ITPR1 converts inositol trisphosphate (IP3) signaling to intracellu... |
10.1371/journal.ppat.1001104 | Role of Acetyl-Phosphate in Activation of the Rrp2-RpoN-RpoS Pathway in Borrelia burgdorferi | Borrelia burgdorferi, the Lyme disease spirochete, dramatically alters its transcriptome and proteome as it cycles between the arthropod vector and mammalian host. During this enzootic cycle, a novel regulatory network, the Rrp2-RpoN-RpoS pathway (also known as the σ54–σS sigma factor cascade), plays a central role in ... | Borrelia burgdorferi, the causative agent of Lyme disease, is maintained in nature in a complex enzootic cycle involving Ixodes ticks and mammals. A novel regulatory network, the Rrp2-RpoN-RpoS pathway, which governs differential expression of numerous genes of B. burgdorferi, is essential for this complex life cycle. ... | The enzootic life-cycle of Borrrelia burgdorferi is complex and typically involves transmission between an arthropod vector (Ixodes ticks) and a mammalian host (e.g., Peromyscus rodents) [1]. Accumulated evidence have shown that the alternative sigma factor RpoS plays a central role in this complex natural cycle of B. ... |
10.1371/journal.pntd.0001727 | In-silico Investigation of Antitrypanosomal Phytochemicals from Nigerian Medicinal Plants | Human African trypanosomiasis (HAT), a parasitic protozoal disease, is caused primarily by two subspecies of Trypanosoma brucei. HAT is a re-emerging disease and currently threatens millions of people in sub-Saharan Africa. Many affected people live in remote areas with limited access to health services and, therefore,... | Traditional herbal medicine continues to play a key role in health, particularly in remote areas with limited access to “modern medicines”. Many plants are used in traditional Nigerian medicine to treat parasitic diseases. While many of these plants have shown notable activity against parasitic protozoa, in most cases ... | Human African trypanosomiasis (HAT), also known as sleeping sickness, is caused by the single-celled kinetoplastid parasites, Trypanosoma brucei, which are transmitted to humans by infected tsetse flies (Glossina spp.). Two sub-species of T. brucei (rhodesiense and gambiense) cause the two different forms of the diseas... |
10.1371/journal.ppat.1003190 | Intracellular Bacillary Burden Reflects a Burst Size for Mycobacterium tuberculosis In Vivo | We previously reported that Mycobacterium tuberculosis triggers macrophage necrosis in vitro at a threshold intracellular load of ∼25 bacilli. This suggests a model for tuberculosis where bacilli invading lung macrophages at low multiplicity of infection proliferate to burst size and spread to naïve phagocytes for repe... | Macrophages patrol the lung to ingest and destroy inhaled microbes. Mycobacterium tuberculosis, the bacteria causing tuberculosis, can survive within macrophages and use them as a protected environment for growth. Macrophages by themselves are poorly equipped to kill M. tuberculosis but may undergo programmed cell deat... | Natural infection with Mycobacterium tuberculosis (Mtb) occurs by inhalation, followed by invasion of resident alveolar macrophages that provide the major initial replication niche for the pathogen. Macrophages infected with Mtb in vitro may die with primarily apoptotic or necrotic features [1]; the cell death mode mos... |
10.1371/journal.pntd.0005837 | Community effectiveness of indoor spraying as a dengue vector control method: A systematic review | The prevention and control of dengue rely mainly on vector control methods, including indoor residual spraying (IRS) and indoor space spraying (ISS). This study aimed to systematically review the available evidence on community effectiveness of indoor spraying.
A systematic review was conducted using seven databases (P... | The effectiveness of indoor residual spraying (IRS) and indoor space spraying (ISS) as dengue vector control methods depends on many factors. This study aims to systematically review the evidence on the community effectiveness of indoor spraying of insecticides to reduce Aedes mosquito populations and thereby to contro... | Dengue is the most prevalent arthropod-borne viral disease, infecting 300 to 500 million individuals each year. Approximately 100 million infections are symptomatic, which can range from mild to severe disease [1,2,3]. An estimated 500 000 people suffer from the severe forms, nearly 90% of whom are children, with a res... |
10.1371/journal.pgen.1000789 | TGF-ß Sma/Mab Signaling Mutations Uncouple Reproductive Aging from Somatic Aging | Female reproductive cessation is one of the earliest age-related declines humans experience, occurring in mid-adulthood. Similarly, Caenorhabditis elegans' reproductive span is short relative to its total life span, with reproduction ceasing about a third into its 15–20 day adulthood. All of the known mutations and tre... | Female reproductive cessation is the earliest aging phenotype humans experience, and its importance as a clinical issue is growing as more women opt to have children later in life. While much work has been done to understand the general aging process, little is currently known about the regulation of reproductive aging... | Among human age-related declines, female reproductive cessation is one of the earliest to occur, with infertility and maternal age-related birth defects arising during the fourth decade of life [1]. While artificial reproductive technologies have improved late conception success [2]–[5], the underlying molecular regula... |
10.1371/journal.pgen.1006162 | Fragment Length of Circulating Tumor DNA | Malignant tumors shed DNA into the circulation. The transient half-life of circulating tumor DNA (ctDNA) may afford the opportunity to diagnose, monitor recurrence, and evaluate response to therapy solely through a non-invasive blood draw. However, detecting ctDNA against the normally occurring background of cell-free ... | During cell death, DNA that is not contained within a membrane (i.e., cell-free DNA) enters the circulation. Detecting cell-free DNA originating from solid tumors (i.e., circulating tumor DNA, ctDNA), particularly solid tumors that have not metastasized, has proven challenging due to the relatively abundant background ... | Increased quantity of cell-free DNA in the circulation has been associated with malignant solid tumors [1]. Longitudinal studies have reported reductions in cell-free DNA quantity in response to therapy and elevations associated with recurrence suggesting quantification of cell-free DNA may be useful for monitoring dis... |
10.1371/journal.ppat.1000202 | Rac1 Is Required for Pathogenicity and Chm1-Dependent Conidiogenesis in Rice Fungal Pathogen Magnaporthe grisea | Rac1 is a small GTPase involved in actin cytoskeleton organization and polarized cell growth in many organisms. In this study, we investigate the biological function of MgRac1, a Rac1 homolog in Magnaporthe grisea. The Mgrac1 deletion mutants are defective in conidial production. Among the few conidia generated, they a... | The fungus Magnaporthe grisea (M. grisea) is an important pathogen in plants and has a great impact on agriculture. Its infection of rice causes one of the most destructive diseases, the rice blast disease, around the world. M. grisea starts infection by producing conidia, which generate infectious structures and deter... | Magnaporthe grisea (M. grisea) is a good model organism to study plant pathogenic filamentous fungi [1],[2]. In addition, it is closely related to other prominent non-pathogenic model fungi, such as Neurospora crassa and Aspergillus nidulans [3]. The fungus infects many cereal crops such as rice, barley, and wheat, and... |
10.1371/journal.ppat.1004838 | Group Selection and Contribution of Minority Variants during Virus Adaptation Determines Virus Fitness and Phenotype | Understanding how a pathogen colonizes and adapts to a new host environment is a primary aim in studying emerging infectious diseases. Adaptive mutations arise among the thousands of variants generated during RNA virus infection, and identifying these variants will shed light onto how changes in tropism and species jum... | When RNA viruses replicate, they do so with a high rate of error; hence, their populations are not composed of a single genotype, but of a swarm of different, yet related, genomes. This mutant spectrum has been described as the viral quasispecies, and its composition has important consequences for evolution, adaptation... | The extreme mutation rates of RNA viruses and the highly diverse populations they generate in few replication cycles are considered the basis for their rapid adaptation to new environments [1,2]. Such adaptive steps result in the emergence of new variants capable of escaping immune responses, resisting antiviral approa... |
10.1371/journal.ppat.1000650 | The E3 Ubiquitin Ligase Triad3A Negatively Regulates the RIG-I/MAVS Signaling Pathway by Targeting TRAF3 for Degradation | The primary role of the innate immune response is to limit the spread of infectious pathogens, with activation of Toll-like receptor (TLR) and RIG-like receptor (RLR) pathways resulting in a pro-inflammatory response required to combat infection. Limiting the activation of these signaling pathways is likewise essential... | RNA virus infection is detected through TLR-dependent and TLR-independent mechanisms. Early viral replicative intermediates are detected by two recently characterized cystolic viral RNA receptors, RIG-I and MDA-5, leading to the production of pro-inflammatory cytokines and type I interferons (IFNs). Dysfunctional respo... | Upon recognition of specific molecular components of viruses, the host cell activates multiple signaling cascades that stimulate an innate antiviral response, resulting in the disruption of viral replication, and the mobilization of the adaptive arm of the immune system. Central to the host antiviral response is the pr... |
10.1371/journal.pgen.1003108 | The GATA Transcription Factor egl-27 Delays Aging by Promoting Stress Resistance in Caenorhabditis elegans | Stress is a fundamental aspect of aging, as accumulated damage from a lifetime of stress can limit lifespan and protective responses to stress can extend lifespan. In this study, we identify a conserved Caenorhabditis elegans GATA transcription factor, egl-27, that is involved in several stress responses and aging. We ... | Stress is a fundamental aspect of aging, but it is unclear whether the molecular mechanisms underlying stress response become altered during normal aging and whether these alterations can affect the aging process. In this study, we found a GATA transcription factor called egl-27, whose targets are significantly enriche... | Responses to various forms of stress play an important role in aging and longevity. Several types of stress result in damage that can accumulate over time (e.g. oxidative stress results in damaged proteins that often accumulate with age) [1]–[3]. Responses to these stresses have protective effects that can alleviate th... |
10.1371/journal.pgen.1006121 | Network Analysis of Genome-Wide Selective Constraint Reveals a Gene Network Active in Early Fetal Brain Intolerant of Mutation | Using robust, integrated analysis of multiple genomic datasets, we show that genes depleted for non-synonymous de novo mutations form a subnetwork of 72 members under strong selective constraint. We further show this subnetwork is preferentially expressed in the early development of the human hippocampus and is enriche... | Some genes are extremely intolerant of mutations that alter their amino acid sequence. Such mutations are highly likely to drive disease, and previous reports have implicated these genes in multiple diseases. To better understand the function of these constrained genes and their place in cellular organization, we devel... | Genetic variation is introduced into the human genome by spontaneously arising de novo mutations in the germline. The majority of these mutations have, at most, modest effects on phenotype; they are thus subject to nearly neutral drift and can be transmitted through the population, with some increasing in frequency to ... |
10.1371/journal.pntd.0006125 | Tegumentary leishmaniasis and coinfections other than HIV | Tegumentary leishmaniasis (TL) is a disease of skin and/or mucosal tissues caused by Leishmania parasites. TL patients may concurrently carry other pathogens, which may influence the clinical outcome of TL.
This review focuses on the frequency of TL coinfections in human populations, interactions between Leishmania and... | Infectious diseases are often studied one by one, but people can have more than one infection at the same time. This is likely to happen when different microorganisms are linked to specific geographical regions or living conditions. In this paper, we summarise the literature about infections occurring together with teg... | Tegumentary leishmaniasis (TL) is a disease of the skin and mucosal tissues caused by several species of the genus Leishmania (Protozoa, Trypanosomatida, Trypanosomatidae) that are transmitted by the bite of phlebotomine sandflies [1]. Parasites belonging to the subgenus Leishmania are found in the Old and the New Worl... |
10.1371/journal.pntd.0006411 | Serosurveillance of Coxiellosis (Q-fever) and Brucellosis in goats in selected provinces of Lao People’s Democratic Republic | Goat raising is a growing industry in Lao People’s Democratic Republic, with minimal disease investigation to date, especially zoonoses. This study determined the proportional seropositivity of two zoonotic diseases: Q fever (causative agent Coxiella burnetii) and Brucellosis (Brucella species) in goats across five pro... | Goat raising is a growing industry in Lao People’s Democratic Republic however there is very little information whether or not goat raising poses a disease threat to farmers and the general population through diseases that may be transmitted between animals and humans (i.e., zoonotic diseases). To determine this, we te... | Lao People’s Democratic Republic (Laos) is a landlocked country in the Greater Mekong Sub-region with an economy greatly dependent on agriculture [1]. Livestock have become increasingly important for improving rural livelihoods in Laos, providing a source of high quality protein, manure as fertiliser for plant growth, ... |
10.1371/journal.pgen.1002136 | Multiple Regulatory Mechanisms to Inhibit Untimely Initiation of DNA Replication Are Important for Stable Genome Maintenance | Genomic instability is a hallmark of human cancer cells. To prevent genomic instability, chromosomal DNA is faithfully duplicated in every cell division cycle, and eukaryotic cells have complex regulatory mechanisms to achieve this goal. Here, we show that untimely activation of replication origins during the G1 phase ... | Chromosomal DNA replication occurs as a two-step reaction in eukaryotes. In the first reaction, called licensing, the replicative helicase is loaded onto replication origin in an inactive form during the G1 phase of the cell cycle. In the second reaction, called initiation, the replicative helicase is activated, and re... | When eukaryotic cells proliferate, their chromosomes must be precisely duplicated and segregated to daughter cells to maintain genome stability over generations. Failure of these processes is directly connected to lethality and severe disease, such as cancer. Genome instability is a hallmark of human cancer cells. To d... |
10.1371/journal.pcbi.1000299 | Alignment and Prediction of cis-Regulatory Modules Based on a Probabilistic Model of Evolution | Cross-species comparison has emerged as a powerful paradigm for predicting cis-regulatory modules (CRMs) and understanding their evolution. The comparison requires reliable sequence alignment, which remains a challenging task for less conserved noncoding sequences. Furthermore, the existing models of DNA sequence evolu... | Comparison of noncoding DNA sequences across species has the potential to significantly improve our understanding of gene regulation and our ability to annotate regulatory regions of the genome. This potential is evident from recent publications analyzing 12 Drosophila genomes for regulatory annotation. However, becaus... | The spatial-temporal expression pattern of a gene is controlled by its regulatory sequences, sometimes called a cis-regulatory module (CRM). A CRM contains a number of transcription factor binding sites (TFBSs), which read the expression level of the cognate transcription factors (TFs) and drive the appropriate express... |
10.1371/journal.pcbi.1002265 | Speed, Sensitivity, and Bistability in Auto-activating Signaling Circuits | Cells employ a myriad of signaling circuits to detect environmental signals and drive specific gene expression responses. A common motif in these circuits is inducible auto-activation: a transcription factor that activates its own transcription upon activation by a ligand or by post-transcriptional modification. Exampl... | Different times call for different measures. Therefore, cells adjust their protein levels depending on their environment. Upon the detection of certain environmental signals, transcription factors are activated, which activate or inhibit the production of specific sets of proteins. As it turns out, these transcription ... | Biological organisms employ a variety of signaling networks to respond to changes in environmental conditions. An interesting class of examples is given by the two-component signaling (TCS) systems, which are ubiquitous in bacteria and plants [1]. TCS systems typically consist of two proteins: a sensor histidine kinase... |
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