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10.1371/journal.pgen.1007093 | MITF – A controls branching morphogenesis and nephron endowment | Congenital nephron number varies widely in the human population and individuals with low nephron number are at risk of developing hypertension and chronic kidney disease. The development of the kidney occurs via an orchestrated morphogenetic process where metanephric mesenchyme and ureteric bud reciprocally interact to... | The number of nephrons, the functional unit of kidney, varies widely among humans. Indeed, it has been shown that kidneys may contain from 0.3 to more than 2 million of nephrons. Nephrons are formed during development via a coordinated morphogenetic program in which the metanephric mesenchyme reciprocally and recursive... | For decades, it was believed that the number of nephrons in the kidneys does not vary among normal individuals. However, several studies performed over the last 30 years have clearly demonstrated that the number of nephrons varies widely among human populations and even among healthy individuals of the same ethnicity [... |
10.1371/journal.pgen.1007168 | Genetic variants in pachyonychia congenita-associated keratins increase susceptibility to tooth decay | Pachyonychia congenita (PC) is a cutaneous disorder primarily characterized by nail dystrophy and painful palmoplantar keratoderma. PC is caused by mutations in KRT6A, KRT6B, KRT6C, KRT16, and KRT17, a set of keratin genes expressed in the nail bed, palmoplantar epidermis, oral mucosal epithelium, hair follicle and swe... | Tooth decay, more commonly known as dental cavities, is the most common chronic disease worldwide, both in children and in adults. It consists in the destruction of tooth enamel, the outer layer of the teeth, by acid-producing bacteria. Enamel is the hardest tissue in the body, comprised of 96% minerals. However, it co... | Tooth enamel is made of 96% hydroxyapatite minerals, which makes it the hardest tissue in the human body. Enamel is also the first compartment of the tooth to be attacked by dental caries, a chronic disease that affects 42% of children and 92% of adults, with various degrees of severity (number of teeth and tooth surfa... |
10.1371/journal.ppat.1002498 | The Intracellular DNA Sensor IFI16 Gene Acts as Restriction Factor for Human Cytomegalovirus Replication | Human interferon (IFN)-inducible IFI16 protein, an innate immune sensor of intracellular DNA, modulates various cell functions, however, its role in regulating virus growth remains unresolved. Here, we adopt two approaches to investigate whether IFI16 exerts pro- and/or anti-viral actions. First, the IFI16 gene was sil... | Only recently, intrinsic cellular-based defense mechanisms which give cells the capacity to resist pathogens have been discovered as an essential component of immunity. However, unlike the innate and adaptive branches of the immune system, intrinsic immune defenses are mediated by cellular restriction factors that are ... | Human Cytomegalovirus (HCMV) is a β-Herpesvirus that commonly and persistently infects humans [1]–[2]. HCMV does not constitute a serious threat to immunocompetent individuals, but causes life-threatening complications in individuals with suppressed immune systems, such as patients with AIDS, cancer patients undergoing... |
10.1371/journal.pntd.0000550 | Role of the Endogenous Antioxidant System in the Protection of Schistosoma mansoni Primary Sporocysts against Exogenous Oxidative Stress | Antioxidants produced by the parasite Schistosoma mansoni are believed to be involved in the maintenance of cellular redox balance, thus contributing to larval survival in their intermediate snail host, Biomphalaria glabrata. Here, we focused on specific antioxidant enzymes, including glutathione-S-transferases 26 and ... | Species of the human blood fluke Schistosoma are estimated to infect approximately 200 million people worldwide, resulting in loss of health, vitality and productivity mainly among the world's poorest inhabitants. Since snail intermediate hosts represent an essential part of the flukes' life cycle, an understanding of ... | Miracidial penetration and entry into the molluscan intermediate host represent a critical transition period in which the previously free-living larval stage is now confronted with a potentially hostile environment as it attempts to establish a viable infection [1],[2]. Miracidia of the human blood fluke Schistosoma ma... |
10.1371/journal.pcbi.1007208 | Where did you come from, where did you go: Refining metagenomic analysis tools for horizontal gene transfer characterisation | Horizontal gene transfer (HGT) has changed the way we regard evolution. Instead of waiting for the next generation to establish new traits, especially bacteria are able to take a shortcut via HGT that enables them to pass on genes from one individual to another, even across species boundaries. The tool Daisy offers the... | Evolution is traditionally viewed as a process where changes are only vertically inherited from parent to offspring across generations. Many principles such as phylogenetic trees and even the “tree of life” are based on that doctrine. The concept of horizontal gene transfer changed the way we regard evolution completel... | For a long time, evolution in terms of gene transfer was thought to happen only along the tree of life, i.e. from parent to offspring generation. The discovery of horizontal gene transfer (HGT) [1–4] has revolutionised this dogma, and revealed the mechanism that enables bacteria to quickly adapt to environmental pressu... |
10.1371/journal.pntd.0001553 | Mapping of Schistosomiasis and Soil-Transmitted Helminthiasis in the Regions of Centre, East and West Cameroon | Schistosomiasis and soil-transmitted helminthiasis (STH) are widely distributed in Cameroon. Although mass drug administration (MDA) of mebendazole is implemented nationwide, treatment with praziquantel was so far limited to the three northern regions and few health districts in the southern part of Cameroon, based on ... | Schistosomiasis and soil-transmitted helminthiasis (STH) are a major public health problem in Cameroon. The national control strategy of these diseases was based on historical data collected 25 years ago, which might be outdated in some situations due to several factors including control activities, improved or degrade... | Recent years have witnessed an increased interest in the control of neglected tropical diseases (NTDs), and today there exists a global momentum for the control of these diseases, as well as an unprecedented opportunity for cost-effective action, through an integrated control [1]–[5]. Interest in the integrated control... |
10.1371/journal.pntd.0005884 | Feasibility of utilizing the SD BIOLINE Onchocerciasis IgG4 rapid test in onchocerciasis surveillance in Senegal | As effective onchocerciasis control efforts in Africa transition to elimination efforts, different diagnostic tools are required to support country programs. Senegal, with its long standing, successful control program, is transitioning to using the SD BIOLINE Onchocerciasis IgG4 (Ov16) rapid test over traditional skin ... | As onchocerciasis control programs succeed and transition to elimination efforts, different diagnostic tools are needed. The goal of this study was to determine if integrating the Ov16 rapid test is feasible based on acceptability, usability, and cost. A study was conducted in 13 villages in southeastern Senegal in May... | Onchocerciasis, commonly known as river blindness, is caused by the filarial parasite O. volvulus (Ov) that affects an estimated 37 million people, with an estimated 187 million living in areas at risk of infection, primarily in Africa.[1,2] An estimated 1.1 million disability-adjusted life years (DALYs) were lost in 2... |
10.1371/journal.ppat.1002674 | A Single Polar Residue and Distinct Membrane Topologies Impact the Function of the Infectious Bronchitis Coronavirus E Protein | The coronavirus E protein is a small membrane protein with a single predicted hydrophobic domain (HD), and has a poorly defined role in infection. The E protein is thought to promote virion assembly, which occurs in the Golgi region of infected cells. It has also been implicated in the release of infectious particles a... | Coronaviruses are enveloped viruses that bud and assemble intracellularly, and therefore must use the host secretory pathway for release. Coronavirus E is a small protein that contains a single predicted hydrophobic domain and is targeted to the Golgi region. The E protein has been implicated in the assembly of coronav... | Coronaviruses (CoVs) are enveloped, positive strand RNA viruses that infect a variety of mammalian and avian species. In humans, CoVs are responsible for nearly 20% of common cold cases. CoVs can also lead to more serious disease as seen during the outbreak of the severe acute respiratory syndrome coronavirus (SARS-CoV... |
10.1371/journal.pcbi.1003151 | Improving Pharmacokinetic-Pharmacodynamic Modeling to Investigate Anti-Infective Chemotherapy with Application to the Current Generation of Antimalarial Drugs | Mechanism-based pharmacokinetic-pharmacodynamic (PK/PD) modelling is the standard computational technique for simulating drug treatment of infectious diseases with the potential to enhance our understanding of drug treatment outcomes, drug deployment strategies, and dosing regimens. Standard methodologies assume only a... | Pharmacokinetic-pharmacodynamic (PK/PD) models of infectious diseases provide vital insights into the effectiveness of drug treatments (including the optimal dosage level, frequency and duration) by explicitly relating drug concentration after treatment to a pathogen kill rate, and ultimately the models describe whethe... | Most human infections are currently treatable by drugs. Clinical trials remain the gold standard, empirical approach guiding drug deployment policy and practical issues such as dosing regimes. However in silico simulations based on computational predictions of drug treatment outcome have the potential to play a vital a... |
10.1371/journal.ppat.1003571 | Schistosoma mansoni Mucin Gene (SmPoMuc) Expression: Epigenetic Control to Shape Adaptation to a New Host | The digenetic trematode Schistosoma mansoni is a human parasite that uses the mollusc Biomphalaria glabrata as intermediate host. Specific S. mansoni strains can infect efficiently only certain B. glabrata strains (compatible strain) while others are incompatible. Strain-specific differences in transcription of a conse... | Schistosoma mansoni is a parasitic worm and agent of a disease that causes a considerable economic burden in African and South American countries. The propagation of the parasite requires passage through a freshwater snail of Biomphalaria genus. In the field, actually very few snails are infected. This is due to the fa... | The interaction of hosts and parasites is one of the best-studied examples of evolution in a changing environment [1]. Their reciprocal antagonistic co-evolution can be illustrated by an arms race in which host and parasite develop mechanisms to circumvent counter-measures developed by their opponents [2], [3]. Under c... |
10.1371/journal.pcbi.1001072 | Ribavirin-Induced Anemia in Hepatitis C Virus Patients Undergoing Combination Therapy | The current standard of care for hepatitis C virus (HCV) infection – combination therapy with pegylated interferon and ribavirin – elicits sustained responses in only ∼50% of the patients treated. No alternatives exist for patients who do not respond to combination therapy. Addition of ribavirin substantially improves ... | The treatment of HCV infection poses a major global health-care challenge today. The current standard of care, combination therapy with interferon and ribavirin, works in only about half of the patients treated. Because no alternatives are available yet for patients in whom combination therapy fails, identifying ways t... | 130–170 million people worldwide are currently infected with hepatitis C virus (HCV) [1]. Over 70% of HCV infections become chronic and if untreated may lead to cirrhosis and hepatocellular carcinoma, necessitating liver transplantation [1]. The standard of care for HCV infection involves combination therapy with pegyl... |
10.1371/journal.ppat.1003914 | Genome-Wide RNAi Screen Identifies Broadly-Acting Host Factors That Inhibit Arbovirus Infection | Vector-borne viruses are an important class of emerging and re-emerging pathogens; thus, an improved understanding of the cellular factors that modulate infection in their respective vertebrate and insect hosts may aid control efforts. In particular, cell-intrinsic antiviral pathways restrict vector-borne viruses inclu... | West Nile virus (WNV) is an insect-borne virus that has re-emerged globally and for which there are no specific therapeutics or vaccines. We set out to identify cellular factors that impact infection using Drosophila as a model insect. Using a genome-wide RNAi screen we identified a large number of genes that altered W... | Historically, West Nile virus (WNV) epidemics were observed in Africa, the Middle East, Europe, India, Australia, and parts of Asia, In 1999, WNV entered into the North America as part of an outbreak of neuroinvasive disease in New York City [1], and since then has become endemic in the United States with large numbers... |
10.1371/journal.pntd.0005633 | First evidence of lymphatic filariasis transmission interruption in Cameroon: Progress towards elimination | Lymphatic filariasis (LF) is among the 10 neglected tropical diseases targeted for control or elimination by 2020. For LF elimination, the World Health Organization (WHO) has proposed a comprehensive strategy including (i) interruption of LF transmission through large-scale annual treatment (or mass drug administration... | Lymphatic filariasis (LF) affects more than 120 million people worldwide, and is considered the second leading cause of permanent and long-term disability. In response to the important burden of this disease, the World Health Organization (WHO) elaborated a strategic plan to eliminate LF as a public health problem thro... | Lymphatic filariasis (LF) is among the most widespread neglected tropical diseases. In the mid-1990s, it was reported that about 1.4 billion people were exposed to the disease worldwide, of whom 120 million were infected and more than 40 million disfigured by the disease [1].
One of the core resolutions of the 50th Wo... |
10.1371/journal.pntd.0001326 | Schistosomiais and Soil-Transmitted Helminth Control in Niger: Cost Effectiveness of School Based and Community Distributed Mass Drug Administration | In 2004 Niger established a large scale schistosomiasis and soil-transmitted helminths control programme targeting children aged 5–14 years and adults. In two years 4.3 million treatments were delivered in 40 districts using school based and community distribution.
Four districts were surveyed in 2006 to estimate the e... | Schistosomiasis and soil-transmitted helminth control programmes are important, relatively low cost means to improve the health of those affected, in particular rural school age children. It can also reduce schistosomiasis related morbidity in their later lives. The paper presents information on the implementation and ... | Schistosomiasis is one of the most prevalent chronic infectious diseases found world-wide and is associated with anaemia, chronic pain, diarrhoea, and under nutrition. It is recognised as a major public health problem in many rural areas, particularly in school-age children. With affordable and sustained control measur... |
10.1371/journal.ppat.0030032 | Transport of Streptococcus pneumoniae Capsular Polysaccharide in MHC Class II Tubules | Bacterial capsular polysaccharides are virulence factors and are considered T cell–independent antigens. However, the capsular polysaccharide Sp1 from Streptococcus pneumoniae serotype 1 has been shown to activate CD4+ T cells in a major histocompatibility complex (MHC) class II–dependent manner. The mechanism of carbo... | Microorganisms are comprised of proteins, carbohydrates, lipids, and nucleic acids. Current immunologic paradigms state that activation of T lymphocytes required for humoral and cellular immune responses resulting in immunologic memory to the pathogens is solely brought about by proteinaceous antigens, processed and de... | The immune response to polysaccharide antigens is considered T cell–independent [1]. However, emerging evidence suggests that bacterial polysaccharides from Streptococcus pneumoniae, Bacteroides fragilis, and Staphylococcus aureus activate CD4+ T cells in vivo and in vitro due to their zwitterionic charge motif within ... |
10.1371/journal.pcbi.1002031 | Identification of Hammerhead Ribozymes in All Domains of Life Reveals Novel Structural Variations | Hammerhead ribozymes are small self-cleaving RNAs that promote strand scission by internal phosphoester transfer. Comparative sequence analysis was used to identify numerous additional representatives of this ribozyme class than were previously known, including the first representatives in fungi and archaea. Moreover, ... | The expanding diversity of noncoding RNA discoveries is revealing a broader spectrum of roles RNA plays in cellular signaling and in biochemical functions. These discoveries in part are being facilitated by the expanding collection of genomic sequence data and by computational methods used to search for novel RNAs. In ... | Hammerhead ribozymes [1] represent one of five distinct structural classes of natural self-cleaving RNAs identified to date [2]. The first hammerheads were discovered in viroids and plant satellite RNA viruses where they process RNA transcripts containing multimeric genomes to yield individual genomic RNAs [1], [3], [4... |
10.1371/journal.ppat.1004940 | Geometric Constraints Dominate the Antigenic Evolution of Influenza H3N2 Hemagglutinin | We have carried out a comprehensive analysis of the determinants of human influenza A H3 hemagglutinin evolution. We consider three distinct predictors of evolutionary variation at individual sites: solvent accessibility (as a proxy for protein fold stability and/or conservation), Immune Epitope Database (IEDB) epitope... | The influenza virus is one of the most rapidly evolving human viruses. Every year, it accumulates mutations that allow it to evade the host immune response of previously infected individuals. Which sites in the virus’ genome allow this immune escape and the manner of escape is not entirely understood, but conventional ... | The influenza virus causes one of the most common infections in the human population. The success of influenza is largely driven by the virus’s ability to rapidly adapt to its host and escape host immunity. The antibody response to the influenza virus is determined by the surface proteins hemagglutinin (HA) and neurami... |
10.1371/journal.pbio.1002073 | Cortical Hierarchies Perform Bayesian Causal Inference in Multisensory Perception | To form a veridical percept of the environment, the brain needs to integrate sensory signals from a common source but segregate those from independent sources. Thus, perception inherently relies on solving the “causal inference problem.” Behaviorally, humans solve this problem optimally as predicted by Bayesian Causal ... | How can the brain integrate signals into a veridical percept of the environment without knowing whether they pertain to same or different events? For example, I can hear a bird and I can see a bird, but is it one bird singing on the branch, or is it two birds (one sitting on the branch and the other singing in the bush... | Our senses are constantly bombarded with many different signals. Imagine you are crossing a street and suddenly hear a loud motor noise. Is that motor noise coming from the car on the opposite side of the street or from a rapidly approaching car that you have not yet spotted? To locate the source of the motor noise mor... |
10.1371/journal.pbio.1001524 | A Conserved Role for Human Nup98 in Altering Chromatin Structure and Promoting Epigenetic Transcriptional Memory | The interaction of nuclear pore proteins (Nups) with active genes can promote their transcription. In yeast, some inducible genes interact with the nuclear pore complex both when active and for several generations after being repressed, a phenomenon called epigenetic transcriptional memory. This interaction promotes fu... | Cells respond to changes in nutrients or signaling molecules by altering the expression of genes. The rate at which genes are turned on is not uniform; some genes are induced rapidly and others are induced slowly. In brewer's yeast, previous experience can enhance the rate at which genes are turned on again, a phenomen... | The nuclear pore complex (NPC) is a conserved macromolecular structure that mediates the essential transport of molecules between the nucleus and the cytoplasm [1]. The NPC is an 8-fold symmetric channel derived from ∼30 proteins associated with cytoplasmic filaments and a nucleoplasmic “basket” [2],[3]. Natively unstr... |
10.1371/journal.pgen.1006207 | Mutational Biases Drive Elevated Rates of Substitution at Regulatory Sites across Cancer Types | Disruption of gene regulation is known to play major roles in carcinogenesis and tumour progression. Here, we comprehensively characterize the mutational profiles of diverse transcription factor binding sites (TFBSs) across 1,574 completely sequenced cancer genomes encompassing 11 tumour types. We assess the relative r... | Regulatory regions of the genome are important players in cancer initiation and progression. Here, we study the patterns of mutations accumulating at short DNA segments bound by regulatory proteins (transcription factor binding sites) across many cancer types and in the human population. We find strikingly high rates o... | Most large-scale surveys of somatic mutation in cancer have focussed on protein-coding sequences, and catalogues of genes that carry recurrent mutations already number in the hundreds [1–3], but it has long been speculated that driver mutations are likely to exist in the 98% of the genome sequence outside protein-codin... |
10.1371/journal.ppat.1005889 | Microbiome Composition and Function Drives Wound-Healing Impairment in the Female Genital Tract | The mechanism(s) by which bacterial communities impact susceptibility to infectious diseases, such as HIV, and maintain female genital tract (FGT) health are poorly understood. Evaluation of FGT bacteria has predominantly been limited to studies of species abundance, but not bacterial function. We therefore sought to e... | The female genital tract (FGT) is a key mucosal surface in the context of HIV transmission. Lactobacillus species are beneficial to the FGT, while Garderella vaginalis and other anaerobic bacteria are detrimental. Bacterial vaginosis (BV) is an inflammatory condition characterized by an outgrowth of G. vaginalis and ot... | Mucosal surfaces exposed to the external environment contain distinct bacterial communities that exist in relationship with the host and can contribute to health and functioning. These bacterial communities have been linked to several human diseases and overall health [1], and can vary between individuals, but also ove... |
10.1371/journal.pntd.0000393 | Two Distinct Triatoma dimidiata (Latreille, 1811) Taxa Are Found in Sympatry in Guatemala and Mexico | Approximately 10 million people are infected with Trypanosoma cruzi, the causative agent of Chagas disease, which remains the most serious parasitic disease in the Americas. Most people are infected via triatomine vectors. Transmission has been largely halted in South America in areas with predominantly domestic vector... | The Chagas disease parasite, transmitted to humans by triatomine bugs, remains a leading cause of heart and digestive disease in Latin America. Pesticide spraying has effectively halted transmission in most of southern South America, especially where the bugs live exclusively inside houses. In Mesoamerica, bugs living ... | Chagas disease is considered the largest parasitic disease burden in Latin America with a cost of the loss of 667,000 Disability Adjusted Life Years (DALYs) in 2002 [1]. Trypanosoma cruzi, the parasite that causes Chagas disease, infects approximately 9.8 million people in the Americas [2] with 200,000 new Chagas cases... |
10.1371/journal.pgen.1002403 | The RNA–Methyltransferase Misu (NSun2) Poises Epidermal Stem Cells to Differentiate | Homeostasis of most adult tissues is maintained by balancing stem cell self-renewal and differentiation, but whether post-transcriptional mechanisms can regulate this process is unknown. Here, we identify that an RNA methyltransferase (Misu/Nsun2) is required to balance stem cell self-renewal and differentiation in ski... | We demonstrate that the RNA methyltransferase activity of Misu/NSun2 is required for the proper maintenance of the epidermal differentiation program, and thus post-transcriptional mechanisms are involved in controlling the balance between stem cell self-renewal and differentiation.
| Stem cells are defined by their ability to continuously maintain their population (self-renewal) while generating progeny (differentiation). During self-renewal, stem cells have to avoid cell cycle exit and differentiation; however, when differentiating they have to evade uncontrolled proliferation. Thus, the question ... |
10.1371/journal.pbio.1002026 | Specific Phosphorylation of Histone Demethylase KDM3A Determines Target Gene Expression in Response to Heat Shock | Histone lysine (K) residues, which are modified by methyl- and acetyl-transferases, diversely regulate RNA synthesis. Unlike the ubiquitously activating effect of histone K acetylation, the effects of histone K methylation vary with the number of methyl groups added and with the position of these groups in the histone ... | Histone methylation regulates gene expression and can have drastic consequences for health if the process is defective. Histone lysine demethylases (KDMs) counteract the activity of methyl-transferases and remove methyl group(s) from histones. KDM3A is a H3K9me2/1 demethylase that performs diverse functions via the reg... | Histone modifications, such as methylation and acetylation, regulate RNA synthesis [1],[2]. Unlike the activating impact of acetylation, the methylation of lysine residues in histones can exert either an activating or a repressive effect on genes, depending on the number of methyl groups that are added and the position... |
10.1371/journal.pntd.0000801 | Impact of Increased Economic Burden Due to Human Echinococcosis in an Underdeveloped Rural Community of the People's Republic of China | Ningxia is located in western People's Republic of China, which is hyperendemic for human cystic echinococcosis (CE) throughout the entire area with alveolar echinococcosis (AE) hyperendemic in the south. This is in part due to its underdeveloped economy. Despite the recent rapid growth in P.R. China's economy, medical... | This paper compares medical expenditure for hospital treatment of echinococcosis in NHAR, western People's Republic of China, for different years, different regions and different socioeconomic groups. The results show that the level of household income strongly influences health care decisions. This study represents an... | Since the inception of market reforms in the early 1980s, the annual health expenditure of People's Republic of China (P.R. China) has increased consistently [1], [2]. But, contrary to this increase, two national healthcare surveys [3], [4] showed that health insurance decreased from 30.2% of coverage in 1993 to 23.6% ... |
10.1371/journal.pcbi.1004486 | A Dynamic Gene Regulatory Network Model That Recovers the Cyclic Behavior of Arabidopsis thaliana Cell Cycle | Cell cycle control is fundamental in eukaryotic development. Several modeling efforts have been used to integrate the complex network of interacting molecular components involved in cell cycle dynamics. In this paper, we aimed at recovering the regulatory logic upstream of previously known components of cell cycle cont... | In multicellular organisms, cells undergo a cyclic behavior of DNA duplication and delivery of a copy to daughter cells during cell division. In each of the main cell-cycle (CC) stages different sets of proteins are active and genes are expressed. Understanding how such cycling cellular behavior emerges and is robustly... | The eukaryotic cell cycle (CC) in multicellular organisms is regulated spatio-temporally to yield normal morphogenetic patterns. In plants, organogenesis occurs over the entire lifespan, thus CC arrest, reactivation, and cell differentiation, as well as endoreduplication should be dynamically controlled at different po... |
10.1371/journal.pcbi.1003250 | The Lazy Visual Word Form Area: Computational Insights into Location-Sensitivity | In a recent study, Rauschecker et al. convincingly demonstrate that visual words evoke neural activation signals in the Visual Word Form Area that can be classified based on where they were presented in the visual fields. This result goes against the prevailing consensus, and begs an explanation. We show that one of th... | There is a mild form of modern “mind-reading” that involves, with heavy fMRI apparatus and software assistance, to guess from brain signals alone the locations of words that have been seen by a (consenting) subject. The recent surprise brought to us by Rauschecker et al. is not that we can currently do that, but that w... | Until recently the undisputed agreement amongst essentially all researchers in the field of visual word recognition, the current authors included, was that the Visual Word Form Area (VWFA hereafter, [1]) is a location-invariant area: that it is the seat of a computing device for “word form” representations whose mechan... |
10.1371/journal.pgen.1004570 | Pooled Segregant Sequencing Reveals Genetic Determinants of Yeast Pseudohyphal Growth | The pseudohyphal growth response is a dramatic morphological transition and presumed foraging mechanism wherein yeast cells form invasive and surface-spread multicellular filaments. Pseudohyphal growth has been studied extensively as a model of conserved signaling pathways controlling stress responses, cell morphogenes... | Cellular processes in eukaryotes are brought about through the contributions of large gene sets, and a continuing obstacle in studying these processes lies in the identification of critical constituent genes. The yeast pseudohyphal growth transition is an important example of a complex cellular growth transition. Durin... | The budding yeast Saccharomyces cerevisiae undergoes a pronounced growth transition in response to nitrogen limitation or glucose limitation, forming multicellular pseudohyphal filaments that can spread outward from a colony and/or invade the surface of a solid growth substrate [1], [2]. Yeast pseudohyphal filament for... |
10.1371/journal.pntd.0003959 | Is PCR the Next Reference Standard for the Diagnosis of Schistosoma in Stool? A Comparison with Microscopy in Senegal and Kenya | The current reference test for the detection of S. mansoni in endemic areas is stool microscopy based on one or more Kato-Katz stool smears. However, stool microscopy has several shortcomings that greatly affect the efficacy of current schistosomiasis control programs. A highly specific multiplex real-time polymerase c... | In the developing world, over 207 million people are infected with parasitic Schistosoma worms. Schistosoma mansoni is one of the most widespread species, and its routine diagnosis is based on microscopic detection of parasite eggs in stool samples. This technique is, however, highly observer-dependent and has suboptim... | Schistosomiasis control strategies are currently based on mass drug administration (MDA) with praziquantel to populations at risk [1]. Disease mapping, MDA allocation, and post-MDA monitoring of infection are based on standard microscopy techniques: urine filtration for Schistosoma haematobium, and Kato-Katz on stool f... |
10.1371/journal.pntd.0006451 | Seasonal temperature variation influences climate suitability for dengue, chikungunya, and Zika transmission | Dengue, chikungunya, and Zika virus epidemics transmitted by Aedes aegypti mosquitoes have recently (re)emerged and spread throughout the Americas, Southeast Asia, the Pacific Islands, and elsewhere. Understanding how environmental conditions affect epidemic dynamics is critical for predicting and responding to the geo... | Mosquito-borne viruses like dengue, Zika, and chikungunya have recently caused large epidemics that are partly driven by temperature. Using a mathematical model built from laboratory experimental data for Aedes aegypti mosquitoes and dengue virus, we examine the impact of variation in seasonal temperature regimes on ep... | Over the last 30–40 years, arboviral outbreaks have dominated the public health landscape globally [1]. These viruses, most notably dengue (DENV), chikungunya (CHIKV), and Zika (ZIKV), can cause symptoms ranging from rash, arthralgia, and fever to hemorrhagic fever (DENV), long-term arthritis (CHIKV), Guillain-Barré sy... |
10.1371/journal.pbio.3000068 | Identification and characterization of a mosquito-specific eggshell organizing factor in Aedes aegypti mosquitoes | Mosquito-borne diseases are responsible for several million human deaths annually around the world. One approach to controlling mosquito populations is to disrupt molecular processes or antagonize novel metabolic targets required for the production of viable eggs. To this end, we focused our efforts on identifying prot... | Mosquito-borne pathogens infect millions of people worldwide, and the rise in insecticide resistance is exacerbating this problem. A new generation of environmentally safe insecticides will be essential to control insecticide-resistant mosquitoes. One potential route to such novel insecticide targets is the identificat... | Developing new strategies for vector control is becoming critical because worldwide cases of Aedes aegypti-transmitted dengue and Zika virus infections have risen dramatically in the last decade [1–3]. Researchers have been investigating metabolic regulation of blood meal metabolism in A. aegypti mosquitoes as a strate... |
10.1371/journal.pntd.0004620 | Use of Molecular Diagnostic Tools for the Identification of Species Responsible for Snakebite in Nepal: A Pilot Study | Snakebite is an important medical emergency in rural Nepal. Correct identification of the biting species is crucial for clinicians to choose appropriate treatment and anticipate complications. This is particularly important for neurotoxic envenoming which, depending on the snake species involved, may not respond to ava... | Snakebite is an important medical problem in sub-tropical and tropical regions, including Nepal where tens of thousands of people are bitten every year. Snakebite can result in life-threatening envenoming, and correct identification of the biting species is crucial for care providers to choose appropriate treatment and... | In rural Nepal snakebite is an important public health problem. A survey conducted in the 1980s showed that about 20’000 people were bitten each year, resulting in over 1’000 deaths [1]. These official figures, however, significantly underestimate the true burden [2–7]. Annual incidence and mortality figures of 1’162/1... |
10.1371/journal.ppat.1002124 | Divergent Effects of Human Cytomegalovirus and Herpes Simplex Virus-1 on Cellular Metabolism | Viruses rely on the metabolic network of the host cell to provide energy and macromolecular precursors to fuel viral replication. Here we used mass spectrometry to examine the impact of two related herpesviruses, human cytomegalovirus (HCMV) and herpes simplex virus type-1 (HSV-1), on the metabolism of fibroblast and e... | Enveloped viruses draw on cellular machinery and materials to generate copies of their genome, structural proteins, and membrane. These biosynthetic processes use the host metabolic network to provide energy and small-molecule precursors. We have investigated how two important enveloped viruses, human cytomegalovirus a... | Herpesviruses are large, enveloped, double-stranded DNA viruses, capable of both lytic infection and life-long latency in mammalian hosts [1]. They are major causes of human disease. A majority of adults are infected with herpes simplex virus 1 (HSV-1) and/or human cytomegalovirus (HCMV). An alpha-herpesvirus, HSV-1 in... |
10.1371/journal.ppat.1005185 | Modulation of the Host Lipid Landscape to Promote RNA Virus Replication: The Picornavirus Encephalomyocarditis Virus Converges on the Pathway Used by Hepatitis C Virus | Cardioviruses, including encephalomyocarditis virus (EMCV) and the human Saffold virus, are small non-enveloped viruses belonging to the Picornaviridae, a large family of positive-sense RNA [(+)RNA] viruses. All (+)RNA viruses remodel intracellular membranes into unique structures for viral genome replication. Accumula... | All positive-sense RNA viruses [(+)RNA viruses] replicate their viral genomes in tight association with reorganized membranous structures. Viruses generate these unique structures, often termed “replication organelles” (ROs), by efficiently manipulating the host lipid metabolism. While the molecular mechanisms underlyi... | Picornaviridae is a large family of positive-sense RNA viruses [(+)RNA viruses] comprising many clinically relevant human and animal pathogens. Members of the genus Enterovirus include important human viruses like poliovirus (PV), the causative agents of poliomyelitis, coxsackieviruses (CV), causing meningitis and myoc... |
10.1371/journal.pcbi.1004792 | Training Excitatory-Inhibitory Recurrent Neural Networks for Cognitive Tasks: A Simple and Flexible Framework | The ability to simultaneously record from large numbers of neurons in behaving animals has ushered in a new era for the study of the neural circuit mechanisms underlying cognitive functions. One promising approach to uncovering the dynamical and computational principles governing population responses is to analyze mode... | Cognitive functions arise from the coordinated activity of many interconnected neurons. As neuroscientists increasingly use large datasets of simultaneously recorded neurons to study the brain, one approach that has emerged as a promising tool for interpreting population responses is to analyze model recurrent neural n... | Computations in the brain are carried out by populations of interconnected neurons. While single-neuron responses can reveal a great deal about the neural mechanisms underlying various sensory, motor, and cognitive functions, neural mechanisms often involve the coordinated activity of many neurons whose complex individ... |
10.1371/journal.pcbi.1000063 | Sequence Similarity Network Reveals Common Ancestry of Multidomain Proteins | We address the problem of homology identification in complex multidomain families with varied domain architectures. The challenge is to distinguish sequence pairs that share common ancestry from pairs that share an inserted domain but are otherwise unrelated. This distinction is essential for accuracy in gene annotatio... | New genes evolve through the duplication and modification of existing genes. As a result, genes that share common ancestry tend to have similar structure and function. Computational methods that use common ancestry have been extraordinarily successful in inferring function. The practice of discerning evolutionary relat... | Accurate identification of homologs, sequences that share common ancestry, is essential for accuracy in function prediction and comparative genomics. Homology identification is integral to the annotation of novel genes [1] and prediction of gene function by various methods, including phylogenetic clustering [2], gene f... |
10.1371/journal.ppat.1003699 | Deletion of IL-4 Receptor Alpha on Dendritic Cells Renders BALB/c Mice Hypersusceptible to Leishmania major Infection | In BALB/c mice, susceptibility to infection with the intracellular parasite Leishmania major is driven largely by the development of T helper 2 (Th2) responses and the production of interleukin (IL)-4 and IL-13, which share a common receptor subunit, the IL-4 receptor alpha chain (IL-4Rα). While IL-4 is the main induce... | Leishmaniasis is a parasitic infection caused by protozoan parasites of Leishmania species and is transmitted by the sandfly. Disease in humans ranges from localized cutaneous lesions to disseminated visceral Leishmaniasis. Mouse models of Leishmania major infection have demonstrated that a “healing” response in C57BL/... | Leishmania spp. are protozoan parasites that are transmitted by Phlebotomus spp. sandflies and can cause several forms of disease in humans, ranging from localized cutaneous lesions to visceral Leishmaniasis, where parasites invade internal organs such as the spleen and liver. The incidence of disease is approximately ... |
10.1371/journal.pbio.1000092 | Structural Studies of the Giant Mimivirus | Mimivirus is the largest known virus whose genome and physical size are comparable to some small bacteria, blurring the boundary between a virus and a cell. Structural studies of Mimivirus have been difficult because of its size and long surface fibers. Here we report the use of enzymatic digestions to remove the surfa... | Mimiviruses are larger than any other known virus, yet despite their size, the capsid has been shown to be a regular icosahedron. Using cryo-electron microscopy and atomic force microscopy, we show that the icosahedral symmetry is only approximate, in part because one of the 5-fold vertices has a unique “starfish-shape... | Mimivirus, Acanthamoeba polyphaga Mimivirus, is the largest known virus [1–3] and a putative human pneumonia agent [4]. It has an icosahedral shape with a 0.75-μm diameter [3] and a ∼1.2-Mbp genome that contains most of the genes found in small bacteria [5]. The external morphology of Mimivirus had initially led to its... |
10.1371/journal.ppat.1002722 | Polydnavirus Ank Proteins Bind NF-κB Homodimers and Inhibit Processing of Relish | Recent studies have greatly increased understanding of how the immune system of insects responds to infection, whereas much less is known about how pathogens subvert immune defenses. Key regulators of the insect immune system are Rel proteins that form Nuclear Factor-κB (NF-κB) transcription factors, and inhibitor κB (... | Central to the study of host-pathogen interactions is understanding how the immune system of hosts responds to infection, and reciprocally how pathogens subvert host defenses. In the case of insects, understanding of how the immune system responds to infection greatly exceeds understanding of pathogen counterstrategies... | The innate immune system defends insects against a diversity of potential pathogens [1]. As part of this system, the Toll and Imd pathways activate Nuclear Factor-κB (NF-κB) transcription factors, which regulate the expression of antimicrobial peptides (AMPs) and many other genes [2]–[6]. Both pathways have also been i... |
10.1371/journal.pcbi.1001114 | CAERUS: Predicting CAncER oUtcomeS Using Relationship between Protein Structural Information, Protein Networks, Gene Expression Data, and Mutation Data | Carcinogenesis is a complex process with multiple genetic and environmental factors contributing to the development of one or more tumors. Understanding the underlying mechanism of this process and identifying related markers to assess the outcome of this process would lead to more directed treatment and thus significa... | It is widely known that cancer is a complex process in which a large number of genes appear to be involved. Through experimental approaches, some oncogenes and tumor suppressors have been identified as playing important roles in the signaling and the regulatory pathways. However, we have not fully understood the comple... | Cancer development is a complex process driven by multiple genetic and environmental factors [1], [2], [3]. Understanding the underlying mechanism of this process and identifying related markers to assess the outcome of this process could lead to better management and treatment of this complex disease. For example, the... |
10.1371/journal.ppat.1003397 | Host Defense and Recruitment of Foxp3+ T Regulatory Cells to the Lungs in Chronic Mycobacterium tuberculosis Infection Requires Toll-like Receptor 2 | Acute resistance to low dose M. tuberculosis (Mtb) infection is not dependent on Toll-like receptor (TLR) 2. However, whether TLR2 contributes to resistance in chronic Mtb infection has remained uncertain. Here we report that, following low dose aerosol infection with Mtb, mice lacking TLR2 (TLR2KO), in comparison with... | Tuberculosis (TB) is an important cause of mortality in many parts of the world. Infection with Mycobacterium tuberculosis (Mtb), the causative agent of TB, is usually acquired via inhalation of airborne droplets containing the bacteria. Following inhalation, Mtb interacts with specialized receptors, called Toll-like r... | Mtb expresses a large diversity of TLR2 ligands, including several types of lipoproteins and glycolipids, and also a trehalose dimycolate [1]–[3]. Interaction of these ligands with TLR2 expressed on macrophages and dendritic cells has multiple downstream effects. Several studies have reported that Mtb-derived TLR2 liga... |
10.1371/journal.pgen.1004582 | PRO40 Is a Scaffold Protein of the Cell Wall Integrity Pathway, Linking the MAP Kinase Module to the Upstream Activator Protein Kinase C | Mitogen-activated protein kinase (MAPK) pathways are crucial signaling instruments in eukaryotes. Most ascomycetes possess three MAPK modules that are involved in key developmental processes like sexual propagation or pathogenesis. However, the regulation of these modules by adapters or scaffolds is largely unknown. He... | The specific response to environmental cues is crucial for cell differentiation and is often mediated by highly conserved eukaryotic MAP kinase (MAPK) pathways. How these pathways react specifically to huge numbers of different cues is still unclear, and current literature about adapter and scaffolding proteins remains... | Mitogen-activated protein kinase (MAPK) cascades are central components of signaling networks in all eukaryotic organisms [1]–[3]. They consist of a three-tiered module containing a MAPK kinase kinase (MAPKKK), a MAPK kinase (MAPKK), and a MAPK, each activating the subsequent one via phosphorylation. MAPK signaling has... |
10.1371/journal.pntd.0005820 | Knowledge, attitudes and practices towards yaws and yaws-like skin disease in Ghana | Yaws is endemic in Ghana. The World Health Organization (WHO) has launched a new global eradication campaign based on total community mass treatment with azithromycin. Achieving high coverage of mass treatment will be fundamental to the success of this new strategy; coverage is dependent, in part, on appropriate commun... | Yaws, a bacterial skin infection, is endemic in Ghana. WHO has launched a campaign to eradicate yaws based on community mass treatment with the antibiotic azithromycin. Community perceptions of disease are an important contributor to participation in mass treatment interventions. This study used questionnaires to under... | Yaws, caused by Treponema pallidum subsp. pertenue, is endemic in Ghana. The disease is reported in all districts but predominantly in the south of the country. The majority of clinical disease is seen in young children, with the organism being transmitted by skin to skin contact with infectious lesions. In 2012, the W... |
10.1371/journal.pgen.1002159 | Transportin-SR Is Required for Proper Splicing of Resistance Genes and Plant Immunity | Transportin-SR (TRN-SR) is a member of the importin-β super-family that functions as the nuclear import receptor for serine-arginine rich (SR) proteins, which play diverse roles in RNA metabolism. Here we report the identification and cloning of mos14 (modifier of snc1-1, 14), a mutation that suppresses the immune resp... | Plant immune receptors encoded by Resistance (R) genes play essential roles in defense against pathogens. Multiple R genes are alternatively spliced. How plants regulate the splicing of these R genes is unclear. In this study, we identified MOS14 as an important regulator of two R genes, SNC1 and RPS4. Further analysis... | In eukaryotes, the nuclear envelope forms a barrier between the cytoplasm and the nucleus. Trafficking of macromolecules across the nuclear envelope occurs through the nuclear pore complex (NPC) [1]. Previous studies on MOS3 [2], MOS6 [3], MOS7 [4] and MOS11 [5] have revealed the importance of nucleocytoplasmic traffic... |
10.1371/journal.pbio.0050052 | FMRP Mediates mGluR5-Dependent Translation of Amyloid Precursor Protein | Amyloid precursor protein (APP) facilitates synapse formation in the developing brain, while beta-amyloid (Aβ) accumulation, which is associated with Alzheimer disease, results in synaptic loss and impaired neurotransmission. Fragile X mental retardation protein (FMRP) is a cytoplasmic mRNA binding protein whose expres... | Alzheimer disease (AD) and fragile X syndrome (FXS) are devastating neurological disorders associated with synaptic dysfunction resulting in cognitive impairment and behavioral deficits. Despite these similar endpoints, the pathobiology of AD and FXS have not previously been linked. We have established that translation... | Alzheimer disease (AD) is a neurodegenerative disorder characterized by senile plaques and neurofibrillary tangles. The plaques are predominantly composed of beta-amyloid (Aβ), a 39–42 amino acid peptide cleaved from the amyloid precursor protein (APP). APP is likely important for synapse formation in the developing br... |
10.1371/journal.pcbi.1000453 | A Generalized Framework for Quantifying the Dynamics of EEG Event-Related Desynchronization | Brains were built by evolution to react swiftly to environmental challenges. Thus, sensory stimuli must be processed ad hoc, i.e., independent—to a large extent—from the momentary brain state incidentally prevailing during stimulus occurrence. Accordingly, computational neuroscience strives to model the robust processi... | When Hans Berger described the human EEG in the 1920s, a pivotal finding was the demonstration of prominent oscillations in the frequency range between 8 and 12 Hz, which he called alpha wave rhythm. He also described for the first time the so-called “alpha blockade,” i.e., the suppression of the ongoing alpha activity... | When Hans Berger [1] described the human EEG in the 1920s, a pivotal finding was the demonstration of prominent oscillations in the frequency range between 8 and 12 Hz, which he called alpha wave rhythm. He also described for the first time the so-called “alpha blockade”, i.e., the suppression of the ongoing alpha acti... |
10.1371/journal.ppat.1004553 | Discovery of Replicating Circular RNAs by RNA-Seq and Computational Algorithms | Replicating circular RNAs are independent plant pathogens known as viroids, or act to modulate the pathogenesis of plant and animal viruses as their satellite RNAs. The rate of discovery of these subviral pathogens was low over the past 40 years because the classical approaches are technical demanding and time-consumin... | Viroids are a unique class of subviral pathogens found in plants, and they are difficult to identify since they are free circular non-coding RNAs and often replicate to low levels in host cells. We previously described the computational algorithm PFOR that discovers viroids by analyzing total small RNAs of the infected... | Viroids and a group of satellite RNAs (satRNAs) have single-stranded circular RNA genomes that range in size from 220 to 457 nucleotides (nt) [1]–[4]. These subviral pathogenic RNAs lack protein-coding capabilities and thus depend on either host-encoded DNA-dependent RNA polymerase (viroids) or helper virus-encoded RNA... |
10.1371/journal.pntd.0001337 | Proteomic Analysis of Human Skin Treated with Larval Schistosome Peptidases Reveals Distinct Invasion Strategies among Species of Blood Flukes | Skin invasion is the initial step in infection of the human host by schistosome blood flukes. Schistosome larvae have the remarkable ability to overcome the physical and biochemical barriers present in skin in the absence of any mechanical trauma. While a serine peptidase with activity against insoluble elastin appears... | Schistosome parasites are a major cause of disease in the developing world, but the mechanism by which these parasites first infect their host has been studied at the molecular level only for S. mansoni. In this paper, we have mined recent genome annotations of S. mansoni and S. japonicum, a zoonotic schistosome specie... | Human skin is a formidable barrier for much of the microbial world. In addition to the mechanical barrier of structural proteins in the epidermis, basement membrane and dermal extracellular matrix, both the epidermis and dermis are bathed in plasma proteins, including early sentinels of the immune system [1]. In order ... |
10.1371/journal.pgen.1003035 | Biochemical Diversification through Foreign Gene Expression in Bdelloid Rotifers | Bdelloid rotifers are microinvertebrates with unique characteristics: they have survived tens of millions of years without sexual reproduction; they withstand extreme desiccation by undergoing anhydrobiosis; and they tolerate very high levels of ionizing radiation. Recent evidence suggests that subtelomeric regions of ... | Bdelloid rotifers are tiny invertebrates with unusual characteristics: they withstand stresses, such as desiccation and high levels of ionising radiation, that kill other animals, and they have survived over millions of years without sexual reproduction, which contradicts theories on the evolutionary advantages of sex.... | Bdelloid rotifers (Rotifera, Bdelloidea) are abundant, ubiquitous microinvertebrates that inhabit aqueous habitats [1]. They possess an extraordinary and unique combination of characteristics among the Metazoa: they have survived for tens of millions of years without sexual reproduction, while speciating similarly to s... |
10.1371/journal.pntd.0000968 | Clinical Presentation of T.b. rhodesiense Sleeping Sickness in Second Stage Patients from Tanzania and Uganda | A wide spectrum of disease severity has been described for Human African Trypanosomiasis (HAT) due to Trypanosoma brucei rhodesiense (T.b. rhodesiense), ranging from chronic disease patterns in southern countries of East Africa to an increase in virulence towards the north. However, only limited data on the clinical pr... | Sleeping sickness, or Human African Trypanosomiasis (HAT), caused by Trypanosoma brucei rhodesiense is one of the most neglected tropical diseases. It affects mainly rural, poor East African populations and has very high socio-economic impacts. T.b. rhodesiense HAT is an acute disease; patients quickly progress from th... | Human African Trypanosomiasis (HAT), also known as sleeping sickness, is caused by the protozoan parasites T.b. gambiense (West and Central Africa) and T.b. rhodesiense (East and South Africa). The disease is transmitted by tsetse flies (Glossina ssp.) predominantly in the rural areas of most of sub Saharan Africa. 60 ... |
10.1371/journal.pcbi.1006485 | Active dendrites regulate the spatiotemporal spread of signaling microdomains | Microdomains that emerge from spatially constricted spread of biochemical signaling components play a central role in several neuronal computations. Although dendrites, endowed with several voltage-gated ion channels, form a prominent structural substrate for microdomain physiology, it is not known if these channels re... | The spatiotemporal spread of biochemical signals in neurons and other cells regulate signaling specificity, tuning of signal propagation, along with specificity and clustering of adaptive plasticity. Theoretical and experimental studies have demonstrated a critical role for cellular morphology and the topology of signa... | Microdomains that emerge from spatially constricted spread of biochemical signaling components play a central role in defining several neuronal computations, including compartmentalization of neuronal plasticity and localized targeting of membrane components [1–10]. Theoretical and experimental studies have demonstrate... |
10.1371/journal.pbio.1000068 | Quantifying the Integration of Quorum-Sensing Signals with Single-Cell Resolution | Cell-to-cell communication in bacteria is a process known as quorum sensing that relies on the production, detection, and response to the extracellular accumulation of signaling molecules called autoinducers. Often, bacteria use multiple autoinducers to obtain information about the vicinal cell density. However, how ce... | Although bacteria are unicellular, the individual cells communicate with each other via small diffusible molecules. This communication process, known as quorum sensing, allows groups of bacteria to track the density of the population they are in, synchronize gene expression across the population, and thereby carry out ... | In a process called quorum sensing, bacteria communicate with one another using extracellular signaling molecules called autoinducers. Quorum sensing allows groups of bacteria to track their cell numbers, synchronize gene expression on a population-wide scale, and thereby carry out collective activities. In quorum sens... |
10.1371/journal.pntd.0002977 | Synergy Testing of FDA-Approved Drugs Identifies Potent Drug Combinations against Trypanosoma cruzi | An estimated 8 million persons, mainly in Latin America, are infected with Trypanosoma cruzi, the etiologic agent of Chagas disease. Existing antiparasitic drugs for Chagas disease have significant toxicities and suboptimal effectiveness, hence new therapeutic strategies need to be devised to address this neglected tro... | Chronic infection with Trypanosoma cruzi causes progressive damage to the heart and other organs that is fatal in about 30% of cases. Known as Chagas disease, this is a major public health problem in Latin America. The existing medicines were developed over forty years ago and are not widely used because of toxicity an... | The need for new more effective drugs to treat Chagas disease has not been matched by drug discovery efforts. An estimated 8 million people have chronic infection with the etiologic agent, Trypanosoma cruzi [1]. Existing treatments consist of two nitroaromatic compounds (benznidazole and nifurtimox) that are poorly tol... |
10.1371/journal.pcbi.1004161 | Perturbation-Expression Analysis Identifies RUNX1 as a Regulator of Human Mammary Stem Cell Differentiation | The search for genes that regulate stem cell self-renewal and differentiation has been hindered by a paucity of markers that uniquely label stem cells and early progenitors. To circumvent this difficulty we have developed a method that identifies cell-state regulators without requiring any markers of differentiation, t... | The discovery of stem cell regulators is a major goal of biological research, but progress is often limited by a lack of definitive markers capable of distinguishing stem cells from early progenitors. Even in cases where markers have been identified, they often only enrich for certain cell states and do not uniquely id... | Adult stem cells are functionally defined based on their ability to regenerate tissues. This unique regenerative ability can be recapitulated in culture models, where single stem cells, but not differentiated cells, form tissue rudiments in three-dimensional extracellular matrices. These tissue rudiments, or organoids,... |
10.1371/journal.pntd.0005540 | The phosphatidylinositol-3-phosphate 5-kinase inhibitor apilimod blocks filoviral entry and infection | Phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) is a lipid kinase involved in endosome maturation that emerged from a haploid genetic screen as being required for Ebola virus (EBOV) infection. Here we analyzed the effects of apilimod, a PIKfyve inhibitor that was reported to be well tolerated in humans in phase 2 c... | The recent outbreak of Ebola virus (EBOV) disease in Western Africa highlights the urgent need to develop therapeutics to help quell this devastating hemorrhagic fever virus, especially in resource-limited areas around the globe. Here we show that apilimod, an investigational drug that was well-tolerated in phase 2 cli... | The epidemic of Ebola virus disease (EVD) that raged through Western Africa between 2013 and 2016 was the most severe filovirus disease epidemic in recorded history [1,2]. While several promising therapeutic antibodies [3–11] and novel small molecules [12–19] remain in development, no therapeutic is yet approved to tre... |
10.1371/journal.pgen.1005462 | Histone H2AFX Links Meiotic Chromosome Asynapsis to Prophase I Oocyte Loss in Mammals | Chromosome abnormalities are common in the human population, causing germ cell loss at meiotic prophase I and infertility. The mechanisms driving this loss are unknown, but persistent meiotic DNA damage and asynapsis may be triggers. Here we investigate the contribution of these lesions to oocyte elimination in mice wi... | Chromosome abnormalities, such as aneuploidies and structural variants (i.e. translocations, inversions), are strikingly common in the human population, causing disorders such as Down syndrome and Turner syndrome. One important consequence of chromosome abnormalities in mammals is errors during meiosis, the specialized... | Prophase I of mammalian meiosis entails alignment, synapsis and reciprocal recombination between homologues, which together enable crossover formation. Without crossovers, homologues mis-segregate, giving rise to aneuploidy [1]. To protect against this, germ cells exhibiting defects in the key prophase I events are eli... |
10.1371/journal.pmed.1002306 | Association between expansion of primary healthcare and racial inequalities in mortality amenable to primary care in Brazil: A national longitudinal analysis | Universal health coverage (UHC) can play an important role in achieving Sustainable Development Goal (SDG) 10, which addresses reducing inequalities, but little supporting evidence is available from low- and middle-income countries. Brazil’s Estratégia de Saúde da Família (ESF) (family health strategy) is a community-b... | The Sustainable Development Goals include reducing inequalities and making commitments to universal health coverage (UHC).
There is little evidence about the relationship between expanding primary healthcare (PHC)—as part of the commitment to UHC—and health inequalities, including racial inequalities. This is particula... | Reducing inequalities within and among countries is the tenth goal of the Sustainable Development Goals (SDGs). This goal includes the target to “adopt policies, especially fiscal, wage and social protection policies” that “progressively achieve greater equality” (http://www.un.org/sustainabledevelopment/inequality/). ... |
10.1371/journal.pntd.0001256 | Profiles of Small Non-Coding RNAs in Schistosoma japonicum during Development | The gene regulation mechanism along the life cycle of the genus Schistosoma is complex. Small non-coding RNAs (sncRNAs) are essential post transcriptional gene regulation elements that affect gene expression and mRNA stability. Preliminary studies indicated that sncRNAs in schistosomal parasites are generated through d... | Schistosomiasis, a debilitating disease, caused by agents of the genus Schistosoma afflicts more than 200 million people worldwide. Schistosomes could serve as an interesting model to explore gene regulation due to its evolutional position, complex life cycle and sexual dimorphism. We previously indicated that sncRNA p... | Schistosomiasis is a chronic debilitating disease that afflicts more than 200 million individuals in the tropics and sub-tropics regions [1]. The agents of this disease, parasitic flatworms of the genus Schistosoma, have a complex developmental life cycle characterized by a distinct parasitic phase in mammalian and mol... |
10.1371/journal.pcbi.1006624 | Reservoir computing model of prefrontal cortex creates novel combinations of previous navigation sequences from hippocampal place-cell replay with spatial reward propagation | As rats learn to search for multiple sources of food or water in a complex environment, they generate increasingly efficient trajectories between reward sites. Such spatial navigation capacity involves the replay of hippocampal place-cells during awake states, generating small sequences of spatially related place-cell ... | As rats search for multiple sources of food in a complex environment, they generate increasingly efficient trajectories between reward sites, across multiple trials. This spatial navigation optimization behavior can be measured in the laboratory using a traveling salesperson task (TSP). This likely involves the coordin... | Spatial navigation in the rat involves the replay of place-cell sub-sequences, that we refer to as snippets, during awake and sleep states in the hippocampus during sharp-wave-ripples (SWR) [1–4]. In the awake state, replay has been observed to take place in forward and reverse direction [2, 5–8], with respect to the p... |
10.1371/journal.pntd.0007173 | The safety and efficacy of miltefosine in the long-term treatment of post-kala-azar dermal leishmaniasis in South Asia – A review and meta-analysis | Miltefosine (MF) is the only oral drug available for treatment of visceral leishmaniasis (VL) and post-kala-azar dermal leishmaniasis (PKDL). Although the drug is effective and well tolerated in treatment of VL, the efficacy and safety of MF for longer treatment durations (>28 days) in PKDL remains unclear. This study ... | In this study, we reviewed the available literature on the subject of safety and efficacy of the oral drug miltefosine in the treatment of post-kala-azar dermal leishmaniasis (PKDL). Literature was searched systematically in the PubMed database and eight articles, with a total of 324 PKDL patients, were included. A met... | Post-Kala-Azar Dermal Leishmaniasis (PKDL) is a dermal complication of visceral leishmaniasis (VL) caused by the Leishmania donovani parasite, which is transmitted by phlebotomine sandflies. The PKDL disease can appear weeks to years after the successful cure of VL and is characterised by skin lesions, mainly present o... |
10.1371/journal.pntd.0001501 | Using Molecular Data for Epidemiological Inference: Assessing the Prevalence of Trypanosoma brucei rhodesiense in Tsetse in Serengeti, Tanzania | Measuring the prevalence of transmissible Trypanosoma brucei rhodesiense in tsetse populations is essential for understanding transmission dynamics, assessing human disease risk and monitoring spatio-temporal trends and the impact of control interventions. Although an important epidemiological variable, identifying fli... | Human African trypanosomiasis is a fatal disease that is carried by a tsetse vector. Assessing the proportion of tsetse which carries human-infective trypanosomes is important in assessing human disease risk and understanding disease transmission dynamics. However, identifying flies which carry transmissible infections... | For the vector-borne diseases, pathogen prevalence in a vector population is an indicator of disease risk, and accurate measures of the proportion of vectors carrying infections are needed for (i) guiding allocation of resources or targeting intervention programs [1]; (ii) monitoring the success of control intervention... |
10.1371/journal.pgen.1005771 | Arabidopsis Flower and Embryo Developmental Genes are Repressed in Seedlings by Different Combinations of Polycomb Group Proteins in Association with Distinct Sets of Cis-regulatory Elements | Polycomb repressive complexes (PRCs) play crucial roles in transcriptional repression and developmental regulation in both plants and animals. In plants, depletion of different members of PRCs causes both overlapping and unique phenotypic defects. However, the underlying molecular mechanism determining the target speci... | Polycomb group proteins (PcGs) are essential for development in both animals and plants. Studies in plants are advantageous for elucidation of specific effects of PcGs during development, since most PcG mutants are viable in plants but not in animals. Previous efforts in genetic study of plant PcGs revealed that differ... | The evolutionarily conserved Polycomb group proteins (PcGs) are the major epigenetic machinery regulating differentiation and development [1–4]. PcGs mediated repression is achieved by establishment and maintenance of epigenetic modifications surrounding target genes. In both plants and animals, PcGs are classified int... |
10.1371/journal.ppat.1001015 | Oseltamivir-Resistant Pandemic A/H1N1 Virus Is as Virulent as Its Wild-Type Counterpart in Mice and Ferrets | The neuraminidase inhibitor oseltamivir is currently used for treatment of patients infected with the pandemic A/H1N1 (pH1N1) influenza virus, although drug-resistant mutants can emerge rapidly and possibly be transmitted. We describe the characteristics of a pair of oseltamivir-resistant and oseltamivir-susceptible pH... | During the 2009 pandemic of the novel A/H1N1 (pH1N1) virus, the World Health Organization recommended oseltamivir as first-line agent for treatment of patients with severe infections leading to hospitalization and for those with underlying diseases predisposing to pulmonary complications. Oseltamivir-resistant isolates... | The novel influenza A (H1N1) virus was initially detected in Mexico and California in April 2009 and then officially became the first pandemic influenza virus of the 21st century on June 11, 2009 [1], [2]. Most confirmed cases of pandemic A/H1N1 (pH1N1) infection have been characterized so far by self-limited flu-like ... |
10.1371/journal.ppat.1002726 | Hsp90 Interacts Specifically with Viral RNA and Differentially Regulates Replication Initiation of Bamboo mosaic virus and Associated Satellite RNA | Host factors play crucial roles in the replication of plus-strand RNA viruses. In this report, a heat shock protein 90 homologue of Nicotiana benthamiana, NbHsp90, was identified in association with partially purified replicase complexes from BaMV-infected tissue, and shown to specifically interact with the 3′ untransl... | Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone in prokaryotes and eukaryotes, and regulates diverse cellular processes through ensuring the correct folding of numerous client proteins. However, there are no reports of direct interactions between Hsp90 with viral RNA. Here, we report that a new ... | Viruses have limited coding capacity and require a multitude of host factors to support their biological functions during the infection cycle [1]–[4]. Researchers have used various experimental approaches in their search for host factors specifically required for viral replication. These approaches have included genome... |
10.1371/journal.pgen.1000302 | The Chromosomal High-Affinity Binding Sites for the Drosophila Dosage Compensation Complex | Dosage compensation in male Drosophila relies on the X chromosome–specific recruitment of a chromatin-modifying machinery, the dosage compensation complex (DCC). The principles that assure selective targeting of the DCC are unknown. According to a prevalent model, X chromosome targeting is initiated by recruitment of t... | In sexually dimorphic species, unequal distribution of sex chromosomes requires adjustment of gene expression levels between the sexes. Male flies enhance transcription from the single X chromosome to meet the levels in females (XX). The specific recognition of sex chromosomes is a crucial step in this dosage compensat... | Genes residing on the single X chromosome in male Drosophila flies are transcribed at elevated rates to match the expression levels of the two X chromosomes in female cells. Transcriptional tuning in male cells depends on the activity of a ribonucleoprotein complex, the dosage compensation complex (DCC, also referred t... |
10.1371/journal.ppat.1000226 | A Structural Model of the Staphylococcus aureus ClfA–Fibrinogen Interaction Opens New Avenues for the Design of Anti-Staphylococcal Therapeutics | The fibrinogen (Fg) binding MSCRAMM Clumping factor A (ClfA) from Staphylococcus aureus interacts with the C-terminal region of the fibrinogen (Fg) γ-chain. ClfA is the major virulence factor responsible for the observed clumping of S. aureus in blood plasma and has been implicated as a virulence factor in a mouse mode... | Staphylococcus aureus (S. aureus) is a common pathogen that can cause a range of diseases from mild skin infections to life-threatening sepsis in humans. Some surface proteins on S. aureus play important roles in the S. aureus disease process. One of these bacterial surface proteins is clumping factor A (ClfA) that bin... | Staphylococcus aureus is a Gram-positive commensal organism that permanently colonizes 20% of healthy adults and transiently colonizes up to 50% of the general population [1]. For many years, S. aureus has been a major nosocomial pathogen causing a range of diseases from superficial skin infections to life-threatening ... |
10.1371/journal.pntd.0005301 | Review of 21 cases of mycetoma from 1991 to 2014 in Rio de Janeiro, Brazil | Mycetoma is caused by the subcutaneous inoculation of filamentous fungi or aerobic filamentous bacteria that form grains in the tissue. The purpose of this study is to describe the epidemiologic, clinic, laboratory, and therapeutic characteristics of patients with mycetoma at the Oswaldo Cruz Foundation in Rio de Janei... | Mycetoma is a major health problem in tropical areas and is prevalent among people of low socio-economic status. As in many other regions of the world, the incidence and prevalence of mycetoma in Brazil is unknown. This study describes some aspects of mycetoma patients in 24 years of experience at the National Institut... | Mycetoma is a chronic subcutaneous infections caused by the inoculation of filamentous fungi (eumycetoma) or aerobic filamentous bacteria (actinomycetoma) that form grains in the affected tissues [1]. It´s considered a neglected disease by the World Health Organization (WHO) since 2016 and remains without any control p... |
10.1371/journal.pntd.0002532 | Combinatory Microarray and SuperSAGE Analyses Identify Pairing-Dependently Transcribed Genes in Schistosoma mansoni Males, Including Follistatin | Schistosomiasis is a disease of world-wide importance and is caused by parasitic flatworms of the genus Schistosoma. These parasites exhibit a unique reproduction biology as the female's sexual maturation depends on a constant pairing-contact to the male. Pairing leads to gonad differentiation in the female, and even g... | Schistosomiasis is an important infectious disease caused by worm parasites of the genus Schistosoma and directly affects more than 240 million people in 78 tropical and sub-tropical countries but also animals. Pathogenesis is triggered by eggs that are produced by paired females and get trapped in liver and gut causin... | Schistosoma mansoni is a species of parasitic flatworms causing schistosomiasis, an infectious disease of worldwide importance for man and animals. Besides vertebrates as final hosts, the parasites' life cycle includes a snail intermediate host, and both are infected by aquatic larval stages. Schistosomiasis occurs in ... |
10.1371/journal.pntd.0004002 | Meteorologically Driven Simulations of Dengue Epidemics in San Juan, PR | Meteorological factors influence dengue virus ecology by modulating vector mosquito population dynamics, viral replication, and transmission. Dynamic modeling techniques can be used to examine how interactions among meteorological variables, vectors and the dengue virus influence transmission. We developed a dengue fev... | Numerous studies have investigated meteorological and climatic influences on mosquito transmitted viruses. However, dengue ecology is complex, necessitating an understanding of the interactions among components in the system. We estimate dengue fever cases in San Juan, Puerto Rico using a mathematical model informed by... | In the last decade dengue infections have increased dramatically in the Americas with cases now occurring in the southern U.S., Mexico and Central America, across the Caribbean, and as far south as Argentina in South America [1]. The Pan American outbreak in 2010 resulted in 1.7 million cases of dengue fever (DF) inclu... |
10.1371/journal.pgen.1006059 | The Great Migration and African-American Genomic Diversity | We present a comprehensive assessment of genomic diversity in the African-American population by studying three genotyped cohorts comprising 3,726 African-Americans from across the United States that provide a representative description of the population across all US states and socioeconomic status. An estimated 82.1%... | Genetic studies of African-Americans identify functional variants, elucidate historical and genealogical mysteries, and reveal basic biology. However, African-Americans have been under-represented in genetic studies, and relatively little is known about nation-wide patterns of genomic diversity in the population. Here,... | The history of African-American populations is marked by dramatic migrations within Africa, through the transatlantic slave trade, and within the United States (US). By 1808, when the transatlantic slave trade was made illegal in the US, approximately 360,000 Africans had been brought forcibly into the US in documented... |
10.1371/journal.pgen.1006113 | Pneumococcal Competence Coordination Relies on a Cell-Contact Sensing Mechanism | Bacteria have evolved various inducible genetic programs to face many types of stress that challenge their growth and survival. Competence is one such program. It enables genetic transformation, a major horizontal gene transfer process. Competence development in liquid cultures of Streptococcus pneumoniae is synchroniz... | Development of competence for genetic transformation by cultures of pneumococcal cells has been considered till now as a classic example of quorum sensing, whereby a culture attaining a sufficient cell density detects a diffusible signaling molecule (in this case, Competence-Stimulating Peptide (CSP)) and switches en m... | Under certain circumstances, single bacterial cells can sense environmental conditions and stimulate collective behavior by using exported signaling molecules that act as auto-inducers (AI). The two first processes found to be stimulated by AI sensing were luminescence in Vibrio fischeri [1] and competence for transfor... |
10.1371/journal.pgen.1002230 | Genomic Analysis of the Necrotrophic Fungal Pathogens Sclerotinia sclerotiorum and Botrytis cinerea | Sclerotinia sclerotiorum and Botrytis cinerea are closely related necrotrophic plant pathogenic fungi notable for their wide host ranges and environmental persistence. These attributes have made these species models for understanding the complexity of necrotrophic, broad host-range pathogenicity. Despite their similari... | Sclerotinia sclerotiorum and Botrytis cinerea are notorious plant pathogenic fungi with very wide host ranges. They cause vast economic damage during crop cultivation as well as in harvested produce. These fungi are typical examples of necrotrophs: they first kill host plant cells and then colonize the dead tissue. The... | Phytopathogenic fungi have evolved a wide range of strategies to infect and colonize plants through both convergent and divergent adaptations. This is reflected in the occurrence of species within common evolutionary branches with widely diverse pathogenic lifestyles, ranging from obligate biotrophs to necrotrophs, and... |
10.1371/journal.pgen.1003931 | Recombinogenic Conditions Influence Partner Choice in Spontaneous Mitotic Recombination | Mammalian common fragile sites are loci of frequent chromosome breakage and putative recombination hotspots. Here, we utilized Replication Slow Zones (RSZs), a budding yeast homolog of the mammalian common fragile sites, to examine recombination activities at these loci. We found that rates of URA3 inactivation of a hi... | Chromosome rearrangements are frequently associated with human cancers. Such rearrangement can result from a DNA break followed by an erroneous repair. Mammalian common fragile sites are one of the most extensively studied naturally occurring breakage prone regions of the genome. It has been proposed that fragile sites... | Accidental DNA double strand breaks (DSBs) arise during unperturbed proliferation. Such “endogenous” or “spontaneous” chromosome breakage does not occur randomly throughout the genome, but at specific loci, often referred to as fragile sites. Fragile sites have been observed in organisms ranging from bacteria to mammal... |
10.1371/journal.pmed.1002138 | Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose–Efficacy Modeling | Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of ne... | The limited diversity of chemical mode of action in the global portfolio of marketed antimalarials along with recently observed artemisinin resistance that threatens the current first-line treatment highlights the urgent need for development of new antimalarials.
In accordance with target product profiles defined by th... | Malaria caused 438,000 deaths worldwide in 2015, of which 70% were in children under the age of 5 y [1]. Between 2000 and 2015, strategies for malaria control and eradication reduced the incidence of malaria by 48% in the WHO African Region. The upscaled interventions consisted of increased accessibility to long-lastin... |
10.1371/journal.ppat.1006677 | KSHV inhibits stress granule formation by viral ORF57 blocking PKR activation | TIA-1 positive stress granules (SG) represent the storage sites of stalled mRNAs and are often associated with the cellular antiviral response. In this report, we provide evidence that Kaposi’s sarcoma-associated herpesvirus (KSHV) overcomes the host antiviral response by inhibition of SG formation via a viral lytic pr... | Mammalian RNA granules, including stress granules (SG), are important components of the host cell antiviral responses and their assembly is widely counteracted by RNA viruses. In Kaposi’s sarcoma-associated herpesvirus (KSHV) lytically infected B cells, we found that KSHV infection inhibits the assembly of SG by expres... | Mammalian somatic cells produce two types of RNA granules, processing bodies (P-bodies, PB) and stress granules (SG) [1,2]. Both granules are physically and mechanistically distinct compartments with many unique biomarkers. While GW182 is confined to PB, RNA-binding proteins TIA-1, poly(A) binding protein (PABP) and G3... |
10.1371/journal.ppat.1001121 | Ebolavirus Is Internalized into Host Cells via Macropinocytosis in a Viral Glycoprotein-Dependent Manner | Ebolavirus (EBOV) is an enveloped, single-stranded, negative-sense RNA virus that causes severe hemorrhagic fever with mortality rates of up to 90% in humans and nonhuman primates. Previous studies suggest roles for clathrin- or caveolae-mediated endocytosis in EBOV entry; however, ebolavirus virions are long, filament... | Ebolavirus (EBOV) is an enveloped, single-stranded, negative-sense RNA virus that causes severe hemorrhagic fever with high mortality rates in humans and nonhuman primates. Previous studies suggest roles for clathrin- or caveolae-mediated endocytosis in EBOV entry; however, questions remain regarding the mechanism of E... | Viruses have evolved a variety of mechanisms to enter host cells [1], [2], [3], including clathrin- and caveolae-mediated endocytosis, phagocytosis, and macropinocytosis. The main route of endocytosis, mediated by clathrin, is characterized by the formation of clathrin-coated pits (CCP) of 85–110 nm in diameter that bu... |
10.1371/journal.pntd.0000481 | The Role of Human Movement in the Transmission of Vector-Borne Pathogens | Human movement is a key behavioral factor in many vector-borne disease systems because it influences exposure to vectors and thus the transmission of pathogens. Human movement transcends spatial and temporal scales with different influences on disease dynamics. Here we develop a conceptual model to evaluate the importa... | Vector-borne diseases constitute a largely neglected and enormous burden on public health in many resource-challenged environments, demanding efficient control strategies that could be developed through improved understanding of pathogen transmission. Human movement—which determines exposure to vectors—is a key behavio... | For vector-borne pathogens heterogeneity in patterns of contact between susceptible hosts and infectious agents is common [1],[2],[3]. Some hosts will be exposed to, harbor, and pass on more parasites than others. Variation in contact patterns can amplify [4],[5] or dampen [6] the rate of transmission, even as it also ... |
10.1371/journal.ppat.1000780 | HIV Controller CD4+ T Cells Respond to Minimal Amounts of Gag Antigen Due to High TCR Avidity | HIV controllers are rare individuals who spontaneously control HIV replication in the absence of antiretroviral treatment. Emerging evidence indicates that HIV control is mediated through very active cellular immune responses, though how such responses can persist over time without immune exhaustion is not yet understo... | HIV infection, if left untreated, leads to the progressive disruption of the immune system, the destruction of the CD4+ T cell population, and the occurrence of multiple opportunistic infections. However, a small fraction of HIV-infected individuals (less than 1%) avoid these deleterious effects by spontaneously contro... | HIV controllers are rare individuals who spontaneously control HIV replication in the absence of antiretroviral treatment [1],[2]. HIV controllers harbor plasma viral loads that remain undetectable by conventional assays and cell-associated HIV DNA loads that are in the very low range, close to one log below those dete... |
10.1371/journal.pbio.1002491 | Paneth Cell-Rich Regions Separated by a Cluster of Lgr5+ Cells Initiate Crypt Fission in the Intestinal Stem Cell Niche | The crypts of the intestinal epithelium house the stem cells that ensure the continual renewal of the epithelial cells that line the intestinal tract. Crypt number increases by a process called crypt fission, the division of a single crypt into two daughter crypts. Fission drives normal tissue growth and maintenance. C... | The intestinal tract undergoes many changes during development, and after birth it has to significantly elongate and widen in order to increase the surface area for absorption. Crypt fission is a key process in intestinal tissue expansion and is also involved in adenoma growth. Despite the importance of crypt fission, ... | The structures of many adult epithelia arise from branching events during development. For instance, the organisation of adult lung, kidney, and mammary epithelia arises by branching of epithelial tubes that ceases once the tissue is fully formed. A related but distinct form of branching is important in the gut, where ... |
10.1371/journal.pcbi.1001040 | Phase-Locked Signals Elucidate Circuit Architecture of an Oscillatory Pathway | This paper introduces the concept of phase-locking analysis of oscillatory cellular signaling systems to elucidate biochemical circuit architecture. Phase-locking is a physical phenomenon that refers to a response mode in which system output is synchronized to a periodic stimulus; in some instances, the number of respo... | Key to robust discernment of cell circuit architecture is to have as many distinct response features as possible for comparison and evaluation. One under-appreciated characteristic of oscillatory circuits is that under periodic stimulation, these systems will exhibit responses synchronized to this stimulatory input, a ... | Determining the circuit architecture of cellular signaling pathways is challenging. Analysis using perturbative tools including siRNA [1], [2], protein over-expression [3], chemical inhibitors [4], or caged compounds [5] usually reveal multiple plausible models that require further refinements and clarification, not ju... |
10.1371/journal.pbio.3000021 | If a fish can pass the mark test, what are the implications for consciousness and self-awareness testing in animals? | The ability to perceive and recognise a reflected mirror image as self (mirror self-recognition, MSR) is considered a hallmark of cognition across species. Although MSR has been reported in mammals and birds, it is not known to occur in any other major taxon. Potentially limiting our ability to test for MSR in other ta... | The ability to perceive and recognise a reflected mirror image as self is considered a hallmark of cognition across species. Here, we show that a fish, the cleaner wrasse, shows behavioural responses that can be interpreted as passing the mark (or mirror) test, a classic test for self-awareness in animals. We ask wheth... | The mark test, in which a coloured mark is placed on a test subject in a location that can only be viewed in a mirror reflection, is held as the benchmark behavioural assay for assessing whether an individual has the capacity for self-recognition [1,2]. In human infants, approximately 65% of individuals pass the mark t... |
10.1371/journal.pcbi.1002640 | A Network-based Approach for Predicting Missing Pathway Interactions | Embedded within large-scale protein interaction networks are signaling pathways that encode response cascades in the cell. Unfortunately, even for well-studied species like S. cerevisiae, only a fraction of all true protein interactions are known, which makes it difficult to reason about the exact flow of signals and t... | Networks of protein interactions encode a variety of molecular processes occurring in the cell. Embedded within these networks are important subnetworks called signaling pathways. Pathways are initiated by upstream proteins (called sources) that receive signals from the environment and trigger a cascade of information ... | Networks of protein interactions can reveal how complex molecular processes are activated in the cell. However, even for model species, only a fraction of true physical interactions are known [1], [2] and experimental verification of all remaining potential interactions is unlikely in the near future. Furthermore, inte... |
10.1371/journal.pbio.0060277 | Chromatin- and Transcription-Related Factors Repress Transcription from within Coding Regions throughout the Saccharomyces cerevisiae Genome | Previous studies in Saccharomyces cerevisiae have demonstrated that cryptic promoters within coding regions activate transcription in particular mutants. We have performed a comprehensive analysis of cryptic transcription in order to identify factors that normally repress cryptic promoters, to determine the amount of c... | Recent studies have shown that much more of the eukaryotic genome is transcribed into RNA than previously thought. In Saccharomyces cerevisiae, when particular factors are defective, cryptic promoters within several coding regions become active and produce shorter transcripts corresponding to the 3′ portions of genes. ... | Several recent studies have demonstrated that transcription occurs across large eukaryotic genomes in a much more widespread and complex pattern than previously imagined. The recent findings of the ENCODE project, which analyzed transcription of 1% of the human genome [1], demonstrated the use of multiple transcription... |
10.1371/journal.pntd.0000834 | Metabolomics-Based Discovery of Diagnostic Biomarkers for Onchocerciasis | Development of robust, sensitive, and reproducible diagnostic tests for understanding the epidemiology of neglected tropical diseases is an integral aspect of the success of worldwide control and elimination programs. In the treatment of onchocerciasis, clinical diagnostics that can function in an elimination scenario ... | Onchocerciasis, caused by the filarial parasite Onchocerca volvulus, afflicts millions of people, causing such debilitating symptoms as blindness and acute dermatitis. There are no accurate, sensitive means of diagnosing O. volvulus infection. Clinical diagnostics are desperately needed in order to achieve the goals of... | Onchocerciasis, commonly referred to as “river blindness” is classified by the World Health Organization (WHO) as a neglected tropical disease, afflicting approximately 37 million people in Africa, Central and South America and Yemen, with 89 million more at risk [1]. Symptoms of the disease include acute dermatitis an... |
10.1371/journal.pbio.0060187 | Multivariate Patterns in Object-Selective Cortex Dissociate Perceptual and Physical Shape Similarity | Prior research has identified the lateral occipital complex (LOC) as a critical cortical region for the representation of object shape in humans. However, little is known about the nature of the representations contained in the LOC and their relationship to the perceptual experience of shape. We used human functional M... | As early as 1031 a.d., the Arab scholar Ibn al-Haytham suggested that visual experience was not veridical, but inherently subjective. During the last few decades, this observation has given rise to one of the core questions in visual neuroscience: how does the subjective experience of visual stimuli relate to their neu... | What is the neural code for object shape? This question has been at the core of systems neuroscience for decades. In monkeys, inferotemporal (IT) cortex has been shown to contain cells selective for complex shapes [1]; in humans, functional magnetic resonance imaging (fMRI) has identified a brain region known as latera... |
10.1371/journal.ppat.1005620 | Ecosystem Interactions Underlie the Spread of Avian Influenza A Viruses with Pandemic Potential | Despite evidence for avian influenza A virus (AIV) transmission between wild and domestic ecosystems, the roles of bird migration and poultry trade in the spread of viruses remain enigmatic. In this study, we integrate ecosystem interactions into a phylogeographic model to assess the contribution of wild and domestic h... | It is assumed that AIV outbreaks in poultry are introduced from wild birds. To test this, we incorporated ecosystem and location of isolation into a comparative genetic analysis. We show high rates of viral transmission from domestic to wild birds within a region and, that wild birds could transmit AIV to poultry betwe... | Intensive agriculture has allowed AIV circulating in wild bird populations and multi-host poultry systems (domestic food birds including chicken, duck, goose, pigeon) to interact, shaping the diversity of subtypes with pandemic potential [1]. The recently emerged H7N9 viruses containing H9N2-origin internal genes highl... |
10.1371/journal.ppat.1006917 | SpdC, a novel virulence factor, controls histidine kinase activity in Staphylococcus aureus | The success of Staphylococcus aureus, as both a human and animal pathogen, stems from its ability to rapidly adapt to a wide spectrum of environmental conditions. Two-component systems (TCSs) play a crucial role in this process. Here, we describe a novel staphylococcal virulence factor, SpdC, an Abi-domain protein, inv... | Staphylococcus aureus is a major human pathogen, and has become a significant worldwide health concern due to the rapid emergence of antibiotic resistant strains. Like most bacteria, S. aureus adapts to its environment by adjusting its genetic expression through sensing and regulatory systems. We show here that the Spd... | Two-component systems (TCSs) are composed of a histidine kinase, usually membrane-bound and acting as an environmental sensor, which phosphorylates a coupled response regulator, often controlling gene transcription. Although these systems have been extensively studied and play an essential role in bacterial adaptation ... |
10.1371/journal.pgen.1001078 | Consistent Association of Type 2 Diabetes Risk Variants Found in Europeans in Diverse Racial and Ethnic Groups | It has been recently hypothesized that many of the signals detected in genome-wide association studies (GWAS) to T2D and other diseases, despite being observed to common variants, might in fact result from causal mutations that are rare. One prediction of this hypothesis is that the allelic associations should be popul... | Single rare causal alleles and/or collections of multiple rare alleles have been suggested to create “synthetic associations” with common variants in genome-wide association studies (GWAS). This model predicts that associations with common variants will not be consistent across populations. In this study, we examined 1... | Multiple common risk alleles have been identified as reproducibly associated with risk of type 2 diabetes (T2D) [1]–[13]. With the exception of the KCNQ1 locus which was identified in the Japanese population [1], [2], all of the well-replicated risk variants were first identified in populations of Northern European anc... |
10.1371/journal.pntd.0002437 | Concurrent Infections of Giardia duodenalis, Enterocytozoon bieneusi, and Clostridium difficile in Children during a Cryptosporidiosis Outbreak in a Pediatric Hospital in China | Over 200 cryptosporidiosis outbreaks have been reported, but little is known if other enteric pathogens were also involved in some of these outbreaks. Recently, an outbreak of cryptosporidiosis linked to poor hygiene by two Cryptosporidium hominis subtypes occurred in a pediatric hospital ward (Ward A) in China, lastin... | The transmission of Giardia duodenalis, Enterocytozoon bieneusi, and Clostridium difficile is poorly understood in developing countries despite their wide occurrence. Because they are transmitted by the same fecal-oral route as Cryptosporidium, in this study, we have examined the occurrence of these enteric pathogens i... | Cryptosporidium is a significant cause of diarrhea in humans worldwide [1]. Humans can acquire Cryptosporidium infections through the fecal-oral route via direct person-to-person or animal-to-person contact, or ingestion of contaminated water or food [2]. Thus far, over 200 waterborne, foodborne, person-to-person, and ... |
10.1371/journal.pgen.1002719 | Karyotypic Determinants of Chromosome Instability in Aneuploid Budding Yeast | Recent studies in cancer cells and budding yeast demonstrated that aneuploidy, the state of having abnormal chromosome numbers, correlates with elevated chromosome instability (CIN), i.e. the propensity of gaining and losing chromosomes at a high frequency. Here we have investigated ploidy- and chromosome-specific dete... | Aneuploidy, the state of harboring an unbalanced number of chromosomes, has long been hypothesized to be at the basis of malignant transformation. Recent studies have also shown that aneuploidy is an important form of genome alteration underlying adaptive evolution of cells in response to harsh environments or genetic ... | The nature of the genetic changes driving cellular evolution has been a central issue in both adaptive evolution of unicellular organisms and somatic evolution of cancer cells. Phenotypic variation, acting as a substrate of Darwinian selection and as an origin of phenotypic innovation, can be driven by sequence-based m... |
10.1371/journal.ppat.1002267 | Exposure to the Viral By-Product dsRNA or Coxsackievirus B5 Triggers Pancreatic Beta Cell Apoptosis via a Bim / Mcl-1 Imbalance | The rise in type 1 diabetes (T1D) incidence in recent decades is probably related to modifications in environmental factors. Viruses are among the putative environmental triggers of T1D. The mechanisms regulating beta cell responses to viruses, however, remain to be defined. We have presently clarified the signaling pa... | The global prevalence of type 1 diabetes (T1D) is approximately 20 million individuals, and projections indicate that this will double in the coming decades. This increase in T1D incidence is probably related to modification in the exposure to environmental factors. Viruses are one of the putative environmental agents ... | Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the progressive and selective destruction of the insulin-producing pancreatic beta cells [1]. It mainly affects individuals during childhood or adolescence and requires a life-long treatment with insulin, which at the US represents a cost of $14.4 b... |
10.1371/journal.pcbi.1003572 | Contribution of Network Connectivity in Determining the Relationship between Gene Expression and Metabolite Concentration Changes | One of the primary mechanisms through which a cell exerts control over its metabolic state is by modulating expression levels of its enzyme-coding genes. However, the changes at the level of enzyme expression allow only indirect control over metabolite levels, for two main reasons. First, at the level of individual rea... | Regulation of metabolic activity in response to environmental and genetic perturbations is fundamental to the growth and maintenance of all cells. A primary regulatory process used by cells to control the activity of their metabolic network is the alteration in the expression of enzyme-coding genes. How these alteratio... | Cellular metabolic networks provide basic biochemical building blocks and a thermodynamically favorable environment for growth and maintenance. Due to this crucial role of metabolism, cells have evolved various mechanisms to regulate metabolic reactions in response to genetic and environmental changes. Metabolic reacti... |
10.1371/journal.ppat.1001266 | Entrapment of Viral Capsids in Nuclear PML Cages Is an Intrinsic Antiviral Host Defense against Varicella-Zoster Virus | The herpesviruses, like most other DNA viruses, replicate in the host cell nucleus. Subnuclear domains known as promyelocytic leukemia protein nuclear bodies (PML-NBs), or ND10 bodies, have been implicated in restricting early herpesviral gene expression. These viruses have evolved countermeasures to disperse PML-NBs, ... | Many DNA viruses, including varicella-zoster virus (VZV), a herpesvirus that causes varicella (chickenpox) and zoster (shingles), replicate in the host cell nucleus. Here, we have identified an intrinsic antiviral mechanism that specifically targets newly assembled VZV capsids and contains these essential viral structu... | Promyelocytic leukemia protein (PML) is a major organizing component of structures that are referred to as PML nuclear bodies (PML-NBs) or nuclear domain 10 (ND10) bodies [1]–[3]. These nuclear bodies are heterogenous in size, shape and molecular composition [4]–[6], are prominent in most mammalian cell types and parti... |
10.1371/journal.pntd.0004616 | The Burden of Typhoid and Paratyphoid in India: Systematic Review and Meta-analysis | Typhoid is an important public health challenge for India, especially with the spread of antimicrobial resistance. The decision about whether to introduce a public vaccination programme needs to be based on an understanding of disease burden and the age-groups and geographic areas at risk.
We searched Medline and Web o... | Typhoid fever is an important cause of avoidable mortality in regions without adequate access to safe water and sanitation. Highly immunogenic typhoid conjugate vaccines are now licensed and under consideration as a public health intervention in India. The decision about whether and how to introduce a public vaccinatio... | Typhoid (enteric) fever caused by Salmonella enterica serovar Typhi (S. Typhi) is an important cause of morbidity and mortality. The global annual burden was estimated at approximately 12 million cases for 2010 [1,2]. Most of these were effectively treated with antibiotics, although the case fatality rate remains at ab... |
10.1371/journal.pgen.1004904 | ALIX and ESCRT-III Coordinately Control Cytokinetic Abscission during Germline Stem Cell Division In Vivo | Abscission is the final step of cytokinesis that involves the cleavage of the intercellular bridge connecting the two daughter cells. Recent studies have given novel insight into the spatiotemporal regulation and molecular mechanisms controlling abscission in cultured yeast and human cells. The mechanisms of abscission... | Cytokinesis, the final step of cell division, concludes with a process termed abscission, during which the two daughter cells physically separate. In spite of their importance, the molecular machineries controlling abscission are poorly characterized especially in the context of living metazoan tissues. Here we provide... | Cytokinesis is the final step of cell division that leads to the physical separation of the two daughter cells. It is tightly controlled in space and time and proceeds in multiple steps via sequential specification of the cleavage plane, assembly and constriction of the actomyosin-based contractile ring (CR), formation... |
10.1371/journal.ppat.1002494 | Development of Functional and Molecular Correlates of Vaccine-Induced Protection for a Model Intracellular Pathogen, F. tularensis LVS | In contrast with common human infections for which vaccine efficacy can be evaluated directly in field studies, alternative strategies are needed to evaluate efficacy for slowly developing or sporadic diseases like tularemia. For diseases such as these caused by intracellular bacteria, serological measures of antibodie... | Diseases such as tuberculosis (caused by Mycobacterium tuberculosis) or tularemia (caused by Francisella tularensis) result from infections by microbes that live within cells of a person's body. New vaccines are being developed against such intracellular pathogens, but some will be difficult to test, because disease ta... | Most vaccines against infectious diseases in clinical use today act by stimulating the production of antibodies, which block virus entry, neutralize toxins, or otherwise limit infection through a variety of mechanisms. Measurements of serum antibodies have therefore been applied to predict successful vaccine-induced pr... |
10.1371/journal.pntd.0003547 | Economic and Disease Burden of Dengue in Mexico | Dengue imposes a substantial economic and disease burden in most tropical and subtropical countries. Dengue incidence and severity have dramatically increased in Mexico during the past decades. Having objective and comparable estimates of the economic burden of dengue is essential to inform health policy, increase dise... | During the past decades, dengue fever has become the most common arthropod-borne viral disease, imposing a substantial economic and disease burden in most tropical and subtropical countries, including Mexico. Dengue incidence and severity have dramatically increased in Mexico, with transmission regularly reported in 28... | Dengue fever is the most important arthropod-borne viral disease affecting humans, with about half the world’s population estimated to be at risk of infection, and epidemics increasing in frequency, magnitude, and geographical reach [1–4]. Dengue imposes a substantial economic and disease burden in most tropical and su... |
10.1371/journal.pgen.1005526 | A Systems Approach Identifies Essential FOXO3 Functions at Key Steps of Terminal Erythropoiesis | Circulating red blood cells (RBCs) are essential for tissue oxygenation and homeostasis. Defective terminal erythropoiesis contributes to decreased generation of RBCs in many disorders. Specifically, ineffective nuclear expulsion (enucleation) during terminal maturation is an obstacle to therapeutic RBC production in v... | Red blood cells (RBCs) are highly specialized cells that transport oxygen throughout the body and are essential for survival. However, RBCs have a limited lifespan and need to be replenished continuously by stem cells in the bone marrow. Mammalian RBCs are unique in that in order to fully mature they exclude their nucl... | Erythropoiesis ensures the daily production of over 200 billion RBCs whose main function is to carry oxygen. Decreased production of RBCs is associated with many human disorders involving impaired erythroblast maturation. The generation of RBCs in vitro from embryonic stem cells or human-induced pluripotent stem cells ... |
10.1371/journal.pntd.0007471 | Therapeutic efficacy of albendazole against soil-transmitted helminthiasis in children measured by five diagnostic methods | Preventive chemotherapy (PC) with benzimidazole drugs is the backbone of soil-transmitted helminth (STH) control programs. Over the past decade, drug coverage has increased and with it, the possibility of developing anthelmintic resistance. It is therefore of utmost importance to monitor drug efficacy. Currently, a var... | During the last decade, the scale of deworming programs that aim to eliminate the morbidity caused by intestinal worms has increased to a level that is unprecedented in history. It is therefore of utmost importance to monitor any change in therapeutic efficacy that may arise from emerging drug resistance. Currently, a ... | Infections with soil-transmitted helminths (STHs; Ascaris lumbricoides, Trichuris trichiura, Necator americanus and Ancylostoma duodenale) are responsible for the highest burden among all neglected tropical diseases. Recent global estimates indicate that in 2015, more than 1.6 billion people were infected with at least... |
10.1371/journal.pntd.0002778 | Molecular Analysis of Echinostome Metacercariae from Their Second Intermediate Host Found in a Localised Geographic Region Reveals Genetic Heterogeneity and Possible Cryptic Speciation | Echinostome metacercariae are the infective stage for humans and animals. The identification of echinostomes has been based until recently on morphology but molecular techniques using sequences of ribosomal RNA and mitochondrial DNA have indicated major clades within the group. In this study we have used the ITS2 regio... | Infections by food-borne trematodes are estimated to infect over 40 million people worldwide, although infections by echinostomes make up only a portion of these cases, usually in regions where their prevalence is high. In South East Asia and in the far east of Asia, human infection is associated with cultural and diet... | Echinostomes are intestinal trematodes of humans and animals that are endemic to Southeast Asia and the Far East, i.e. mainland China, Taiwan, India, Korea, Malaysia, Philippines, Indonesia, and Thailand, and present a public health problem [1]. Human echinostomiasis has been attributed to at least twenty species belon... |
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