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10.1371/journal.pntd.0001762 | Whole Organism High-Content Screening by Label-Free, Image-Based Bayesian Classification for Parasitic Diseases | Sole reliance on one drug, Praziquantel, for treatment and control of schistosomiasis raises concerns about development of widespread resistance, prompting renewed interest in the discovery of new anthelmintics. To discover new leads we designed an automated label-free, high content-based, high throughput screen (HTS) ... | Schistosomiasis is a severe helminth infection affecting an estimated 600 million people. The one drug widely available, praziquantel (PZQ), is not ideal. PZQ kills the adult worms but not the developing juveniles so the treated patient may not be cured long-term. In addition, use of repeated mass treatment campaigns w... | Infection with parasitic worms (helminths) causes a huge burden of human disease [1] and economic loss to the livestock industry [2]. Currently the major control strategy for the human diseases is by large scale drug administration to schools or by mass drug administration [3]. However, the drugs available are limited ... |
10.1371/journal.pntd.0006899 | Continuing evidence of Chagas disease along the Texas-Mexico border | Chagas disease is a chronic parasitic infection that progresses to dilated cardiomyopathy in 30% of human cases. Public health efforts target diagnosing asymptomatic cases, as therapeutic efficacy diminishes as irreversible tissue damage progresses. Physician diagnosis of Chagas disease cases in the United States is lo... | Chagas disease is a parasitic infection, which in 30% of people results in chronic dilated organomegaly over the course of decades. This progressive disease typically advances subclinically until end stage heart failure is established, at which point treatment is no longer efficacious. Thus, current public health effor... | Chagas disease is caused by infection with the protozoan parasite Trypanosoma cruzi. Primarily transmitted by infected triatomine vector species in the Americas, congenital transmission, blood transfusion, organ transplantation, or ingestion of contaminated beverage/food products are also known to contribute to human d... |
10.1371/journal.pntd.0003952 | Role of sph2 Gene Regulation in Hemolytic and Sphingomyelinase Activities Produced by Leptospira interrogans | Pathogenic members of the genus Leptospira are the causative agents of leptospirosis, a neglected disease of public and veterinary health concern. Leptospirosis is a systemic disease that in its severest forms leads to renal insufficiency, hepatic dysfunction, and pulmonary failure. Many strains of Leptospira produce h... | The spirochete Leptospira causes leptospirosis, a potentially deadly disease of humans and animals. Candidate factors that promote infection include hemolysins encoded by several leptospiral genes. Hemolysins rupture red blood cells in vitro. Some hemolysins are sphingomyelinases, which target sphingomyelin in the host... | Leptospirosis is a neglected zoonotic disease that afflicts humans and animals [1–3]. Although the disease occurs worldwide, it is observed most frequently in tropical countries, where conditions for environmental survival and transmission are most favorable [4]. The causative organisms are spirochetes belonging to the... |
10.1371/journal.pcbi.1005090 | When Does Model-Based Control Pay Off? | Many accounts of decision making and reinforcement learning posit the existence of two distinct systems that control choice: a fast, automatic system and a slow, deliberative system. Recent research formalizes this distinction by mapping these systems to “model-free” and “model-based” strategies in reinforcement learni... | When you make a choice about what groceries to get for dinner, you can rely on two different strategies. You can make your choice by relying on habit, simply buying the items you need to make a meal that is second nature to you. However, you can also plan your actions in a more deliberative way, realizing that the frie... | Theoretical accounts of decision making emphasize a distinction between two systems competing for control of behavior [1–6]: one that is fast and automatic, and one that is slow and deliberative. These systems occupy different points along a trade-off between accuracy and computational demand (henceforth demand), makin... |
10.1371/journal.pgen.1003905 | Robust Demographic Inference from Genomic and SNP Data | We introduce a flexible and robust simulation-based framework to infer demographic parameters from the site frequency spectrum (SFS) computed on large genomic datasets. We show that our composite-likelihood approach allows one to study evolutionary models of arbitrary complexity, which cannot be tackled by other curren... | We present a new likelihood-based method to infer the past demography of a set of populations from large genomic datasets. Our method can be applied to arbitrarily complex models as the likelihood is estimated by coalescent simulations. Under simple scenarios, our method behaves similarly to a widely used diffusion-bas... | Reconstructing the past history of a given species is important not only for its own sake, but for disentangling demographic from selective effects [1], [2]. Demography is indeed often estimated on a set of markers and the best neutral model is used as a null for evidencing markers under selection [3], [4] or for findi... |
10.1371/journal.pbio.1001329 | A Systematic Approach to Pair Secretory Cargo Receptors with Their Cargo Suggests a Mechanism for Cargo Selection by Erv14 | The endoplasmic reticulum (ER) is the site of synthesis of secreted and membrane proteins. To exit the ER, proteins are packaged into COPII vesicles through direct interaction with the COPII coat or aided by specific cargo receptors. Despite the fundamental role of such cargo receptors in protein traffic, only a few ha... | All cells sense their environment, respond to it, and communicate with neighboring cells. To perform these functions, cells use an impressive array of proteins that they display on their surface membranes and secrete into their external environment. Newly synthesized proteins destined for the surface of nucleated cells... | The endoplasmic reticulum (ER) is the entry site into the secretory pathway, responsible for the folding, maturation, and trafficking of all secreted, membrane-bound, and secretory pathway resident proteins. Once folded, the proteins exit the ER as cargo within COPII-coated vesicles that bud from ER exit sites [1],[2].... |
10.1371/journal.pntd.0000416 | Optimization of Control Strategies for Non-Domiciliated Triatoma dimidiata, Chagas Disease Vector in the Yucatán Peninsula, Mexico | Chagas disease is the most important vector-borne disease in Latin America. Regional initiatives based on residual insecticide spraying have successfully controlled domiciliated vectors in many regions. Non-domiciliated vectors remain responsible for a significant transmission risk, and their control is now a key chall... | Chagas disease is the most important vector-borne disease in Latin America. Residual insecticide spraying has been used successfully for the elimination of domestic vectors in many regions. However, some vectors of non-domestic origin are able to invade houses, and they are now a key challenge for further disease contr... | Chagas disease is a major vector-borne parasitic disease in Latin America, with 9.8 to 11 million infected people, 60 million at risk of infection [1],[2] and a disease burden of over 800,000 DALYs [3]. International travel and immigration are also turning it into a global disease [4]. It is caused by the protozoan par... |
10.1371/journal.pntd.0002114 | Serovar Diversity of Pathogenic Leptospira Circulating in the French West Indies | Leptospirosis is one of the most important neglected tropical bacterial diseases in Latin America and the Caribbean. However, very little is known about the circulating etiological agents of leptospirosis in this region. In this study, we describe the serological and molecular features of leptospires isolated from 104 ... | Leptospirosis is an emerging zoonotic disease caused by infection with pathogenic strains of Leptospira. Isolation of Leptospira strains is rare, making it difficult to assess their distribution worldwide. In this study, we characterized cultures of Leptospira obtained from more than one hundred leptospirosis patients ... | Leptospirosis is an emerging zoonosis with a worldwide distribution. The World Health Organization (WHO) estimates that there are over 1,700,000 severe cases of leptospirosis worldwide, with an higher incidence in impoverished populations in developing countries and tropical regions [1]–[3]. The disease is transmitted ... |
10.1371/journal.ppat.1006348 | HIV-1 competition experiments in humanized mice show that APOBEC3H imposes selective pressure and promotes virus adaptation | APOBEC3 (A3) family proteins are DNA cytosine deaminases recognized for contributing to HIV-1 restriction and mutation. Prior studies have demonstrated that A3D, A3F, and A3G enzymes elicit a robust anti-HIV-1 effect in cell cultures and in humanized mouse models. Human A3H is polymorphic and can be categorized into th... | Human APOBEC3 family proteins are known as intrinsic defenses against HIV-1, whereas HIV-1 Vif counteracts APOBEC3-mediated anti-viral action. Using a hematopoietic stem cell-transplanted humanized mouse model, we demonstrated that endogenous APOBEC3D, APOBEC3F and APOBEC3G play pivotal roles in restricting HIV-1 repli... | Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3; A3) enzymes are cellular single-stranded DNA cytosine deaminases that are specifically encoded in mammals [1,2]. Rodents including mice (Mus musculus) have a single A3 gene, while primates including humans (Homo sapiens), chimpanzees (Pan trogl... |
10.1371/journal.pntd.0002013 | Vectorial Capacity of Aedes aegypti for Dengue Virus Type 2 Is Reduced with Co-infection of Metarhizium anisopliae | Aedes aegypti, is the major dengue vector and a worldwide public health threat combated basically by chemical insecticides. In this study, the vectorial competence of Ae. aegypti co-infected with a mildly virulent Metarhizium anisopliae and fed with blood infected with the DENV-2 virus, was examined.
The study encompas... | Dengue is a worldwide public health problem. There is not an effective vaccine yet; the chemical struggle against its transmitter, the mosquito Aedes aegypti, is onerous and erratic, and the community participation to eliminate vector breeding sites is unconfident. Here, we examined mosquitoes fed on human blood mixed ... | The susceptibility of Aedes aegypti adults to infection with Beauveria bassiana was first reported in the late 1960s [1]. However the potential of entomopathogenic Ascomycetes (Hypocreales) as adulticides of vector mosquitoes was largely overlooked until Metarhizium anisopliae was demonstrated to induce mortality of Cu... |
10.1371/journal.pcbi.1004509 | Beyond the E-Value: Stratified Statistics for Protein Domain Prediction | E-values have been the dominant statistic for protein sequence analysis for the past two decades: from identifying statistically significant local sequence alignments to evaluating matches to hidden Markov models describing protein domain families. Here we formally show that for “stratified” multiple hypothesis testing... | Despite decades of research, it remains a challenge to distinguish homologous relationships between proteins from sequence similarities arising due to chance alone. This is an increasingly important problem as sequence database sizes continue to grow, and even today many computational analyses require that the statisti... | The evaluation of statistical significance is crucial in genome-wide studies, such as detecting differentially-expressed genes in microarray or proteomic studies, performing genome-wide association studies, and uncovering homologous sequences. Different biological applications have settled for different statistics to s... |
10.1371/journal.ppat.1002026 | A Yersinia Effector with Enhanced Inhibitory
Activity on the NF-κB Pathway Activates the NLRP3/ASC/Caspase-1 Inflammasome
in Macrophages | A type III secretion system (T3SS) in pathogenic Yersinia
species functions to translocate Yop effectors, which modulate cytokine
production and regulate cell death in macrophages. Distinct pathways of
T3SS-dependent cell death and caspase-1 activation occur i... | Pathogenic bacteria in the genus Yersinia use multiple virulence
determinants to counteract innate immunity and facilitate infection. A type III
system in Yersinia translocates an effector called YopJ that
elicits cell death in macrophages. YopJ inhibits the p... | Microbial pathogens encode numerous types of virulence factors that are used to
circumvent or usurp immune responses within cells of their hosts. A protein export
pathway known as the type III secretion system (T3SS) allows Gram-negative bacterial
pathogens to deliver eff... |
10.1371/journal.pcbi.1005588 | Mitochondrial respiration and ROS emission during β-oxidation in the heart: An experimental-computational study | Lipids are main fuels for cellular energy and mitochondria their major oxidation site. Yet unknown is to what extent the fuel role of lipids is influenced by their uncoupling effects, and how this affects mitochondrial energetics, redox balance and the emission of reactive oxygen species (ROS). Employing a combined exp... | Lipids are main sources of energy for liver and cardiac and skeletal muscle. Mitochondria are the main site of lipid oxidation which, in the heart, supplies most of the energy required for its blood pumping function. Paradoxically, however, lipids over supply impair mitochondrial function leading to metabolic syndrome,... | Fatty Acids (FAs) are main sources of cellular energy affecting mitochondrial energetics and redox balance. The lipid energy content becomes available from β-oxidation as reducing equivalents and acetyl CoA (AcCoA) of which the latter, after further processing in the tricarboxylic acid cycle, also supplies most of the ... |
10.1371/journal.ppat.1004379 | Neutrophil Crawling in Capillaries; A Novel Immune Response to Staphylococcus aureus | Methicillin-resistant Staphylococcus aureus (MRSA), particularly the USA300 strain, is a highly virulent pathogen responsible for an increasing number of skin and soft tissue infections globally. Furthermore, MRSA-induced soft tissue infections can rapidly progress into life-threatening conditions, such as sepsis and n... | Methicillin-resistant Staphylococcus aureus (MRSA) is a highly virulent pathogen responsible for a significant portion of skin and soft tissue infections throughout the world. We investigated the role of neutrophils in soft tissue infections, as these immune cells have been shown to be both essential for clearance of t... | Staphylococcus aureus is a Gram-positive, facultatively anaerobic bacterium that poses considerable challenges to human health as a re-emerging pathogen in both hospital and community settings. As a commensal bacterium, approximately 50% of the general population carry S. aureus in the anterior nares [1]. Despite its c... |
10.1371/journal.pntd.0005489 | Pre-control relationship of onchocercal skin disease with onchocercal infection in Guinea Savanna, Northern Nigeria | Onchocerca volvulus infection can result in blindness, itching and skin lesions. Previous research concentrated on blindness.
A clinical classification system of the cutaneous changes in onchocerciasis was used for the first time in this study within the context of an early ivermectin drug trial in the savanna region o... | Onchocerciasis is a tropical parasitic infection caused by the nematode worm Onchocerca volvulus. The disease mainly occurs across tropical Africa and infection can result in blindness, debilitating itching and a variety of skin changes. Initial research concentrated mainly on the problem of blindness. A number of stud... | Onchocerciasis affects approximately 17 million people worldwide [1] with the main burden of disease occurring throughout tropical Africa. The consequences of infection with the nematode Onchocerca volvulus include blindness, debilitating pruritus and skin lesions. Initial research concentrated on blindness because of ... |
10.1371/journal.pgen.1003225 | Loci Associated with N-Glycosylation of Human Immunoglobulin G Show Pleiotropy with Autoimmune Diseases and Haematological Cancers | Glycosylation of immunoglobulin G (IgG) influences IgG effector function by modulating binding to Fc receptors. To identify genetic loci associated with IgG glycosylation, we quantitated N-linked IgG glycans using two approaches. After isolating IgG from human plasma, we performed 77 quantitative measurements of N-glyc... | After analysing glycans attached to human immunoglobulin G in 4,095 individuals, we performed the first genome-wide association study (GWAS) of the glycome of an individual protein. Nine genetic loci were found to associate with glycans with genome-wide significance. Of these, four were enzymes that directly participat... | Glycosylation is a ubiquitous post-translational protein modification that modulates the structure and function of polypeptide components of glycoproteins [1], [2]. N-glycan structures are essential for multicellular life [3]. Mutations in genes involved in modification of glycan antennae are common and can lead to sev... |
10.1371/journal.ppat.1006966 | The impact of serotype-specific vaccination on phylodynamic parameters of Streptococcus pneumoniae and the pneumococcal pan-genome | In the United States, the introduction of the heptavalent pneumococcal conjugate vaccine (PCV) largely eliminated vaccine serotypes (VT); non-vaccine serotypes (NVT) subsequently increased in carriage and disease. Vaccination also disrupts the composition of the pneumococcal pangenome, which includes mobile genetic ele... | Pneumococcal disease caused by the bacteria Streptococcus pneumoniae remains a significant cause of morbidity and mortality despite the existence of an effective vaccine. This is because the vaccines only target a small proportion of the total pneumococcal population. Introduction of vaccine in the United States remove... | Pneumococcal conjugate vaccines (PCV) target capsular serotype-specific polysaccharides of the respiratory pathogen Streptococcus pneumoniae, which causes substantial morbidity and mortality [1,2]. Since the heptavalent PCV and 13-valent PCV were introduced in the United States (US) in 2000 and 2010, respectively, thei... |
10.1371/journal.pcbi.1002672 | Interplay of Gene Expression Noise and Ultrasensitive Dynamics Affects Bacterial Operon Organization | Bacterial chromosomes are organized into polycistronic cotranscribed operons, but the evolutionary pressures maintaining them are unclear. We hypothesized that operons alter gene expression noise characteristics, resulting in selection for or against maintaining operons depending on network architecture. Mathematical m... | In some species, most notably bacteria, chromosomal genes are arranged into clusters called operons. In operons, the process of transcription is physically coupled: a single pass of the RNA polymerase enzyme reading that region of the chromosome simultaneously produces messenger RNA encoding multiple proteins. So far, ... | The organization of genes into operons is a prominent feature of bacterial chromosomes [1] that appear in some eukaryotes as well [2]. An operon is typically characterized as a promoter followed by multiple genes that are cotranscribed so that each transcription initiation event produces a polycistronic messenger RNA (... |
10.1371/journal.pgen.1007408 | The effector of Hippo signaling, Taz, is required for formation of the micropyle and fertilization in zebrafish | The mechanisms that ensure fertilization of egg by a sperm are not fully understood. In all teleosts, a channel called the ‘micropyle’ is the only route of entry for sperm to enter and fertilize the egg. The micropyle forms by penetration of the vitelline envelope by a single specialized follicle cell, the micropylar c... | In many fish, sperm enters eggs through a specialized channel called the ‘micropyle’. The micropyle is formed by a special follicle cell, the ‘micropylar cell’, which sits on the top of the developing egg during oogenesis, and forms the sperm entry canal. The underlying mechanisms of this process are unknown. We find t... | In vertebrates, fertilization occurs by two major strategies. Amniotes such as reptiles, birds and mammals, undergo copulation and internal insemination to ensure gamete fusion. The acrosome reaction is necessary for sperm to penetrate the zona pellucida, a protective egg envelope, and entry of sperm can occur at any p... |
10.1371/journal.pcbi.1006031 | Cytosolic proteins can exploit membrane localization to trigger functional assembly | Cell division, endocytosis, and viral budding would not function without the localization and assembly of protein complexes on membranes. What is poorly appreciated, however, is that by localizing to membranes, proteins search in a reduced space that effectively drives up concentration. Here we derive an accurate and p... | In a multitude of cellular processes, including cell division and endocytosis, proteins must bind to one another to form large multi-protein complexes. To initiate the formation of these critical multi-protein assemblies at the right time and the right place, the constituent proteins must be present at sufficient conce... | When clathrin, the essential cytosolic protein of clathrin-mediated endocytosis (CME), self-assembles into multi-protein cages, the same protein-protein contacts are used regardless of whether clathrin is in solution or on the membrane [1–3]. However, more binding [2] is observed on the membrane. A fundamental phenomen... |
10.1371/journal.pgen.1002706 | Loss of Gnas Imprinting Differentially Affects REM/NREM Sleep and Cognition in Mice | It has been suggested that imprinted genes are important in the regulation of sleep. However, the fundamental question of whether genomic imprinting has a role in sleep has remained elusive up to now. In this work we show that REM and NREM sleep states are differentially modulated by the maternally expressed imprinted ... | REM and NREM sleep are two distinct stages of the sleeping brain that are involved in the modulation of metabolic, physiological, and cognitive processes. Clinical evidence suggests that epigenetic mechanisms, such as genomic imprinting, play a role in sleep. Here we show that REM and NREM brain states are differential... | Mammalian evolution from the reptile lineage involved important changes in gene regulation and sleep. Many genetic mechanisms play important roles in various electrophysiological and behavioral traits that set the three major states of mammalian life: Wakefulness, Rapid Eye Movement (REM) and Non-REM (NREM) sleep [1], ... |
10.1371/journal.pntd.0004182 | Using Co-authorship Networks to Map and Analyse Global Neglected Tropical Disease Research with an Affiliation to Germany | Research on Neglected Tropical Diseases (NTDs) has increased in recent decades, and significant need-gaps in diagnostic and treatment tools remain. Analysing bibliometric data from published research is a powerful method for revealing research efforts, partnerships and expertise. We aim to identify and map NTD research... | Neglected tropical disease research has changed considerably in recent decades, and the German government is committed to addressing its past neglect of NTD research. Our aim was to use an innovative social network analysis of bibliometric data to map neglected tropical disease research networks that are inside of and ... | In recent decades, global efforts against neglected tropical diseases (NTDs) have undoubtedly been successful in raising awareness and implementing ambitious treatment programs [1]. NTD research and development (R&D) efforts have shown a substantial increase [2], and necessary resources have largely been made available... |
10.1371/journal.ppat.1002066 | Lymphoadenopathy during Lyme Borreliosis Is Caused by Spirochete Migration-Induced Specific B Cell Activation | Lymphadenopathy is a hallmark of acute infection with Borrelia burgdorferi, a tick-borne spirochete and causative agent of Lyme borreliosis, but the underlying causes and the functional consequences of this lymph node enlargement have not been revealed. The present study demonstrates that extracellular, live spirochete... | Acute Lyme Disease is one of the most important emerging diseases in the US. People with acute Lyme disease often develop swollen lymph nodes, or lymphadenopathy, but we do not know why this happens or what effect it has on the course of the disease. We show here that when mice are infected with live Borrelia burgdorfe... | Lyme borreliosis, caused by Borrelia burgdorferi transmitted by Ixodes spp. ticks, is the most common arthropod-borne illness in the US and Europe, and is increasing in prevalence and expanding in geographic distribution in the US [1], [2]. Clinical manifestations are highly varied, including involvement of the cutaneo... |
10.1371/journal.pcbi.1003611 | Histone Modifications Are Associated with Transcript Isoform Diversity in Normal and Cancer Cells | Mechanisms that generate transcript diversity are of fundamental importance in eukaryotes. Although a large fraction of human protein-coding genes and lincRNAs produce more than one mRNA isoform each, the regulation of this phenomenon is still incompletely understood. Much progress has been made in deciphering the role... | Traditionally, the regulation of gene expression was thought to be largely based on DNA and RNA sequence motifs. However, this dogma has recently been challenged as other factors, such as epigenetic patterning of the genome, have become better understood. Sparse but convincing experimental evidence suggests that the ep... | Molecular processes such as alternative splicing and transcription start-site switching are primary drivers of transcript diversity. About 95% of the ∼23,000 human genes are estimated to produce more than one mRNA isoform [1]. Beyond the genes with protein-coding potential, recent discoveries suggest that the approxima... |
10.1371/journal.pgen.1005704 | Retromer Is Essential for Autophagy-Dependent Plant Infection by the Rice Blast Fungus | The retromer mediates protein trafficking through recycling cargo from endosomes to the trans-Golgi network in eukaryotes. However, the role of such trafficking events during pathogen-host interaction remains unclear. Here, we report that the cargo-recognition complex (MoVps35, MoVps26 and MoVps29) of the retromer is e... | The rice blast fungus Magnaporthe oryzae utilizes key infection structures, called appressoria, elaborated at the tips of the conidial germ tubes to gain entry into the host tissue. Development of the appressorium is accompanied with autophagy in the conidium leading to programmed cell death. This work highlights the s... | Rice blast is one of the most serious and recurrent diseases destroying rice production worldwide [1,2]. The ascomycete fungus Magnaporthe oryzae infects rice tissues by forming a dome-shaped and melanized infection structure called appressorium [3,4]. Differentiation of appressorium is regulated by cell cycle progress... |
10.1371/journal.ppat.1005794 | Thermoregulation of Meningococcal fHbp, an Important Virulence Factor and Vaccine Antigen, Is Mediated by Anti-ribosomal Binding Site Sequences in the Open Reading Frame | During colonisation of the upper respiratory tract, bacteria are exposed to gradients of temperatures. Neisseria meningitidis is often present in the nasopharynx of healthy individuals, yet can occasionally cause severe disseminated disease. The meningococcus can evade the human complement system using a range of strat... | The bacterium Neisseria meningitidis is exquisitely adapted to survive in the human host, and possesses several mechanisms to interact with host cells in the upper airway and to circumvent immune responses. However, the mechanisms that govern the expression of factors that contribute to colonisation and disease are inc... | Neisseria meningitidis is a harmless member of the human nasopharyngeal flora in a significant proportion of healthy individuals [1]. However in some instances, the bacterium spreads from the upper airway into the systemic circulation, where it can replicate and spread to the rest of the body [2], especially the cerebr... |
10.1371/journal.pgen.1007287 | Identification and characterization of wheat stem rust resistance gene Sr21 effective against the Ug99 race group at high temperature | Wheat stem rust, caused by Puccinia graminis f. sp. tritici (Pgt), is a devastating foliar disease. The Ug99 race group has combined virulence to most stem rust (Sr) resistance genes deployed in wheat and is a threat to global wheat production. Here we identified a coiled-coil, nucleotide-binding leucine-rich repeat pr... | Wheat stem rust is a devastating disease that is threatening global wheat production. The emergence of new virulent races of this pathogen in Africa, including the Ug99 race group, has prompted global efforts to find effective resistance genes. We report here the identification of stem rust resistance gene Sr21 that is... | More than 700 million tons of wheat are produced every year, but further increases are needed to feed a rapidly growing human population. Reducing yield losses caused by wheat pathogens can contribute to this goal. Wheat stem rust, caused by the fungal pathogen Puccinia graminis f. sp. tritici (henceforth Pgt), poses a... |
10.1371/journal.ppat.1004075 | Cytosolic Peroxidases Protect the Lysosome of Bloodstream African Trypanosomes from Iron-Mediated Membrane Damage | African trypanosomes express three virtually identical non-selenium glutathione peroxidase (Px)-type enzymes which preferably detoxify lipid-derived hydroperoxides. As shown previously, bloodstream Trypanosoma brucei lacking the mitochondrial Px III display only a weak and transient proliferation defect whereas parasit... | In many cell types, mitochondria are the main source of intracellular reactive oxygen species but iron-induced oxidative lysosomal damage has been described as well. African trypanosomes are the causative agents of human sleeping sickness and the cattle disease Nagana. The parasites are obligate extracellular pathogens... | In many tissues, the mitochondrial electron transport chain constitutes the primary source of endogenously produced superoxide anion, the precursor molecule of most reactive oxygen species [1], [2]. Hydrogen peroxide and lipid hydroperoxides formed as products are primarily removed by glutathione peroxidases (GPxs) [3]... |
10.1371/journal.pgen.1001203 | Epigenetic Silencing of Spermatocyte-Specific and Neuronal Genes by SUMO Modification of the Transcription Factor Sp3 | SUMO modification of transcription factors is linked to repression of transcription. The physiological significance of SUMO attachment to a particular transcriptional regulator, however, is largely unknown. We have employed the ubiquitously expressed murine transcription factor Sp3 to analyze the role of SUMOylation in... | Cell type–specific gene expression patterns are largely regulated by positively or negatively acting transcription factors binding to promoter and enhancer elements. The ubiquitous transcription factor Sp3 represents a paradigm for a dual function transcription factor as it can activate and repress transcription. The r... | A plethora of proteins involved in regulating gene expression such as promoter-specific transcription factors, cofactors and chromatin-modifying enzymes are reversibly modified by the Small Ubiquitin-like MOdifier SUMO (reviewed in [1], [2]). With few exceptions, SUMO modification of transcriptional regulators correlat... |
10.1371/journal.pbio.1000542 | A Polarised Population of Dynamic Microtubules Mediates Homeostatic Length Control in Animal Cells | Because physical form and function are intimately linked, mechanisms that maintain cell shape and size within strict limits are likely to be important for a wide variety of biological processes. However, while intrinsic controls have been found to contribute to the relatively well-defined shape of bacteria and yeast ce... | Because many physical processes change with scale, size control is a fundamental problem for living systems. While in some instances the size of a structure is directly determined by the dimensions of its individual constituents, many biological structures are dynamic, self-organising assemblies of relatively small com... | The physical properties of a system depend to a large extent upon its scale. Therefore, it is not surprising to find that many biological structures are maintained within relatively tightly constrained size limits [1],[2]. In some cases, the dimensions of macromolecular assemblies are enforced by “molecular rulers” lik... |
10.1371/journal.ppat.1005018 | Human Immunodeficiency Virus Type 1 Nef Inhibits Autophagy through Transcription Factor EB Sequestration | HIV Nef acts as an anti-autophagic maturation factor through interaction with beclin-1 (BECN1). We report that exposure of macrophages to infectious or non-infectious purified HIV induces toll-like receptor 8 (TLR8) and BECN1 dependent dephosphorylation and nuclear translocation of TFEB and that this correlates with an... | Under basal conditions, the mammalian target of rapamycin (MTOR) phosphorylates transcription factor EB (TFEB) resulting in its cytoplasmic retention. When MTOR is inhibited, TFEB is dephosphorylated and translocated to the nucleus where it increases autophagy and lysosomal gene expression. As human immunodeficiency vi... | As an obligate intracellular parasite, human immunodeficiency virus type 1 (HIV) survival is dependent upon its ability to exploit host cell machinery for replication and dissemination, and to evade intrinsic cellular processes and defenses that may limit viral replication and pathogenesis including macroautophagy (her... |
10.1371/journal.pgen.1005415 | BMP Inhibition in Seminomas Initiates Acquisition of Pluripotency via NODAL Signaling Resulting in Reprogramming to an Embryonal Carcinoma | Type II germ cell cancers (GCC) can be subdivided into seminomas and non-seminomas. Seminomas are similar to carcinoma in situ (CIS) cells, the common precursor of type II GCCs, with regard to epigenetics and expression, while embryonal carcinomas (EC) are totipotent and differentiate into teratomas, yolk-sac tumors an... | The understanding of germ cell cancer pathogenesis is based on a linear model, where seminomas and non-seminomas represent distinct entities, although originating from a common precursor lesion, the carcinoma in situ. We demonstrate that germ cell cancer development is a microenvironment-dependent plastic process that ... | Type II germ cell cancers (GCC) arise from a precursor lesion termed carcinoma in situ (CIS) [1]. CIS cells are thought to be the result of a defective germ cell development and progress into seminomatous and non-seminomatous GCCs [1] [2]. Seminomas grow as a uniform tumor mass and are similar to CIS and PGCs with resp... |
10.1371/journal.pntd.0002484 | Ongoing Spillover of Hantaan and Gou Hantaviruses from Rodents Is Associated with Hemorrhagic Fever with Renal Syndrome (HFRS) in China | Longquan City, Zhejiang province, China, has been seriously affected by hemorrhagic fever with renal syndrome (HFRS) since the first cases were registered in 1974. To understand the epidemiology and emergence of HFRS in Longquan, which may be indicative of large parts of rural China, we studied long-term incidence patt... | Hemorrhagic fever with renal syndrome (HFRS) is a major public health problem in China despite human vaccination. We investigated the epidemiology and emergence of HFRS in Longquan (Zhejiang Province), a rural area with a high incidence of HFRS. During 1974–2011, a total of 1866 cases of HFRS were recorded in Longquan,... | Hantaviruses are important zoonotic pathogens. Although they can establish a persistent and asymptomatic infection in their natural rodent reservoirs [1], in humans hantaviruses can cause two severe diseases: hemorrhagic fever with renal syndrome (HFRS) and hantavirus (cardio) pulmonary syndrome (HPS) [2]. In Eurasia H... |
10.1371/journal.pcbi.1004065 | A Biologically Constrained, Mathematical Model of Cortical Wave Propagation Preceding Seizure Termination | Epilepsy—the condition of recurrent, unprovoked seizures—manifests in brain voltage activity with characteristic spatiotemporal patterns. These patterns include stereotyped semi-rhythmic activity produced by aggregate neuronal populations, and organized spatiotemporal phenomena, including waves. To assess these spatiot... | Nearly 50 million people worldwide suffer from epilepsy, a chronic neurological condition characterized by recurrent, unprovoked seizures. Although some clinical and biological principles of seizures are known, many aspects of spontaneous human seizures remain poorly understood. Recordings from electrodes placed direct... | Epilepsy is a dynamical disease [1] that manifests in many ways, including as organized patterns of brain voltage activity during a seizure. In general, a patient’s epilepsy may be classified through established clinical and imaging procedures and, based on the classification, a treatment strategy may be developed [2].... |
10.1371/journal.pcbi.1002724 | MOSAIC: A Multiscale Model of Osteogenesis and Sprouting Angiogenesis with Lateral Inhibition of Endothelial Cells | The healing of a fracture depends largely on the development of a new blood vessel network (angiogenesis) in the callus. During angiogenesis tip cells lead the developing sprout in response to extracellular signals, amongst which vascular endothelial growth factor (VEGF) is critical. In order to ensure a correct develo... | The healing of a fracture largely depends on the development of a new blood vessel network (angiogenesis), which can be investigated and simulated with mathematical models. The current mathematical models of angiogenesis during fracture healing do not, however, implement all relevant biological scales (e.g. a tissue, c... | The biological process of fracture healing comprises three main stages: (i) the “inflammation phase”, where the trauma site becomes hypoxic and is invaded by inflammatory cells, fibroblasts, endothelial cells and mesenchymal stem cells [1]; (ii) the “reparative phase”, which starts with the production of cartilaginous ... |
10.1371/journal.pgen.1001005 | Dual Roles for DNA Polymerase Theta in Alternative End-Joining Repair of Double-Strand Breaks in Drosophila | DNA double-strand breaks are repaired by multiple mechanisms that are roughly grouped into the categories of homology-directed repair and non-homologous end joining. End-joining repair can be further classified as either classical non-homologous end joining, which requires DNA ligase 4, or “alternative” end joining, wh... | DNA double-strand breaks, in which both strands of the DNA double helix are cut, must be recognized and accurately repaired in order to promote cell survival and prevent the accumulation of mutations. However, error-prone repair occasionally occurs, even when accurate repair is possible. We have investigated the geneti... | DNA double-strand breaks (DSBs) and interstrand crosslinks pose serious threats to cell survival and genome stability. Because these lesions compromise both strands of the double helix, they impede DNA replication and transcription and therefore must be removed in a timely and coordinated manner. Interstrand crosslink ... |
10.1371/journal.pgen.1004612 | Arabidopsis RRP6L1 and RRP6L2 Function in FLOWERING LOCUS C Silencing via Regulation of Antisense RNA Synthesis | The exosome complex functions in RNA metabolism and transcriptional gene silencing. Here, we report that mutations of two Arabidopsis genes encoding nuclear exosome components AtRRP6L1 and AtRRP6L2, cause de-repression of the main flowering repressor FLOWERING LOCUS C (FLC) and thus delay flowering in early-flowering A... | Arabidopsis FLOWERING LOCUS C (FLC) delays flowering; therefore, repressing expression of FLC provides a critical mechanism to regulate flowering. This mechanism involves multiple levels of regulation, including genetic regulation by transcription factors, and epigenetic regulation by modifications of genomic DNA and h... | The regulation of gene silencing occurs at multiple levels and non-coding RNAs (ncRNAs) have emerged as important regulators of genome silencing at the transcriptional and posttranscriptional levels [1]. At the chromatin structure level, chromatin remodeling factors and DNA- and histone-modifying enzymes alter chromati... |
10.1371/journal.ppat.1003749 | A Viral Genome Landscape of RNA Polyadenylation from KSHV Latent to Lytic Infection | RNA polyadenylation (pA) is one of the major steps in regulation of gene expression at the posttranscriptional level. In this report, a genome landscape of pA sites of viral transcripts in B lymphocytes with Kaposi sarcoma-associated herpesvirus (KSHV) infection was constructed using a modified PA-seq strategy. We iden... | A genome-wide polyadenylation landscape in the expression of human herpesviruses has not been reported. In this study, we provide the first genome landscape of viral RNA polyadenylation sites in B cells from KSHV latent to lytic infection by using a modified PA-seq protocol and selectively validated by 3′ RACE. We foun... | Kaposi sarcoma-associated herpesvirus (KSHV), also referred as human herpesvirus 8 (HHV-8), is a member of gammaherpervirus subfamily [1]. KSHV infection in healthy individuals is well-controlled by host immune system and other host factors, and hence, it is usually asymptomatic. However prolonged immunosuppression may... |
10.1371/journal.ppat.1003879 | Inflammatory Stimuli Reprogram Macrophage Phagocytosis to Macropinocytosis for the Rapid Elimination of Pathogens | Following an infectious challenge, macrophages have to be activated in order to allow efficient clearance of infectious pathogens, but how macrophage activation is coupled to increased clearance remains largely unknown. We here describe that inflammatory stimuli induced the reprogramming of the macrophage endocytic mac... | The main cells that are involved in cleaning up microbial pathogens are macrophages. Upon an infection, macrophages are being recruited to the site of infection by a number of different stimuli. In addition, during an infection, macrophages are also activated by cytokines such as interferon-γ and tumor necrosis factor-... | Macrophages are the main scavengers responsible for clearance of solutes and particulate material as well as to act as defense cells against invading microbes [1]. The main mechanisms via which macrophages can internalize and clear microbial material occurs through receptor-mediated phagocytosis. This process, making u... |
10.1371/journal.pntd.0001334 | Histopathological Changes and Clinical Responses of Buruli Ulcer Plaque Lesions during Chemotherapy: A Role for Surgical Removal of Necrotic Tissue? | Buruli ulcer (BU) caused by Mycobacterium ulcerans is a necrotizing skin disease usually starting with a subcutaneous nodule or plaque, which may ulcerate and progress, if untreated, over months and years. During the currently recommended antibiotic treatment with rifampicin/streptomycin plaque lesions tend to ulcerate... | The tropical necrotizing skin disease Buruli ulcer (BU) caused by Mycobacterium ulcerans is associated with extensive tissue destruction and local immunosuppression caused by the macrolide exotoxin mycolactone. Chemotherapy with a combination of rifampicin and streptomycin for 8 weeks is the currently recommended treat... | Buruli ulcer (BU), the third most common human mycobacterial disease, is caused by M. ulcerans [1], [2]. While the disease is present in around 30 countries worldwide the main focus with the highest prevalence is found in West African countries like Benin, Ghana, Cameroon and the Ivory Coast [3], [4]. Three categories ... |
10.1371/journal.pcbi.0030167 | Functional Representation of Enzymes by Specific Peptides | Predicting the function of a protein from its sequence is a long-standing goal of bioinformatic research. While sequence similarity is the most popular tool used for this purpose, sequence motifs may also subserve this goal. Here we develop a motif-based method consisting of applying an unsupervised motif extraction al... | Sequence motifs are known to provide information about functional properties of proteins. In the past, many approaches have looked for deterministic motifs in protein sequences, by searching for functionally over-represented k-mers, with moderate levels of success. Here we revisit and renew the utility of deterministic... | One of the major efforts of computational research in molecular biology is to predict the function and spatial structure of proteins from the protein sequence of amino acids [1,2]. Conventional approaches to function prediction rely on sequence [3] or structure [4] similarity with proteins whose functions are known. Th... |
10.1371/journal.ppat.1003682 | Bacterial Pathogens Activate a Common Inflammatory Pathway through IFNλ Regulation of PDCD4 | The type III interferon (IFNλ) receptor IL-28R is abundantly expressed in the respiratory tract and has been shown essential for host defense against some viral pathogens, however no data are available concerning its role in the innate immune response to bacterial pathogens. Staphylococcus aureus and Pseudomonas aerugi... | The role of interferons (types I, II, and III) in viral and bacterial infections has been a topic of intense research over the last decade. The contribution of the type I interferons during bacterial pneumonias particularly has been shown to be highly variable depending on the specific pathogen. Our data for the first ... | The interferon (IFN) family is composed of three subgroups (types I, II, and III IFN), and through their distinct receptors, IFNs signal through STAT transcription factors to upregulate expression of over 300 IFN dependent genes. In the lung bacterial pathogen associated molecular patterns (PAMPs) can be internalized a... |
10.1371/journal.pcbi.1005086 | Likelihood-Based Inference of B Cell Clonal Families | The human immune system depends on a highly diverse collection of antibody-making B cells. B cell receptor sequence diversity is generated by a random recombination process called “rearrangement” forming progenitor B cells, then a Darwinian process of lineage diversification and selection called “affinity maturation.” ... | Antibodies must recognize a great diversity of antigens to protect us from infectious disease. The binding properties of antibodies are determined by the DNA sequences of their corresponding B cell receptors (BCRs). These BCR sequences are created in naive form by VDJ recombination, which randomly selects and trims the... | B cells effect the antibody-mediated component of the adaptive immune system. The antigen-binding properties of B cells are defined by their B cell receptor, or BCR. BCRs bind a wide variety of antigens, and this flexibility arises from their developmental pathway. B cells begin life as hematopoietic stem cells. After ... |
10.1371/journal.ppat.1004020 | MAVS-MKK7-JNK2 Defines a Novel Apoptotic Signaling Pathway during Viral Infection | Viral infection induces innate immunity and apoptosis. Apoptosis is an effective means to sacrifice virus-infected host cells and therefore restrict the spread of pathogens. However, the underlying mechanisms of this process are still poorly understood. Here, we show that the mitochondrial antiviral signaling protein (... | The mitochondrial antiviral signaling protein (MAVS/VISA/Cardif/IPS-1) is critical for the innate immune response during viral infection, and its function has been well documented in mediating type I interferon production. In this study, we revealed the essential role of MAVS in virus-induced apoptosis, independent of ... | The induction of innate immunity upon viral infection represents the first line of host defense against microbe invasion. During infection with a RNA virus, the mitochondrial antiviral signaling protein (MAVS/VISA/Cardif/IPS-1) has been recently uncovered to seed a critical protein complex on the mitochondrial outer me... |
10.1371/journal.pgen.1000354 | LINE Retrotransposon RNA Is an Essential Structural and Functional Epigenetic Component of a Core Neocentromeric Chromatin | We have previously identified and characterized the phenomenon of ectopic human centromeres, known as neocentromeres. Human neocentromeres form epigenetically at euchromatic chromosomal sites and are structurally and functionally similar to normal human centromeres. Recent studies have indicated that neocentromere form... | The centromere is an essential chromosomal structure for the correct segregation of chromosomes during cell division. Normal human centromeres comprise a 171-bp α-satellite DNA arranged into tandem and higher-order arrays. Neocentromeres are fully functional centromeres that form epigenetically on noncentromeric region... | Despite the fact that the functional role of the centromere in mitotic and meiotic cell divisions is evolutionarily conserved, the underlying DNA sequences of the centromeres are highly variable across the phylogeny and show no obvious conservation [1],[2]. Thus, a conundrum remains as to whether there are any specific... |
10.1371/journal.ppat.1002769 | Linking the Transcriptional Profiles and the Physiological States of Mycobacterium tuberculosis during an Extended Intracellular Infection | Intracellular pathogens such as Mycobacterium tuberculosis have evolved strategies for coping with the pressures encountered inside host cells. The ability to coordinate global gene expression in response to environmental and internal cues is one key to their success. Prolonged survival and replication within macrophag... | The impact of Mycobacterium tuberculosis on global health is undeniable, with ∼2 million deaths and ∼9 million new cases of tuberculosis each year. A key to the success of M. tuberculosis as a persistent, intracellular pathogen is its ability to survive for extended periods within professional phagocytes. Sustained gro... | Mycobacterium tuberculosis (Mtb) has evolved successful strategies to survive in the human host and thwart the attempts of the immune system to eradicate it. The astounding morbidity and mortality caused by Mtb – with roughly 9 million new cases and 2 million deaths annually – is a testament to the success of this endu... |
10.1371/journal.pgen.1005671 | RNA Polymerase III Output Is Functionally Linked to tRNA Dimethyl-G26 Modification | Control of the differential abundance or activity of tRNAs can be important determinants of gene regulation. RNA polymerase (RNAP) III synthesizes all tRNAs in eukaryotes and it derepression is associated with cancer. Maf1 is a conserved general repressor of RNAP III under the control of the target of rapamycin (TOR) t... | Transfer RNAs (tRNAs) are molecular adapters necessary for translation of the genetic code from DNA to messenger RNA (mRNA) to synthesis of the proteins that constitute the energy producing enzymes and structural components of all cells and organisms on earth. In eukaryotic cells, tRNAs are synthesized by RNA polymeras... | Apart from their role in translation, tRNAs can regulate gene expression [1,2] and serve as metabolic sensors [3], and their over-expression is associated with cell proliferation and transformation [4,5]. RNAP III is activated by oncogenes [6,7] whereas its repression reduces transformation and tumorigenesis [8].
Accu... |
10.1371/journal.ppat.1005826 | The Invertebrate Lysozyme Effector ILYS-3 Is Systemically Activated in Response to Danger Signals and Confers Antimicrobial Protection in C. elegans | Little is known about the relative contributions and importance of antibacterial effectors in the nematode C. elegans, despite extensive work on the innate immune responses in this organism. We report an investigation of the expression, function and regulation of the six ilys (invertebrate-type lysozyme) genes of C. el... | Innate immune defenses against bacterial pathogenesis depend on the activation of antibacterial factors. We examined the expression and relative importance of a gene family encoding six invertebrate-type lysozymes in the much-studied nematode C. elegans. The ilys genes exhibit distinct patterns of tissue-specific expre... | Most animal epithelia possess innate defense systems that sense pathogenic and toxic insults and transmit stranger/danger signals to activate appropriate counter measures. The efficacy with which animals can respond to pathogens determines whether organismal homeostasis can be maintained and microbial clearance achieve... |
10.1371/journal.pgen.1004733 | A Complex Genetic Switch Involving Overlapping Divergent Promoters and DNA Looping Regulates Expression of Conjugation Genes of a Gram-positive Plasmid | Plasmid conjugation plays a significant role in the dissemination of antibiotic resistance and pathogenicity determinants. Understanding how conjugation is regulated is important to gain insights into these features. Little is known about regulation of conjugation systems present on plasmids from Gram-positive bacteria... | Plasmids are extrachromosomal, autonomously replicating units that are harbored by many bacteria. Many plasmids encode transfer function allowing them to be transferred into plasmid-free bacteria by a process named conjugation. Since many of them also carry antibiotic resistance genes, plasmid-mediated conjugation is a... | Bacteria exchange genetic material at high rates by different processes, which are collectively named Horizontal Gene Transfer (HGT). HGT can be beneficial for bacteria because the newly acquired DNA may endow them with novel features enabling them to adapt to changing conditions in the environment, i.e. rapid evolutio... |
10.1371/journal.ppat.1000292 | Differences in APOBEC3G Expression in CD4+ T Helper Lymphocyte Subtypes Modulate HIV-1 Infectivity | The cytidine deaminases APOBEC3G and APOBEC3F exert anti–HIV-1 activity that is countered by the HIV-1 vif protein. Based on potential transcription factor binding sites in their putative promoters, we hypothesized that expression of APOBEC3G and APOBEC3F would vary with T helper lymphocyte differentiation. Naive CD4+ ... | Some host cell proteins can hinder, or restrict, the life cycle of HIV-1. APOBEC3G and APOBEC3F are cellular enzymes that decrease HIV-1's ability to replicate in a subsequent target cell if they are present in the virus particle. As a countermeasure, HIV-1 virion infectivity factor (vif) induces degradation of APOBEC3... | APOBEC3G (hA3G) and APOBEC3F (hA3F), two of several related cytidine deaminases, evolved to limit retrotransposition [1]–[3]. Although the HIV-1 accessory protein vif depletes hA3G and hA3F from the producer cell, hA3G and hA3F are packaged into vif-deleted HIV-1 and significantly impair virion infectivity [4]–[6]. IFN... |
10.1371/journal.pntd.0002232 | Seroprevalence of Entamoeba histolytica Infection among Chinese Men Who Have Sex with Men | Men who have sex with men (MSM) were found to be one of the high-risk populations for Entamoeba histolytica (E. histolytica) infection. Accompanied by the prevalence of human immunodeficiency virus (HIV) among MSM, invasive amebiasis caused by E. histolytica has been paid attention to as an opportunistic parasitic infe... | Entamoeba histolytica (E. histolytica) is a very common human gastrointestinal parasitic disease which affects 50 million people worldwide. Men who have sex with men (MSM) have already been found to be one of the high-risk populations with E. histolytica infection. Previous studies have reported an increased risk for E... | Entamoeba histolytica (E. histolytica) has a worldwide distribution and is endemic in most developing countries. Invasive amebiasis (IA) caused by E. histolytica is a very common human gastrointestinal parasitic disease which affected 50 million people worldwide and caused greater than 100,000 deaths annually. High ris... |
10.1371/journal.ppat.1001131 | Dengue Virus Ensures Its Fusion in Late Endosomes Using Compartment-Specific Lipids | Many enveloped viruses invade cells via endocytosis and use different environmental factors as triggers for virus-endosome fusion that delivers viral genome into cytosol. Intriguingly, dengue virus (DEN), the most prevalent mosquito-borne virus that infects up to 100 million people each year, fuses only in late endosom... | Dengue virus infection is a growing public health problem with up to 100 million cases annually, and neither vaccines nor effective therapies are available. To search for the ways of preventing and treating dengue infections we need to better understand their molecular mechanisms. As with many other viruses, dengue vir... | With almost half of the world's population at risk for dengue infections, including life-threatening dengue hemorrhagic fever and dengue shock syndrome [1], the lack of vaccines and effective therapies lends urgency to the search for new targets for antiviral drugs. In this work we have focused on the membrane fusion s... |
10.1371/journal.pntd.0002435 | Hospital-Based Surveillance for Viral Hemorrhagic Fevers and Hepatitides in Ghana | Viral hemorrhagic fevers (VHF) are acute diseases associated with bleeding, organ failure, and shock. VHF may hardly be distinguished clinically from other diseases in the African hospital, including viral hepatitis. This study was conducted to determine if VHF and viral hepatitis contribute to hospital morbidity in th... | Ghana is endemic for yellow fever and lies between two Lassa fever endemic areas — Guinea, Liberia, Sierra Leone, and Mali in the West, and Nigeria in the East. Ebola hemorrhagic fever has been documented in the neighboring Cote d'Ivoire. Thus, it is plausible that the latter VHFs also occur in Ghana, and there have be... | Viral hemorrhagic fevers (VHF) are acute viral diseases associated with bleeding, organ failure, and shock. The syndrome is caused by RNA viruses belonging to the families Filoviridae (Ebola and Marburg virus), Arenaviridae (Lassa virus), Bunyaviridae (Crimean-Congo hemorrhagic fever [CCHF] and Rift Valley fever [RVF] ... |
10.1371/journal.pcbi.1002179 | Computational Modeling of Allosteric Communication Reveals Organizing Principles of Mutation-Induced Signaling in ABL and EGFR Kinases | The emerging structural information about allosteric kinase complexes and the growing number of allosteric inhibitors call for a systematic strategy to delineate and classify mechanisms of allosteric regulation and long-range communication that control kinase activity. In this work, we have investigated mechanistic asp... | Despite recent progress in computational and experimental studies of dynamic regulation in protein kinases, a mechanistic understanding of long-range communication and mechanisms of mutation-induced signaling controlling kinase activity remains largely qualitative. In this study, we have performed a systematic modeling... | The phenomenon of allosteric communication is fundamental to many biological processes and is recognized as an important factor governing molecular regulation of signal transduction networks [1], [2]. Theoretical and computational studies of allostery in biomolecular systems have witnessed a recent renaissance fueled b... |
10.1371/journal.pbio.1001256 | Multi-Cellular Rosettes in the Mouse Visceral Endoderm Facilitate the Ordered Migration of Anterior Visceral Endoderm Cells | The visceral endoderm (VE) is a simple epithelium that forms the outer layer of the egg-cylinder stage mouse embryo. The anterior visceral endoderm (AVE), a specialised subset of VE cells, is responsible for specifying anterior pattern. AVE cells show a stereotypic migratory behaviour within the VE, which is responsibl... | The mouse visceral endoderm (VE) is a simple epithelium in the egg cylinder stage mouse embryo. Many functions associated with epithelia require them to undergo extensive remodelling through changes in the shape and relative positions of constituent cells, a process about which we understand relatively little. The ante... | Epithelia have structural and functional roles throughout embryonic development and adult life. Their organised, cohesive nature makes them ideal for lining structures and acting as selective barriers. Epithelia show distinct apical-basolateral polarity, with the apical domain characterised by junctional complexes that... |
10.1371/journal.pcbi.1004289 | PF2 fit: Polar Fast Fourier Matched Alignment of Atomistic Structures with 3D Electron Microscopy Maps | There continue to be increasing occurrences of both atomistic structure models in the PDB (possibly reconstructed from X-ray diffraction or NMR data), and 3D reconstructed cryo-electron microscopy (3D EM) maps (albeit at coarser resolution) of the same or homologous molecule or molecular assembly, deposited in the EMDB... | In recent years, advances in cryo-electron microscopy (cryoEM) and three-dimensional (3D) image reconstruction have made it possible to determine the structures of molecular complexes, to sub-nanometer resolutions. These reconstructed 3D cryoEM maps provide a unique challenge, since the resolutions are often sufficient... | Protein structural data is available in primarily two forms. Atomistic scale structures (or atomic structures for short), acquired through X-ray or nuclear magnetic resonance (NMR) imaging, contain information fine enough to localize the position of most, if not all, the atoms of the protein. However these imaging moda... |
10.1371/journal.pgen.1005875 | Which Genetics Variants in DNase-Seq Footprints Are More Likely to Alter Binding? | Large experimental efforts are characterizing the regulatory genome, yet we are still missing a systematic definition of functional and silent genetic variants in non-coding regions. Here, we integrated DNaseI footprinting data with sequence-based transcription factor (TF) motif models to predict the impact of a geneti... | A large fraction of genetic variants that have been associated with complex traits are found outside of protein coding genes and likely affect gene regulation. Many experimental efforts have been dedicated to mapping regulatory regions in the genome but there are not many systematic methods that integrate functional da... | Despite large ongoing efforts to characterize regulatory regions in the human genome (e.g., ENCODE [1], Roadmap Epigenomics [2]), the lack of a regulatory genetic code to discriminate functional from silent non-coding variants in regulatory sequences poses severe limitations in interpreting the results of many human an... |
10.1371/journal.pntd.0001882 | Genetic Diversity within Schistosoma haematobium: DNA Barcoding Reveals Two Distinct Groups | Schistosomiasis in one of the most prevalent parasitic diseases, affecting millions of people and animals in developing countries. Amongst the human-infective species S. haematobium is one of the most widespread causing urogenital schistosomiasis, a major human health problem across Africa, however in terms of research... | Schistosomiasis is a disease caused by parasitic blood flukes of the genus Schistosoma. Species that infect humans are prevalent in developing countries, having a major impact on public health and well-being as well as an impediment to socioeconomic development. More people are infected with Schistosoma haematobium tha... | Schistosomiasis remains one of the world's greatest neglected tropical diseases (NTD). Schistosoma haematobium is one of the most widespread species of Schistosoma and causes urogenital schistosomiasis in humans. More people are infected with S. haematobium than with all the other schistosome species combined. Of the >... |
10.1371/journal.pntd.0005152 | Transfected Babesia bovis Expressing a Tick GST as a Live Vector Vaccine | The Rhipicephalus microplus tick is a notorious blood-feeding ectoparasite of livestock, especially cattle, responsible for massive losses in animal production. It is the main vector for transmission of pathogenic bacteria and parasites, including Babesia bovis, an intraerythrocytic apicomplexan protozoan parasite resp... | The cattle tick Rhipicephalus microplus is a hematophagous ectoparasite, responsible for the transmission of lethal parasites such as Babesia sp, limiting cattle production in tropical and subtropical regions of the world. There is an urgent emerging need for improved methods of control for these currently neglected ti... | The cattle tick Rhipicephalus microplus is a hematophagous ectoparasite limiting cattle production in tropical and subtropical regions of the world [1–4]. Methods to lessen the impact of R. microplus are based almost exclusively on the use of several chemical acaricides, including arsenics, organophosphorus, carbamates... |
10.1371/journal.ppat.1000007 | The Interferon Response Inhibits HIV Particle Production by Induction of TRIM22 | Treatment of human cells with Type 1 interferons restricts HIV replication. Here we report that the tripartite motif protein TRIM22 is a key mediator. We used transcriptional profiling to identify cellular genes that were induced by interferon treatment and identified TRIM22 as one of the most strongly up-regulated gen... | Interferons are produced by cells in response to challenge by foreign pathogens such as viruses. The molecular mechanisms by which Type I interferons (e.g., IFNβ) inhibit the replication of HIV-1 are not fully clarified. We identified a gene called TRIM22 that belongs to the tripartite motif (TRIM) family that was stro... | The interferon system is a well studied branch of the innate immune system active against viruses. Infection of vertebrate cells by many viruses provokes synthesis and secretion of interferons (IFNs), which mediate induction of a cellular antiviral state that obstructs further viral spread. Type I IFNs (α and β) are pr... |
10.1371/journal.ppat.1004192 | Protective Efficacy of Passive Immunization with Monoclonal Antibodies in Animal Models of H5N1 Highly Pathogenic Avian Influenza Virus Infection | Highly pathogenic avian influenza (HPAI) viruses of the H5N1 subtype often cause severe pneumonia and multiple organ failure in humans, with reported case fatality rates of more than 60%. To develop a clinical antibody therapy, we generated a human-mouse chimeric monoclonal antibody (MAb) ch61 that showed strong neutra... | The H5N1 highly pathogenic avian influenza virus has been circulating in poultry in Asia, the Middle East, and Africa since its first appearance in southern China in 1996. This virus occasionally infects humans with a high case mortality rate and poses a significant pandemic threat. Since neutralizing antibodies genera... | Influenza A viruses are divided into subtypes based on the antigenicity of two envelope glycoproteins, hemagglutinin (HA) and neuraminidase (NA). To date, H1-H16 HA and N1-N9 NA subtypes have been found in wild aquatic birds, the natural reservoir of influenza viruses [1]–[3]. Of these HA subtypes, only some avian infl... |
10.1371/journal.pntd.0002794 | Designing a Community Engagement Framework for a New Dengue Control Method: A Case Study from Central Vietnam | The Wolbachia strategy aims to manipulate mosquito populations to make them incapable of transmitting dengue viruses between people. To test its efficacy, this strategy requires field trials. Public consultation and engagement are recognized as critical to the future success of these programs, but questions remain rega... | In recent years, a number of new strategies using novel technologies for the control of dengue fever control have emerged. These strategies are notably different from their predecessors and not without controversy. Many also require open release field trials to test their efficacy. Public consultation and engagement ar... | The Wolbachia strategy aims to ‘manipulate mosquito populations to make them incapable of transmitting dengue viruses between people’ (www.eliminatedengue.com). Its potential emerged following the successful transference of the insect bacterium Wolbachia pipientis from the fruit fly Drosophila melanogaster into the Aed... |
10.1371/journal.pgen.1001235 | Endocytic Sorting and Recycling Require Membrane Phosphatidylserine Asymmetry Maintained by TAT-1/CHAT-1 | Endocytic sorting is achieved through the formation of morphologically and functionally distinct sub-domains within early endosomes. Cargoes destined for recycling are sorted to and transported through newly-formed tubular membranes, but the processes that regulate membrane tubulation are poorly understood. Here, we id... | The process by which cells take up nutrients and other large molecules from the extracellular environment is known as endocytosis. At the cell surface, external molecules become enclosed in membrane spheres called endosomes. Early endosomes serve as a sorting station, directing the contents (cargo molecules) to the cor... | In eukaryotic cells, internalized cargoes are transported to early endosomes where they are sorted to be recycled back to the plasma membrane, degraded in lysosomes or delivered to the trans-Golgi network. Early endosomes display a complex and pleiomorphic organization with many tubular processes emanating from central... |
10.1371/journal.pntd.0002853 | Clinical and Parasitological Protection in a Leishmania infantum-Macaque Model Vaccinated with Adenovirus and the Recombinant A2 Antigen | Visceral leishmaniasis (VL) is a severe vector-born disease of humans and dogs caused by Leishmania donovani complex parasites. Approximately 0.2 to 0.4 million new human VL cases occur annually worldwide. In the new world, these alarming numbers are primarily due to the impracticality of current control methods based ... | Human visceral leishmaniasis causes significant morbidity and mortality, constituting an important global health problem. Absence of safe and cost effective anti-leishmanial drugs, together with emergence of drug resistance and HIV co-infection have posed a serious challenge to the disease containment. Given the urgent... | Human VL is a severe systemic disease caused by protozoan parasites of the Leishmania donovani complex [1]. It remains one of the major infectious diseases primarily affecting some of the poorest regions of the world, with an estimated occurrence of approximately 0.2 to 0.4 million new cases of clinical VL annually wor... |
10.1371/journal.ppat.1002210 | A Communal Bacterial Adhesin Anchors Biofilm and Bystander Cells to Surfaces | While the exopolysaccharide component of the biofilm matrix has been intensively studied, much less is known about matrix-associated proteins. To better understand the role of these proteins, we undertook a proteomic analysis of the V. cholerae biofilm matrix. Here we show that the two matrix-associated proteins, Bap1 ... | The bacterial multilayer biofilm consists of matrix-enclosed cells attached to each other to form large aggregates. The base of these aggregates may be attached to a living or non-living surface. The biofilm matrix most often contains at least one exopolysaccharide component and may also contain protein and DNA. While ... | Bacterial biofilm formation is the process by which bacteria attach to abiotic surfaces, the surfaces of other unicellular organisms, the epithelia of multicellular organisms, and interfaces such as that between air and water. Surface adhesion enables bacteria to arrange themselves favorably in their environment and, t... |
10.1371/journal.pntd.0000960 | Options for Active Case Detection of Visceral Leishmaniasis in Endemic Districts of India, Nepal and Bangladesh, Comparing Yield, Feasibility and Costs | The VL elimination strategy requires cost-effective tools for case detection and management. This intervention study tests the yield, feasibility and cost of 4 different active case detection (ACD) strategies (camp, index case, incentive and blanket approach) in VL endemic districts of India, Nepal and Bangladesh.
Firs... | For the elimination of any infectious disease (i.e., reduction of the burden of a serious public health problem to a minor problem which can be managed by the general health services) the right mix of public health tools has to be identified for the early detection and successful treatment of new cases as well as effec... | India, Nepal and Bangladesh have committed to eliminate VL by 2015 and have adopted multiple public health strategies towards the elimination goal of reducing VL cases to less than 1 per 10,000 population [1]. Treatment with Miltefosine, the first oral effective drug, the possibility of an effective safe and affordable... |
10.1371/journal.pcbi.1000135 | Prediction by Graph Theoretic Measures of Structural Effects in Proteins Arising from Non-Synonymous Single Nucleotide Polymorphisms | Recent analyses of human genome sequences have given rise to impressive advances in identifying non-synonymous single nucleotide polymorphisms (nsSNPs). By contrast, the annotation of nsSNPs and their links to diseases are progressing at a much slower pace. Many of the current approaches to analysing disease-associated... | Non-synonymous single nucleotide polymorphisms (nsSNPs) are single base differences between individual genomes that lead to amino acid changes in protein sequences. They may influence an individual's susceptibility to disease or response to drugs through their impacts on a protein's structure and hence cause functional... | The introduction of large-scale genome sequencing technologies has dramatically increased the number of single nucleotide polymorphisms (SNPs) in public databases. For example, the NCBI (National Center for Biotechnology Information) dbSNP database [1], which is a major repository of human SNPs, contained data about te... |
10.1371/journal.pntd.0003193 | Evaluation of a Dengue NS1 Antigen Detection Assay Sensitivity and Specificity for the Diagnosis of Acute Dengue Virus Infection | Currently, no dengue NS1 detection kit has regulatory approval for the diagnosis of acute dengue fever. Here we report the sensitivity and specificity of the InBios DEN Detect NS1 ELISA using a panel of well characterized human acute fever serum specimens.
The InBios DENV Detect NS1 ELISA was tested using a panel compo... | Infections by the mosquito-transmitted dengue virus continue to increase, threatening the health of people in over a hundred countries worldwide. The lack of effective mosquito control, licensed dengue vaccines or specific therapeutics to treat dengue infections presents challenges to reduce the burden of this disease.... | Dengue fever (DF) and dengue hemorrhagic fever (DHF) are mosquito-borne illnesses caused by infection with four related, but antigenically-distinct, dengue viruses (DENV1, DENV2, DENV3, DENV4). The virus is thought to be responsible for close to 400 million infections per year worldwide, of which approximately 100 mill... |
10.1371/journal.pgen.1005857 | Chromatoid Body Protein TDRD6 Supports Long 3’ UTR Triggered Nonsense Mediated mRNA Decay | Chromatoid bodies (CBs) are spermiogenesis-specific organelles of largely unknown function. CBs harbor various RNA species, RNA-associated proteins and proteins of the tudor domain family like TDRD6, which is required for a proper CB architecture. Proteome analysis of purified CBs revealed components of the nonsense-me... | Tudor-domain containing protein 6 (TDRD6) is a central component of the chromatoid body (CB) in male germ cells. Chromatoid bodies, which are present in spermatids, contain RNA and protein, are not enclosed by membranes, and typically reside close to the nucleus. Without TDRD6, a much distorted CB structure is observed... | During mammalian gametogenesis, substantial changes in chromosome structure and in gene expression profiles occur. Male germ cell transcription and transcriptomes have been studied quite extensively. Some transcriptome studies concern the whole testis, and thus represent combined somatic and germ cell data, which limit... |
10.1371/journal.pbio.1002274 | Scaling the Drosophila Wing: TOR-Dependent Target Gene Access by the Hippo Pathway Transducer Yorkie | Organ growth is controlled by patterning signals that operate locally (e.g., Wingless/Ints [Wnts], Bone Morphogenetic Proteins [BMPs], and Hedgehogs [Hhs]) and scaled by nutrient-dependent signals that act systemically (e.g., Insulin-like peptides [ILPs] transduced by the Target of Rapamycin [TOR] pathway). How cells i... | What mechanisms control the sizes of animal organs? It is known that organ growth is the product of two systems: an intrinsic system that coordinates cell proliferation with the specification of cell fate (patterning), and an extrinsic system that synchronizes growth with nutrient levels. Developing organs integrate th... | A universal property of animal development is the capacity to scale body size and pattern in response to environmental conditions as well as during evolution [1]. For example, when starved during the larval growth phase, Drosophila adults emerge at around one quarter of their normal size but are correctly proportioned.... |
10.1371/journal.pntd.0004391 | Multi-Locus Sequence Typing of Bartonella bacilliformis DNA Performed Directly from Blood of Patients with Oroya’s Fever During a Peruvian Outbreak | Bartonella bacilliformis is the etiological agent of Carrion’s disease, a neglected tropical poverty-linked illness. This infection is endemic of Andean regions and it is estimated that approximately 1.7 million of South Americans are at risk. This bacterium is a fastidious slow growing microorganism, which is difficul... | The bacteria Bartonella bacilliformis is the etiological agent of Carrion’s disease, which is a neglected poverty-related disease, related to Mountain Andean valleys of Peru, Colombia and Ecuador. This disease, in absence of treatment presents a high mortality during the acute phase, called Oroya’s Fever. The second ph... | Carrion’s disease is neglected tropical neglected poverty-linked illness caused by Bartonella bacilliformis. This infection is endemic in low-income areas of Peru, specifically related to Andean regions from Peru, Ecuador and Colombia, covering roughly 145,000Km2 only in Peru, and it is estimated that approximately 1.7... |
10.1371/journal.pntd.0002396 | Adhesins of Leptospira interrogans Mediate the Interaction to Fibrinogen and Inhibit Fibrin Clot Formation In Vitro | We report in this work that Leptospira strains, virulent L. interrogans serovar Copenhageni, attenuated L. interrogans serovar Copenhageni and saprophytic L. biflexa serovar Patoc are capable of binding fibrinogen (Fg). The interaction of leptospires with Fg inhibits thrombin- induced fibrin clot formation that may aff... | Leptospirosis is probably the most widespread zoonosis in the world. Caused by spirochaetes of the genus Leptospira, it has greater incidence in tropical and subtropical regions. The disease has become prevalent in cities with sanitation problems and a large population of urban rodent reservoirs, which contaminate the ... | The spirochete Leptospira interrogans is a highly invasive pathogen and the causal agent of leptospirosis, one of the most widespread zoonosis of human and veterinary concern [1], [2]. The transmission occurs through contact with environmental water contaminated by leptospires shed in the urine of animal carriers [1], ... |
10.1371/journal.pgen.1005838 | Continuous Influx of Genetic Material from Host to Virus Populations | Many genes of large double-stranded DNA viruses have a cellular origin, suggesting that host-to-virus horizontal transfer (HT) of DNA is recurrent. Yet, the frequency of these transfers has never been assessed in viral populations. Here we used ultra-deep DNA sequencing of 21 baculovirus populations extracted from two ... | While gene exchange is known to occur between viruses and their hosts, this phenomenon has never been studied at the level of the viral population. Here we report that each time a virus from the Baculoviridae family infects a moth, a large number (dozens to hundreds) and high diversity of moth DNA sequences (86 differe... | The genomes of large eukaryotic double-stranded DNA viruses contain high proportions of cellular genes resulting from host-to-virus horizontal transfers (HT) [1–4]. For example, at least 10% of giant virus genes and up to 30% of herpesvirus genes likely originated from eukaryote or prokaryote genomes [1, 5, 6]. Some of... |
10.1371/journal.pcbi.1002059 | How Structure Determines Correlations in Neuronal Networks | Networks are becoming a ubiquitous metaphor for the understanding of complex biological systems, spanning the range between molecular signalling pathways, neural networks in the brain, and interacting species in a food web. In many models, we face an intricate interplay between the topology of the network and the dynam... | Many biological systems have been described as networks whose complex properties influence the behaviour of the system. Correlations of activity in such networks are of interest in a variety of fields, from gene-regulatory networks to neuroscience. Due to novel experimental techniques allowing the recording of the acti... | Analysis of networks of interacting elements has become a tool for system analysis in many areas of biology, including the study of interacting species [1], cell dynamics [2] and the brain [3]. A fundamental question is how the dynamics, and eventually the function, of the system as a whole depends on the characteristi... |
10.1371/journal.pntd.0005064 | Investigating the Contribution of Peri-domestic Transmission to Risk of Zoonotic Malaria Infection in Humans | In recent years, the primate malaria Plasmodium knowlesi has emerged in human populations throughout South East Asia, with the largest hotspot being in Sabah, Malaysian Borneo. Control efforts are hindered by limited knowledge of where and when people get exposed to mosquito vectors. It is assumed that exposure occurs ... | The primate knowlesi malaria has now emerged in human populations throughout South East Asia. Our limited knowledge of where and when people get exposed to the vector (Anopheles balabacensis) has resulted in poor control measures, although it is assumed that exposure occurs primarily when people are working in forest a... | The success story of reducing malaria worldwide [1] has been marred by a few notable exceptions where bulk of disease is caused by zoonotic “neglected” malaria species with atypical transmission that makes them less easy to control. Zoonotic malaria, such as Plasmodium knowlesi from the long tailed macaque (Macaca fasc... |
10.1371/journal.pcbi.0030212 | Self-organizing Mechanism for Development of Space-filling Neuronal Dendrites | Neurons develop distinctive dendritic morphologies to receive and process information. Previous experiments showed that competitive dendro-dendritic interactions play critical roles in shaping dendrites of the space-filling type, which uniformly cover their receptive field. We incorporated this finding in constructing ... | Neurons elaborate two types of neuronal extensions. One is axon, which sends outputs to other neurons. Another is dendrite, which is specialized for receiving and processing synaptic or sensory inputs. Like elaborated branches of trees, the shape of dendrites is quite variable from one type to another, and different de... | One of the primary interests in developmental biology is the emergence of function through morphogenesis. Morphological diversity of dendrites and its impact on neuronal computation perfectly represents the importance of this problem: shapes of dendrites are highly variable from one neuronal type to another, and it has... |
10.1371/journal.pntd.0006620 | Dynamic changes in human-gut microbiome in relation to a placebo-controlled anthelminthic trial in Indonesia | Microbiome studies suggest the presence of an interaction between the human gut microbiome and soil-transmitted helminth. Upon deworming, a complex interaction between the anthelminthic drug, helminths and microbiome composition might occur. To dissect this, we analyse the changes that take place in the gut bacteria pr... | Studying the relationship between soil-transmitted helminthiasis and gut microbiota is becoming more important as both have been implicated in modulating immune system in various inflammatory diseases. However, findings of previous studies of the effect of helminth on the microbiome are inconsistent. In this study, an ... | Shortly after birth, the human body is colonized by a community of bacteria [1, 2] with relatively simple composition which increase in number and complexity with age [3]. The densest colonization with commensal microbes of the human body is found in the intestine [4] which has a beneficial impact on gastro-intestinal ... |
10.1371/journal.pgen.1001228 | Competitive Repair by Naturally Dispersed Repetitive DNA during Non-Allelic Homologous Recombination | Genome rearrangements often result from non-allelic homologous recombination (NAHR) between repetitive DNA elements dispersed throughout the genome. Here we systematically analyze NAHR between Ty retrotransposons using a genome-wide approach that exploits unique features of Saccharomyces cerevisiae purebred and Sacchar... | The human genome is structurally dynamic, frequently undergoing loss, duplication, and rearrangement of large chromosome segments. These structural changes occur both in normal and in cancerous cells and are thought to cause both benign and deleterious changes in cell function. Many of these structural alterations are ... | Human structural variation contributes to phenotypic differences and susceptibility to disease [1]. Recent studies suggest that many structural variants are mediated by non-allelic homologous recombination (NAHR) between dispersed repetitive DNA elements [2]–[5]. While the importance of NAHR in shaping genome structure... |
10.1371/journal.pntd.0003214 | Hyperferritinaemia in Dengue Virus Infected Patients Is Associated with Immune Activation and Coagulation Disturbances | During a dengue outbreak on the Caribbean island Aruba, highly elevated levels of ferritin were detected in dengue virus infected patients. Ferritin is an acute-phase reactant and hyperferritinaemia is a hallmark of diseases caused by extensive immune activation, such as haemophagocytic lymphohistiocytosis. The aim of ... | Ferritin is an acute-phase reactant and produced by reticulo-endothelial cells in response to inflammation and infection. In general, ferritin levels are increased in inflammatory conditions, but in this study we found that ferritin levels were much higher in dengue virus infected patients than in patients with other f... | Outbreaks of dengue virus (DENV) infection have become more frequent in the American and Caribbean region, even threatening to spread in the United States [1]. DENV is a flavivirus, which is transmitted by the bite of an Aedes mosquito. Brazil is the country with most reported dengue cases in the Americas. A large DENV... |
10.1371/journal.pcbi.1004599 | Direct Measurements of Local Coupling between Myosin Molecules Are Consistent with a Model of Muscle Activation | Muscle contracts due to ATP-dependent interactions of myosin motors with thin filaments composed of the proteins actin, troponin, and tropomyosin. Contraction is initiated when calcium binds to troponin, which changes conformation and displaces tropomyosin, a filamentous protein that wraps around the actin filament, th... | Despite decades of study, there is no clear connection between muscle contraction at the molecular and the macroscopic scale. For example, we cannot yet predict how a genetic defect in a muscle protein will result in a physiological change in the heart. This multi-scale understanding is difficult, in part, because mole... | Muscle contraction underlies most voluntary and involuntary motion of multicellular animals. The last 100 years have revolutionized our understanding of this process. Advances in light microscopy in the early 20th century culminated in the sliding filament theory, the discovery that muscle contracts via the relative sl... |
10.1371/journal.pcbi.1002663 | Dependencies among Editing Sites in Serotonin 2C Receptor mRNA | The serotonin 2C receptor (5-HT2CR)–a key regulator of diverse neurological processes–exhibits functional variability derived from editing of its pre-mRNA by site-specific adenosine deamination (A-to-I pre-mRNA editing) in five distinct sites. Here we describe a statistical technique that was developed for analysis of ... | The serotonin receptor 2C is a key regulator of diverse neurological processes that affect feeding behavior, sleep, sexual behavior, anxiety and depression. The function of the receptor itself is regulated via so-called pre-mRNA editing, i.e. site-specific adenosine deamination in five distinct sites. The greater the n... | The serotonin receptor 2C (5-HT2CR) is widely distributed within the central nervous system [1], [2], where it mediates diverse neurological processes that affect feeding behavior, sleep, sexual activity, anxiety and depression [reviewed in [3], [4]]. The 5-HT2CR protein belongs to the G-protein-coupled receptor (GPCR)... |
10.1371/journal.ppat.1008040 | HLA-B locus products resist degradation by the human cytomegalovirus immunoevasin US11 | To escape CD8+ T-cell immunity, human cytomegalovirus (HCMV) US11 redirects MHC-I for rapid ER-associated proteolytic degradation (ERAD). In humans, classical MHC-I molecules are encoded by the highly polymorphic HLA-A, -B and -C gene loci. While HLA-C resists US11 degradation, the specificity for HLA-A and HLA-B produ... | The human immune system can cover the presentation of a wide array of pathogen derived antigens owing to the three extraordinary polymorphic MHC class I (MHC-I) gene loci, called HLA-A, -B and -C in humans. Studying the HLA peptide ligands of human cytomegalovirus (HCMV) infected cells, we realized that the HCMV encode... | Human cytomegalovirus (HCMV) represents a prototypic β-herpesvirus persisting throughout life in its host with periodic phases of latency and reactivation of productive infection. Despite rare cases of clinical disease in healthy individuals, HCMV has a permanent impact on immune cells, e.g. resulting in the extraordin... |
10.1371/journal.pgen.1002540 | A Downstream CpG Island Controls Transcript Initiation and Elongation and the Methylation State of the Imprinted Airn Macro ncRNA Promoter | A CpG island (CGI) lies at the 5′ end of the Airn macro non-protein-coding (nc) RNA that represses the flanking Igf2r promoter in cis on paternally inherited chromosomes. In addition to being modified on maternally inherited chromosomes by a DNA methylation imprint, the Airn CGI shows two unusual organization features:... | CpG islands are CG-rich regions associated with the majority of mammalian promoters. Although widely considered to be necessary for promoter activity, their exact function is unknown. CpG islands are mostly unmethylated during development and differentiate with notable exceptions including imprinted genes and genes on ... | Atypical CpG-rich regions known as CpG islands (CGIs) overlap 60–70% of mammalian transcription start sites [1]. Although most CGIs extend downstream of the transcription start and are therefore partly transcribed, they are considered to have promoter regulatory functions and are often described as ‘CGI promoters’. A r... |
10.1371/journal.pgen.1004487 | Comparative Phylogenomics Uncovers the Impact of Symbiotic Associations on Host Genome Evolution | Mutualistic symbioses between eukaryotes and beneficial microorganisms of their microbiome play an essential role in nutrition, protection against disease, and development of the host. However, the impact of beneficial symbionts on the evolution of host genomes remains poorly characterized. Here we used the independent... | Symbiotic associations between eukaryotes and microbes play essential roles in the nutrition, health and behavior of both partners. It is well accepted that hosts control and shape their associated microbiome. In this study, we provide evidence that symbiotic microbes also participate in the evolution of host genomes. ... | Eukaryotes interact with microbes in a dynamic network of symbiotic associations. These associations represent a continuum from parasitic, where one partner takes advantage of the other one, to mutualistic, where both partners benefit from the interaction. Mutualistic symbioses between eukaryotes and a subset of their ... |
10.1371/journal.pgen.1007383 | Analysis of motor dysfunction in Down Syndrome reveals motor neuron degeneration | Down Syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and results in a spectrum of phenotypes including learning and memory deficits, and motor dysfunction. It has been hypothesized that an additional copy of a few Hsa21 dosage-sensitive genes causes these phenotypes, but this has been challenged by observat... | Down Syndrome is caused by an extra copy of chromosome 21 and results in many different phenotypes including learning difficulties, Alzheimer’s disease and problems with motor function such as abnormal gait and poor fine motor skills. These different phenotypes are thought to result from an increased copy of one more o... | Down Syndrome (DS), trisomy 21, is characterized by a wide range of phenotypes including cognitive deficits, early-onset Alzheimer’s disease, locomotor dysfunction and congenital heart defects [1, 2]. These diverse phenotypes could be caused by small numbers of dosage-sensitive genes on Hsa21 whose increased copy numbe... |
10.1371/journal.pntd.0001039 | Microarray-Based Analysis of Differential Gene Expression between
Infective and Noninfective Larvae of Strongyloides
stercoralis | Differences between noninfective first-stage (L1) and infective third-stage (L3i)
larvae of parasitic nematode Strongyloides stercoralis at the
molecular level are relatively uncharacterized. DNA microarrays were developed and
utilized for this purpose.
Oligonucleot... | Strongyloides stercoralis is a soil-transmitted helminth that
affects an estimated 30–100 million people worldwide. Chronically infected
persons who are exposed to corticosteroids can develop disseminated disease, which
carries a high mortality (87–100%) if untreated. Despit... | Strongyloides stercoralis is a parasitic nematode endemic to the
tropics and subtropics that infects an estimated 30–100 million people worldwide.
Chronically infected individuals have the potential to develop hyperinfection syndrome
or disseminated disease, clinical entities that ca... |
10.1371/journal.pcbi.1004882 | Estimating Time of Infection Using Prior Serological and Individual Information Can Greatly Improve Incidence Estimation of Human and Wildlife Infections | Diseases of humans and wildlife are typically tracked and studied through incidence, the number of new infections per time unit. Estimating incidence is not without difficulties, as asymptomatic infections, low sampling intervals and low sample sizes can introduce large estimation errors. After infection, biomarkers su... | Human and wildlife diseases can be tracked by looking at incidence, which is the number of new infections per time unit (typically day, week or month). While theoretically this would only be a matter of counting the number of newly infected individuals, in reality these data are difficult to acquire due to limited samp... | Infection incidence (the number of new infections per time unit) is a basic epidemiological measure that describes the transmission of an infection through time. Because the exact time at which an individual acquired an infection is difficult to assess, time of symptom onset is often used as a proxy (e.g. [1]). When th... |
10.1371/journal.ppat.1005017 | A Structural and Functional Comparison Between Infectious and Non-Infectious Autocatalytic Recombinant PrP Conformers | Infectious prions contain a self-propagating, misfolded conformer of the prion protein termed PrPSc. A critical prediction of the protein-only hypothesis is that autocatalytic PrPSc molecules should be infectious. However, some autocatalytic recombinant PrPSc molecules have low or undetectable levels of specific infect... | A key prediction of the prion hypothesis is that autocatalytic, misfolded PrPSc molecules should be highly infectious. Various recombinant PrPSc conformers are able to self-propagate in vitro, yet paradoxically only some of these conformers possess significant levels of specific infectivity in bioassays. Here we use tw... | The conformational conversion of the host-encoded prion protein (PrP) is a central pathogenic event in the prion diseases [1]. In healthy individuals, PrP adopts a fold that is rich in α-helix, termed PrPC, and is post-translationally modified by the incorporation of N-linked glycans and a C-terminal glycosylphosphatid... |
10.1371/journal.pntd.0005705 | Climate change and sugarcane expansion increase Hantavirus infection risk | Hantavirus Cardiopulmonary Syndrome (HCPS) is a disease caused by Hantavirus, which is highly virulent for humans. High temperatures and conversion of native vegetation to agriculture, particularly sugarcane cultivation can alter abundance of rodent generalist species that serve as the principal reservoir host for HCPS... | Hantavirus, hosted by rodent species, causes HCPS, a disease with a 50% mortality rate in humans. The conversion of native vegetation to sugarcane increases the abundance of hantavirus reservoir rodent species, augmenting disease risk. Additionally, temperature also has positive effects on disease risk because it affec... | Global average temperatures are projected to increase between 1.7 and 4.8°C by the end of this century [1,2], with potential effects on human health, including mortality from extreme heat and cold, and changes in the ecology of infectious diseases [3–5]. Climatic variability and extreme weather events have profound imp... |
10.1371/journal.ppat.1000538 | Salmonella Typhimurium Type III Secretion Effectors Stimulate Innate Immune Responses in Cultured Epithelial Cells | Recognition of conserved bacterial products by innate immune receptors leads to inflammatory responses that control pathogen spread but that can also result in pathology. Intestinal epithelial cells are exposed to bacterial products and therefore must prevent signaling through innate immune receptors to avoid pathology... | Salmonella Typhimurium is one of the most common causes of food-borne illness in the United States and a major cause of diarrheal diseases in developing countries. This pathogen induces diarrhea by stimulating inflammation in the intestinal tract. This study shows that S. Typhimurium delivers molecules into epithelial ... | It is widely believed that one of the main triggers of host inflammation is the recognition of microbial products by receptors of the innate immune system [1]–[3]. Conserved microbial products, collectively known as “pathogen-associated molecular patterns” (PAMPS), stimulate specific host receptors triggering a variety... |
10.1371/journal.pntd.0002454 | Sequence Analysis and Serological Responses against Borrelia turicatae BipA, a Putative Species-Specific Antigen | Relapsing fever spirochetes are global yet neglected pathogens causing recurrent febrile episodes, chills, nausea, vomiting, and pregnancy complications. Given these nonspecific clinical manifestations, improving diagnostic assays for relapsing fever spirochetes will allow for identification of endemic foci and expedit... | Undiagnosed febrile illnesses continue to afflict those in resource poor countries. Relapsing fever spirochetes are one such pathogen causing a significant health burden, yet the pathogenesis, ecology, and distribution of B. turicatae is understudied. To address these shortcomings, we analyzed the amino acid sequence o... | Three causative agents of tick-borne relapsing fever borreliosis in the New World are Borrelia hermsii, Borrelia parkeri, and Borrelia turicatae, with B. hermsii being the most epidemiologically and ecologically characterized species [1]. While B. hermsii is distributed in high elevation coniferous forests and maintain... |
10.1371/journal.pgen.1003210 | A Newly Uncovered Group of Distantly Related Lysine Methyltransferases Preferentially Interact with Molecular Chaperones to Regulate Their Activity | Methylation is a post-translational modification that can affect numerous features of proteins, notably cellular localization, turnover, activity, and molecular interactions. Recent genome-wide analyses have considerably extended the list of human genes encoding putative methyltransferases. Studies on protein methyltra... | Methylation, or transfer of a single or multiple methyl groups (CH3), is one of many post-translational modifications that occur on proteins. Such modifications can, in turn, affect numerous aspects of a protein, notably cellular localization, turnover, activity, and molecular interactions. In addition to post-translat... | Methyltransferases catalyze the transfer of a methyl group (CH3) from a donor, generally S-adenosyl-L-methionine (AdoMet), to various acceptor molecules such as proteins, DNA, RNA, lipids, and small metabolites [1]–[3]. Protein N-methylation predominantly targets the side chains of two amino acids, lysine and arginine,... |
10.1371/journal.pntd.0004082 | Altered Protein Expression in the Ileum of Mice Associated with the Development of Chronic Infections with Echinostoma caproni (Trematoda) | Echinostoma caproni (Trematoda: Echinostomatidae) is an intestinal trematode that has been extensively used as experimental model to investigate the factors determining the expulsion of intestinal helminths or, in contrast, the development of chronic infections. Herein, we analyze the changes in protein expression indu... | Intestinal helminth infections are among the most prevalent parasitic diseases and about 1 billion people are currently infected with intestinal helminths. Incidence of intestinal helminth infections is high due to both socio-economic factors that facilitates continuous re-infections and the lack of effective vaccines.... | Intestinal helminth infections are among the most prevalent parasitic diseases. Recent studies have estimated that about 1 billion people are currently infected with at least one species of intestinal helminth mainly in developing regions of Asia, Africa and Latin-America [1]. Although intestinal helminths rarely kill ... |
10.1371/journal.pgen.1004654 | Mechanism of Suppression of Chromosomal Instability by DNA Polymerase POLQ | Although a defect in the DNA polymerase POLQ leads to ionizing radiation sensitivity in mammalian cells, the relevant enzymatic pathway has not been identified. Here we define the specific mechanism by which POLQ restricts harmful DNA instability. Our experiments show that Polq-null murine cells are selectively hyperse... | The reason for the hypersensitivity of POLQ-defective mammalian cells to ionizing radiation has been elusive. Here we show that POLQ-defective mammalian cells are selectively susceptible to double-strand breaks in DNA. We present experiments in mammalian cells showing that a specific double-strand break repair pathway ... | A diverse group of at least 16 DNA polymerases carry out DNA replication, repair, and damage tolerance in the mammalian genome [1], [2]. One of these is DNA polymerase theta (POLQ). POLQ homologs are found in multicellular eukaryotes including plants, but an equivalent enzyme is absent from yeast [3]. The large 290 kDa... |
10.1371/journal.pgen.1005638 | Tissue-Specific Effects of Reduced β-catenin Expression on Adenomatous Polyposis Coli Mutation-Instigated Tumorigenesis in Mouse Colon and Ovarian Epithelium | Adenomatous polyposis coli (APC) inactivating mutations are present in most human colorectal cancers and some other cancers. The APC protein regulates the β-catenin protein pool that functions as a co-activator of T cell factor (TCF)-regulated transcription in Wnt pathway signaling. We studied effects of reduced dosage... | Enhanced Wnt signaling contributes to colorectal and other cancers. β-catenin functions in Wnt signaling as a T cell factor (TCF) transcriptional co-activator. Previous studies showed specific β-catenin dosage favors Wnt signaling-dependent tumorigenesis for some tumor types. However, earlier studies emphasized the rol... | Colorectal cancers (CRCs) harbor accumulated mutations in tumor suppressor genes and oncogenes along with epigenetic alterations. Many CRCs arise from precursor lesions, such as adenomatous polyps or serrated epithelial lesions with dysplasia. Inactivating mutations in the APC (adenomatous polyposis coli) and TP53 tumo... |
10.1371/journal.pgen.1008136 | Mck1 defines a key S-phase checkpoint effector in response to various degrees of replication threats | The S-phase checkpoint plays an essential role in regulation of the ribonucleotide reductase (RNR) activity to maintain the dNTP pools. How eukaryotic cells respond appropriately to different levels of replication threats remains elusive. Here, we have identified that a conserved GSK-3 kinase Mck1 cooperates with Dun1 ... | The appropriate amount and balance of four dNTPs are crucial for all cells correctly copying and passing on their genetic material generation by generation. Eukaryotes have developed an alert and response system to deal with the disturbance. Here, we uncovered a second-level effector branch. It is activated by the upst... | To ensure the genome stability, DNA replication is under strict surveillance by the S-phase checkpoint (also known as the intra-S or replication checkpoint) in all eukaryotes [1–5]. The main kinases of the cascade, Mec1ATR and Rad53CHK2, are activated in response to aberrations in DNA replication [6–10]. Among all the ... |
10.1371/journal.pntd.0006802 | Histoplasma capsulatum antigen detection tests as an essential diagnostic tool for patients with advanced HIV disease in low and middle income countries: A systematic review of diagnostic accuracy studies | Disseminated histoplasmosis, a disease that often resembles and is mistaken for tuberculosis, is a major cause of death in patients with advanced HIV disease. Histoplasma antigen detection tests are an important addition to the diagnostic arsenal for patients with advanced HIV disease and should be considered for inclu... | Disseminated histoplasmosis, a disease that often resembles and is mistaken for tuberculosis, is a major cause of death in patients with advanced HIV disease. Histoplasma antigen detection tests are an important addition to the diagnostic arsenal for patients with advanced HIV disease and should be considered for inclu... | Histoplasmosis was first described in Panama in 1906 in a patient who appeared to have miliary tuberculosis, a confusion that is still very much present today.[1] Disseminated histoplasmosis has been an AIDS-defining infection since 1987.[2,3] Recent estimates using different methods converge on the conclusion that, in... |
10.1371/journal.pbio.1000419 | Active RNA Polymerases: Mobile or Immobile Molecular Machines? | It is widely assumed that active RNA polymerases track along their templates to produce a transcript. We test this using chromosome conformation capture and human genes switched on rapidly and synchronously by tumour necrosis factor alpha (TNFα); one is 221 kbp SAMD4A, which a polymerase takes more than 1 h to transcri... | We were all taught that an RNA polymerase becomes active by diffusing to a promoter, initiating transcription, and then tracking like a locomotive down the DNA template. We test this using tumour necrosis factor alpha (TNFα) to switch on transcription of two human genes which lie far apart on the genetic map and then m... | It is widely assumed that an RNA polymerase transcribes by diffusing to a promoter, binding, and then tracking down the template as it makes its transcript [1]. Accumulating evidence, however, is consistent with an alternative: a promoter diffuses to a transcription factory where it binds to a transiently immobilized p... |
10.1371/journal.pgen.1002169 | NatF Contributes to an Evolutionary Shift in Protein N-Terminal Acetylation and Is Important for Normal Chromosome Segregation | N-terminal acetylation (N-Ac) is a highly abundant eukaryotic protein modification. Proteomics revealed a significant increase in the occurrence of N-Ac from lower to higher eukaryotes, but evidence explaining the underlying molecular mechanism(s) is currently lacking. We first analysed protein N-termini and their acet... | Small chemical groups are commonly attached to proteins in order to control their activity, localization, and stability. An abundant protein modification is N-terminal acetylation, in which an N-terminal acetyltransferase (NAT) catalyzes the transfer of an acetyl group to the very N-terminal amino acid of the protein. ... | N-terminal acetylation (N-Ac) is a common modification of proteins, but its general role has remained rather enigmatic. For specific proteins, N-Ac is recognized as an important regulator of function and localization [1]–[4]. Recently, it was suggested that it may act as a general destabilization signal for some yeast ... |
10.1371/journal.ppat.1006272 | The aromatic amino acid hydroxylase genes AAH1 and AAH2 in Toxoplasma gondii contribute to transmission in the cat | The Toxoplasma gondii genome contains two aromatic amino acid hydroxylase genes, AAH1 and AAH2 encode proteins that produce L-DOPA, which can serve as a precursor of catecholamine neurotransmitters. It has been suggested that this pathway elevates host dopamine levels thus making infected rodents less fearful of their ... | Toxoplasma gondii is an intracellular parasite that infects up to one-quarter of humans worldwide. Although it can infect virtually any warm-blooded animal, its definitive host is the cat where the sexual cycle occurs in enterocytes of the small intestine, producing microscopic, durable oocysts that are shed in feces a... | Toxoplasma gondii is an obligate intracellular parasite and a member of the phylum Apicomplexa. It is related to Plasmodium spp., the causative agents of malaria, as well as parasites of human and veterinary importance including Cryptosporidium spp., Eimeria spp., and Neospora spp. T. gondii is one of the most widely d... |
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