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10.1371/journal.pntd.0000432 | WR279,396, a Third Generation Aminoglycoside Ointment for the Treatment of Leishmania major Cutaneous Leishmaniasis: A Phase 2, Randomized, Double Blind, Placebo Controlled Study | Cutaneous leishmaniasis (CL) is a disfiguring disease that confronts clinicians with a quandary: leave patients untreated or engage in a complex or toxic treatment. Topical treatment of CL offers a practical and safe option. Accordingly, the treatment of CL with WR279,396, a formulation of paromomycin and gentamicin in... | Cutaneous leishmaniasis is due to a small parasite (Leishmania) that creates disfiguring sores, and affects more than one million persons (mainly children) each year. Treating lesions with a cream—instead of with injections as currently done—would greatly improve the well-being of affected patients. No cream formulatio... | The incidence of cutaneous leishmaniasis (CL) globally is 1.0–1.5 million cases annually [1]. There are several available therapeutic options, but none is optimal [2]. In Tunisia, the standard treatment is with intralesional injections of pentavalent antimonials [2] the recommended drugs used for the treatment of both ... |
10.1371/journal.pbio.1001282 | Convergent Evolution of Escape from Hepaciviral Antagonism in Primates | The ability to mount an interferon response on sensing viral infection is a critical component of mammalian innate immunity. Several viruses directly antagonize viral sensing pathways to block activation of the host immune response. Here, we show that recurrent viral antagonism has shaped the evolution of the host prot... | Hepatitis C virus (HCV) causes chronic liver disease and is estimated to infect 170 million people worldwide. HCV is able to establish a persistent infection in part by inhibiting the innate immune response. It does so by using its protease, NS3, to cleave the host's antiviral factor MAVS, which normally activates the ... | Among the myriad of antiviral mechanisms employed by mammalian cells, the ability to sense viral RNA has emerged as a critical component of innate immunity. Viral RNA is detected in the cytoplasm by sensor proteins RIG-I and MDA-5 [1]–[3]. Both these sensors act through a common downstream effector Mitochondrial antivi... |
10.1371/journal.ppat.1006592 | The macrophage cytoskeleton acts as a contact sensor upon interaction with Entamoeba histolytica to trigger IL-1β secretion | Entamoeba histolytica (Eh) is the causative agent of amebiasis, one of the major causes of dysentery-related morbidity worldwide. Recent studies have underlined the importance of the intercellular junction between Eh and host cells as a determinant in the pathogenesis of amebiasis. Despite the fact that direct contact ... | The protozoan parasite Entamoeba histolytica can establish an enteric infection in human hosts that leads to symptoms ranging from diarrhea to abscesses in the liver and the brain. Host susceptibility to amebic infection is in part determined by the quality and potency of the host immune response that occurs once the p... | Amebiasis is caused by the protozoan parasite Entamoeba histolytica (Eh) and is estimated to affect approximately 50 million people worldwide [1]. It is a major cause of mortality and morbidity, particularly in children of developing countries. Eh carriers remain asymptomatic in most cases, but in approximately 10% of ... |
10.1371/journal.ppat.1002059 | Crystal Structure and Functional Analysis of the SARS-Coronavirus RNA Cap 2′-O-Methyltransferase nsp10/nsp16 Complex | Cellular and viral S-adenosylmethionine-dependent methyltransferases are involved in many regulated processes such as metabolism, detoxification, signal transduction, chromatin remodeling, nucleic acid processing, and mRNA capping. The Severe Acute Respiratory Syndrome coronavirus nsp16 protein is a S-adenosylmethionin... | A novel coronavirus emerged in 2003 and was identified as the etiological agent of the deadly disease called Severe Acute Respiratory Syndrome. This coronavirus replicates and transcribes its giant genome using sixteen non-structural proteins (nsp1-16). Viral RNAs are capped to ensure stability, efficient translation, ... | Most eukaryotic cellular and viral mRNAs are modified by the addition of a polyadenine tail at the 3′- terminal and a cap structure at the 5′-terminal. The RNA cap protects mRNA from degradation by 5′ exoribonucleases, ensures efficient mRNA translation, and prevents recognition of viral RNA via innate immunity mechani... |
10.1371/journal.pgen.1005049 | Replicative DNA Polymerase δ but Not ε Proofreads Errors in Cis and in Trans | It is now well established that in yeast, and likely most eukaryotic organisms, initial DNA replication of the leading strand is by DNA polymerase ε and of the lagging strand by DNA polymerase δ. However, the role of Pol δ in replication of the leading strand is uncertain. In this work, we use a reporter system in Sacc... | Many DNA polymerases are able to proofread their errors: after incorporation of a wrong base, the resulting mispair invokes an exonuclease activity of the polymerase that removes the mispaired base and allows replication to continue. Elimination of the proofreading activity thus results in much higher mutation rates. W... | Unlike prokaryotes, eukaryotic cells have multiple DNA polymerases involved in chromosomal replication. It was first demonstrated in Saccharomyces cerevisiae [1] and then in human cells [2] that Pol α, Pol δ, and Pol ε were necessary for normal replication. It was subsequently found that two of these polymerases, Pol δ... |
10.1371/journal.pcbi.1005930 | Biophysical network modeling of the dLGN circuit: Effects of cortical feedback on spatial response properties of relay cells | Despite half-a-century of research since the seminal work of Hubel and Wiesel, the role of the dorsal lateral geniculate nucleus (dLGN) in shaping the visual signals is not properly understood. Placed on route from retina to primary visual cortex in the early visual pathway, a striking feature of the dLGN circuit is th... | The functional role of the dorsal lateral geniculate nucleus (dLGN), placed on route from retina to primary visual cortex in the early visual pathway, is still poorly understood. A striking feature of the dLGN circuit is that dLGN cells not only receive feedforward input from the retina, but also a prominent feedback f... | Visual signals from the retina pass through the dorsal geniculate nucleus (dLGN), the visual part of thalamus, on the way to the visual cortex. However, this is not simply a one-way flow of information: cortical cells feed back to both relay cells (RCs) and interneurons (INs) in the dLGN and thus shape the transfer of ... |
10.1371/journal.pntd.0002785 | A Dual Drug Sensitive L. major Induces Protection without Lesion in C57BL/6 Mice | Leishmaniasis is a major health problem in some endemic areas and yet, no vaccine is available against any form of the disease. Historically, leishmanization (LZ) which is an inoculation of individual with live Leishmania, is the most effective control measure at least against cutaneous leishmaniasis (CL). Due to vario... | Leishmaniasis is still a major health problem in some endemic foci, yet no vaccine is available against any form of leishmaniasis. It is a general belief that recovery from cutaneous leishmaniasis (CL) is accompanied with long life protection. An inoculation of live pathogenic L. major into healthy individuals to induc... | Cutaneous leishmaniasis (CL) manifests as a localized self-healing lesion(s) that in rare cases develops to a non-healing lesion. If non-healing lesions develop, they are extremely difficult to treat with current therapies [1]. Control measures for leishmaniasis such as vector and/or réservoir control are not always pr... |
10.1371/journal.pntd.0004585 | Diagnostic Accuracy of Antigen 5-Based ELISAs for Human Cystic Echinococcosis | Clinical diagnosis and follow up of cystic echinococcosis (CE) are based on imaging complemented by serology. Several immunodiagnostic tests are commercially available, but the development of new tools is still needed to overcome the lack of standardization of the target antigen, generally consisting of a crude extract... | Cystic echinococcosis is a neglected disease caused by the larval stage of the tapeworm Echinococcus granulosus complex affecting both humans and livestock. The disease is considered one of the world’s major zoonoses, and represents a public health problem. Clinical diagnosis and follow-up is mainly based on imaging, w... | Cystic echinococcosis (CE) is a neglected zoonotic disease caused by the larval form of the tapeworm Echinococcus granulosus complex. The definitive hosts are dogs and other canids, while sheep and other livestock are the natural intermediate hosts; humans are occasional intermediate hosts. Intermediate hosts can be in... |
10.1371/journal.ppat.1003675 | Loss of the TGFβ-Activating Integrin αvβ8 on Dendritic Cells Protects Mice from Chronic Intestinal Parasitic Infection via Control of Type 2 Immunity | Chronic intestinal parasite infection is a major global health problem, but mechanisms that promote chronicity are poorly understood. Here we describe a novel cellular and molecular pathway involved in the development of chronic intestinal parasite infection. We show that, early during development of chronic infection ... | Infection with intestinal parasitic worms is a major global health problem, with billions of people infected world-wide. Often these worms (known as helminths) develop a long-lasting chronic infection, due to failure of the host to mount the correct type of immune response that would normally expel the parasite. Howeve... | Gastrointestinal parasitic helminth infections are extremely prevalent, affecting nearly one quarter of the world population. Development of chronic infection, defined as the presence of adult worms in the host, results in severe morbidity and health problems and has been heavily linked with promotion of poverty in aff... |
10.1371/journal.pcbi.1004083 | Improved Estimation and Interpretation of Correlations in Neural Circuits | Ambitious projects aim to record the activity of ever larger and denser neuronal populations in vivo. Correlations in neural activity measured in such recordings can reveal important aspects of neural circuit organization. However, estimating and interpreting large correlation matrices is statistically challenging. Est... | It is now possible to record the spiking activity of hundreds of neurons at the same time. A meaningful statistical description of the collective activity of these neural populations—their ‘functional connectivity’—is a forefront challenge in neuroscience. We addressed this problem by identifying statistically efficien... | Functional connectivity is a statistical description of observed multineuronal activity patterns not reducible to the response properties of the individual cells. Functional connectivity reflects local synaptic connections, shared inputs from other regions, and endogenous network activity. Although functional connectiv... |
10.1371/journal.pbio.1000473 | Brief Bursts Self-Inhibit and Correlate the Pyramidal Network | Inhibitory pathways are an essential component in the function of the neocortical microcircuitry. Despite the relatively small fraction of inhibitory neurons in the neocortex, these neurons are strongly activated due to their high connectivity rate and the intricate manner in which they interconnect with pyramidal cell... | The neocortex of the mammalian brain contains many more excitatory neurons than inhibitory neurons, yet inhibitory neurons are essential components of neocortical circuitry. Inhibitory neurons form dense and intricate connections with excitatory neurons, which are mainly pyramidal cells. One prominent pathway formed be... | The mammalian neocortex consists of neurons that form an intricate network of recurrent circuits [1]–[3]. The synaptic wiring between cells follows a number of stereotypic rules including targeting specific domains of neurons, specific connection probabilities, target neuron preferences, and specific short-term synapti... |
10.1371/journal.pgen.1005249 | Minor Type IV Collagen α5 Chain Promotes Cancer Progression through Discoidin Domain Receptor-1 | Type IV collagens (Col IV), components of basement membrane, are essential in the maintenance of tissue integrity and proper function. Alteration of Col IV is related to developmental defects and diseases, including cancer. Col IV α chains form α1α1α2, α3α4α5 and α5α5α6 protomers that further form collagen networks. De... | Collagens, the major extracellular matrix components in most vertebrate tissues, provide cells with structural and functional support. Collagens are trimers of collagen α chains. Multiple trimers are formed by highly homologous α chains for certain types of collagens (e.g. α1α1α2, α3α4α5 and α5α5α6 heterotrimers for ty... | Basement membranes (BMs), specialized extracellular matrices separating epithelial and endothelial cells from underlying mesenchyme, provide cells with structural support, as well as morphogenic and functional cues [1–3]. Type IV collagens (Col IV) are major components of BMs [1,3]. Three triple helical protomers, α1α1... |
10.1371/journal.pbio.0050134 | A Helical Structural Nucleus Is the Primary Elongating Unit of Insulin Amyloid Fibrils | Although amyloid fibrillation is generally believed to be a nucleation-dependent process, the nuclei are largely structurally uncharacterized. This is in part due to the inherent experimental challenge associated with structural descriptions of individual components in a dynamic multi-component equilibrium. There are i... | Diseases associated with the presence of amyloid structures, such as Alzheimer and Parkinson disease, are characterized by the presence of protein aggregates in the form of highly ordered fibrils. This amyloid fibril formation is also commonly observed for a number of protein drugs, such as insulin. Detailed informatio... | Amyloid fibrils are associated with critical diseases such as Alzheimer disease and Type 2 diabetes. In each amyloid disease, a particular protein or polypeptide aggregates and forms insoluble fibrils [1]. Moreover, amyloid fibrils play a critical role in unwanted degradation of a number of protein-based drugs [2,3]. I... |
10.1371/journal.ppat.1006194 | Vaccination has minimal impact on the intrahost diversity of H3N2 influenza viruses | While influenza virus diversity and antigenic drift have been well characterized on a global scale, the factors that influence the virus’ rapid evolution within and between human hosts are less clear. Given the modest effectiveness of seasonal vaccination, vaccine-induced antibody responses could serve as a potent sele... | Influenza is a significant global health problem. Vaccination is the best way to prevent influenza virus infection, and seasonal influenza vaccines are considered for reformulation each year in order to keep up with the virus’ evolution. Despite these efforts, vaccine recipients often develop an immune response that do... | Despite recommendations for universal influenza vaccination and the ample availability of vaccines in the United States, influenza continues to cause significant morbidity and mortality [1]. This is, in part, a result of the modest effectiveness of current vaccines, so that considerable numbers of vaccine failures occu... |
10.1371/journal.pcbi.1003987 | How Anacetrapib Inhibits the Activity of the Cholesteryl Ester Transfer Protein? Perspective through Atomistic Simulations | Cholesteryl ester transfer protein (CETP) mediates the reciprocal transfer of neutral lipids (cholesteryl esters, triglycerides) and phospholipids between different lipoprotein fractions in human blood plasma. A novel molecular agent known as anacetrapib has been shown to inhibit CETP activity and thereby raise high de... | Cardiovascular disease is a leading cause of morbidity and mortality in Western societies. One of the most encouraging treatment methods to prevent the generation and progression of cardiovascular disease is the elevation of high density lipoprotein (HDL) levels in circulation, as high HDL levels have been found to cor... | Cholesteryl ester transfer protein (CETP) is a 476-residue-long hydrophobic glycoprotein that transports cholesteryl esters (CEs), triglycerides, and phospholipids between high density lipoprotein (HDL) and other lipoprotein fractions in human blood plasma [1]. To be more specific, CETP exchanges CEs of HDL particles t... |
10.1371/journal.pntd.0004671 | Genetic Variation in Autophagy-Related Genes Influences the Risk and Phenotype of Buruli Ulcer | Buruli ulcer (BU) is a severe necrotizing human skin disease caused by Mycobacterium ulcerans. Clinically, presentation is a sum of these diverse pathogenic hits subjected to critical immune-regulatory mechanisms. Among them, autophagy has been demonstrated as a cellular process of critical importance. Since microtubul... | Buruli ulcer (BU) is a neglected tropical disease caused by Mycobacterium ulcerans. Because the exact trigger is still under investigation, current treatment options rely mostly on the surgical excision of the affected site. There is therefore a pressing demand for improved risk prediction and tailored treatment as wel... | Buruli ulcer (BU) is a severe necrotizing human skin disease caused by Mycobacterium ulcerans, representing the third most common mycobacteriosis worldwide [1]. At least 33 countries from Africa, South America and Western Pacific, with tropical, subtropical and temperate climates, have reported BU [1]. Moreover, in 201... |
10.1371/journal.pntd.0006555 | Genetic diversity in two Plasmodium vivax protein ligands for reticulocyte invasion | The interaction between Plasmodium vivax Duffy binding protein (PvDBP) and Duffy antigen receptor for chemokines (DARC) has been described as critical for the invasion of human reticulocytes, although increasing reports of P. vivax infections in Duffy-negative individuals questions its unique role. To investigate the g... | Until recently, P. vivax was thought to infect only Duffy positive individuals, due to its dependence on binding the Duffy blood group antigen as a receptor for reticulocyte invasion and to be absent from parts of Africa where the Duffy-negative phenotype is highly frequent. However, a number of recent studies from acr... | Plasmodium vivax is a predominant cause of malaria outside Africa, which causes significant morbidity (estimate of 8.5 million cases in 2016) and places an enormous economic burden on many resource poor countries [1]. Until recently, vivax malaria was considered a benign infection compared to P. falciparum, although cl... |
10.1371/journal.ppat.1004702 | γδ T Cells Confer Protection against Murine Cytomegalovirus (MCMV) | Cytomegalovirus (CMV) is a leading infectious cause of morbidity in immune-compromised patients. γδ T cells have been involved in the response to CMV but their role in protection has not been firmly established and their dependency on other lymphocytes has not been addressed. Using C57BL/6 αβ and/or γδ T cell-deficient... | γδ T cells are unconventional T lymphocytes that play a unique role in host protection against pathogens. Human Cytomegalovirus (HCMV) is a widespread virus that can cause severe organ disease such as hepatitis and pneumonitis in immune-compromised patients. Our decade-long study conveys compelling evidence for the imp... | Human CMV (HCMV) is a universally distributed pathogen that infects 50–90% of the world's population. Asymptomatic in healthy people, HCMV infection may lead to increased morbidity and mortality in immunocompromised individuals. Overall survival following transplantation is decreased when either the donor or the recipi... |
10.1371/journal.ppat.1001021 | Plasmodium falciparum Adhesion on Human Brain Microvascular Endothelial Cells Involves Transmigration-Like Cup Formation and Induces Opening of Intercellular Junctions | Cerebral malaria, a major cause of death during malaria infection, is characterised by the sequestration of infected red blood cells (IRBC) in brain microvessels. Most of the molecules implicated in the adhesion of IRBC on endothelial cells (EC) are already described; however, the structure of the IRBC/EC junction and ... | Cerebral malaria, a major cause of death during malaria infection, is characterised by the sequestration of infected red blood cells (IRBC) in brain microvessels. This study describes the interactions between plasmodium infected red blood cell and human brain endothelial cells. It highlights the activation of a trogocy... | Each year 3.2 billion people worldwide are exposed to the threat of malaria, resulting in around 2 million deaths [1]. Even with the best antiparasitic treatments, patients with cerebral malaria (CM) have no significant improvement in their prognosis, with an average fatality rate of 30 to 50% [1]. This outcome is due ... |
10.1371/journal.pcbi.1000449 | Small RNAs Originated from Pseudogenes: cis- or trans-Acting? | Pseudogenes are significant components of eukaryotic genomes, and some have acquired novel regulatory roles. To date, no study has characterized rice pseudogenes systematically or addressed their impact on the structure and function of the rice genome. In this genome-wide study, we have identified 11,956 non-transposon... | Pseudogenes are “defunct” copies of protein-coding genes that have been accumulated in a genome. They have conventionally been considered the junk byproducts of genome evolution, as they cannot code for proteins due to sequence degeneration. Recent important studies, however, have discovered that a subset of them have ... | Pseudogenes are genomic sequences derived from functional genes, but are often considered non-functional due to the accumulation of various deleterious mutations over their evolutionary history [1]–[6]. Compared with its parental gene (more precisely, the direct descendent of the ancestral gene that gave rise to the ps... |
10.1371/journal.pgen.1005578 | The GTP- and Phospholipid-Binding Protein TTD14 Regulates Trafficking of the TRPL Ion Channel in Drosophila Photoreceptor Cells | Recycling of signaling proteins is a common phenomenon in diverse signaling pathways. In photoreceptors of Drosophila, light absorption by rhodopsin triggers a phospholipase Cβ-mediated opening of the ion channels transient receptor potential (TRP) and TRP-like (TRPL) and generates the visual response. The signaling pr... | Protein trafficking in neurons occurs throughout the lifetime of a cell and includes the internalization and redistribution of plasma membrane proteins. Regulated protein trafficking controls the equipment of the plasma membrane with receptors and ion channels and thereby attenuates or enhances neuronal function. Defec... | Photoreceptor membrane proteins undergo a carefully regulated turnover that helps to adjust the sensitivity of the receptors and to renew old and possibly worn out proteins. Throughout the lifetime of a photoreceptor cell, new proteins are synthesized and transported to the photoreceptive membrane while other proteins ... |
10.1371/journal.pbio.1000307 | mRNA Secondary Structures Fold Sequentially But Exchange Rapidly In Vivo | RNAs adopt defined structures to perform biological activities, and conformational transitions among alternative structures are critical to virtually all RNA-mediated processes ranging from metabolite-activation of bacterial riboswitches to pre-mRNA splicing and viral replication in eukaryotes. Mechanistic analysis of ... | Properly folded RNAs are critical for virtually all RNA-mediated processes ranging from feedback regulation of gene expression to RNA maturation. The ability of RNAs to adopt specific structures in living cells is remarkable given their propensity to become trapped in a mixture of stable, misfolded structures in vitro.... | RNAs adopt specific secondary structures to carry out their biological functions, and exchange among alternative secondary structures plays essential roles in virtually all RNA-mediated processes ranging from RNA silencing and metabolite-activation of bacterial riboswitches to pre-mRNA splicing and viral RNA replicatio... |
10.1371/journal.pntd.0000901 | Targeting the Midgut Secreted PpChit1 Reduces Leishmania major Development in Its Natural Vector, the Sand Fly Phlebotomus papatasi | During its developmental cycle within the sand fly vector, Leishmania must survive an early proteolytic attack, escape the peritrophic matrix, and then adhere to the midgut epithelia in order to prevent excretion with remnants of the blood meal. These three steps are critical for the establishment of an infection withi... | For a successful development within the midgut of the sand fly vector, Leishmania must overcome several barriers which are imposed by the vector. The ability to overcome these barriers has been associated with species specificity, and interference with the sand fly vector-parasite balance can change the outcome of the ... | Emerging and reemerging vector-borne diseases pose significant threats to human and animal health [1]. The emergence of insecticide resistance as well as the lack of other efficient insecticidal tools to control disease vectors imply that new methodologies need to be developed in order to reduce vector-borne disease tr... |
10.1371/journal.ppat.1004170 | A Multifactorial Role for P. falciparum Malaria in Endemic Burkitt's Lymphoma Pathogenesis | Endemic Burkitt's lymphoma (eBL) arises from the germinal center (GC). It is a common tumor of young children in tropical Africa and its occurrence is closely linked geographically with the incidence of P. falciparum malaria. This association was noted more than 50 years ago. Since then we have learned that eBL contain... | Endemic Burkitt's lymphoma (eBL) is a common tumor of young children in tropical Africa that is closely linked geographically with P. falciparum malaria. This association was noted more than 50 years ago. Since then we have learned that eBL contains the oncogenic herpes virus Epstein-Barr virus and a defining transloca... | Endemic Burkitt's lymphoma (eBL) is an extremely common tumor of young children in tropical Africa [1]. Genetic, phenotypic and transcriptional analysis suggests that it originates from germinal center (GC) cells [2], [3] although it actually grows in extrafollicular locations. It is defined by a well described chromos... |
10.1371/journal.ppat.1003043 | A Trade-off between the Fitness Cost of Functional Integrases and Long-term Stability of Integrons | Horizontal gene transfer (HGT) plays a major role in bacterial microevolution as evident from the rapid emergence and spread of antimicrobial drug resistance. Few studies have however addressed the population dynamics of newly imported genetic elements after HGT. Here, we show that newly acquired class-1 integrons from... | Horizontal acquisition of mobile and mobilizable genetic elements plays a major role in the development of antimicrobial drug resistance in bacteria. Despite their causal role in drug treatment failure, there is only limited understanding of how horizontal acquisitions of these elements affect bacterial fitness. A prom... | Horizontal gene transfer (HGT) enables bacteria to obtain alien genes and genetic elements from prokaryotic, archaeal, and eukaryotic organisms. This capacity for genetic exchange plays an important role in bacterial adaptive evolution, as exemplified by the rapid spread of antibiotic resistance determinants by HGT [1]... |
10.1371/journal.pcbi.1004669 | Brain Connectivity Dissociates Responsiveness from Drug Exposure during Propofol-Induced Transitions of Consciousness | Accurately measuring the neural correlates of consciousness is a grand challenge for neuroscience. Despite theoretical advances, developing reliable brain measures to track the loss of reportable consciousness during sedation is hampered by significant individual variability in susceptibility to anaesthetics. We addres... | Though scientific understanding of how brain networks generate consciousness has seen rapid advances in recent years, application of this knowledge to accurately track transitions to unconsciousness during general anaesthesia has proven difficult due to considerable variability in this gradual process across individual... | Understanding how the human brain reversibly generates and loses consciousness, through complex interactions of neural activity at multiple spatial and temporal scales, is a grand challenge for modern neuroscience. Recent theoretical advances have argued that consciousness changes when the balance between integrated an... |
10.1371/journal.ppat.1005333 | Intravital Imaging of Vascular Transmigration by the Lyme Spirochete: Requirement for the Integrin Binding Residues of the B. burgdorferi P66 Protein | Vascular extravasation, a key step in systemic infection by hematogenous microbial pathogens, is poorly understood, but has been postulated to encompass features similar to vascular transmigration by leukocytes. The Lyme disease spirochete can cause a variety of clinical manifestations, including arthritis, upon hemato... | Lyme disease is the most common vector-transmitted infection in North America and Europe. Diverse clinical manifestations of Lyme disease result from the dissemination of the spirochetes causing the disease into a variety of tissue sites. Dissemination results from invasion of the vasculature by the bacteria, followed ... | Lyme disease is a spirochetal illness caused by various members of the genus Borrelia, and the most prevalent vector-borne illness in North America and Europe [1–5]. The disease is transmitted to humans during the feeding of infected hard-shelled ticks that have acquired the spirochetes during an earlier blood meal on ... |
10.1371/journal.ppat.1003942 | ‘Death and Axes’: Unexpected Ca2+ Entry Phenologs Predict New Anti-schistosomal Agents | Schistosomiasis is a parasitic flatworm disease that infects 200 million people worldwide. The drug praziquantel (PZQ) is the mainstay therapy but the target of this drug remains ambiguous. While PZQ paralyses and kills parasitic schistosomes, in free-living planarians PZQ caused an unusual axis duplication during rege... | Schistosomiasis (Bilharzia) is one of the most burdensome parasitic worm infections, encumbering third world economies with an annual loss of several million disability-adjusted life years. The key treatment for schistosome infections is the drug praziquantel but the mechanism of action of this drug remains controversi... | Over a third of the world's population is estimated to be infected with parasitic worms. One of the most burdensome infections underpins the neglected tropical disease schistosomiasis (Bilharzia), caused by parasitic flatworms of the genus Schistosoma. The debilitating impact of schistosomiasis results from the host's ... |
10.1371/journal.pcbi.1006969 | A global map of the protein shape universe | Proteins are involved in almost all functions in a living cell, and functions of proteins are realized by their tertiary structures. Obtaining a global perspective of the variety and distribution of protein structures lays a foundation for our understanding of the building principle of protein structures. In light of t... | Proteins are the major molecules involved in almost all cellular processes. In this work, we present a novel mapping of protein shapes that represents the variety and the similarities of 3D shapes of proteins and their assemblies. This mapping provides various novel insights into protein shapes including determinant fa... | Proteins are the primary workers in a living cell, involved in transportation, catalysis, signaling, energy production, and many other processes. Classification of protein structures provides fundamental information for our understanding of the principles that govern and determine protein structures, which is one of th... |
10.1371/journal.ppat.1002730 | Evolution of an Eurasian Avian-like Influenza Virus in Naïve and Vaccinated Pigs | Influenza viruses are characterized by an ability to cross species boundaries and evade host immunity, sometimes with devastating consequences. The 2009 pandemic of H1N1 influenza A virus highlights the importance of pigs in influenza emergence, particularly as intermediate hosts by which avian viruses adapt to mammals... | The latest human influenza pandemic highlights the ability of influenza viruses to jump species barriers and emerge in new hosts, as well as the role of pigs in generating viruses with pandemic potential. The mutational power of influenza virus, caused by intrinsically error-prone viral polymerases, has been directly l... | Influenza viruses are archetypical emerging viruses, as illustrated by the four human pandemics that have taken place since 1918. Although the natural reservoir of influenza viruses is wild waterfowl, the establishment of human lineages derived directly from birds is rare. The pig is therefore thought to play an import... |
10.1371/journal.ppat.1002567 | Comparative Genomics of the Apicomplexan Parasites Toxoplasma gondii and Neospora caninum: Coccidia Differing in Host Range and Transmission Strategy | Toxoplasma gondii is a zoonotic protozoan parasite which infects nearly one third of the human population and is found in an extraordinary range of vertebrate hosts. Its epidemiology depends heavily on horizontal transmission, especially between rodents and its definitive host, the cat. Neospora caninum is a recently d... | Coccidian parasites have a major impact on human and animal health world-wide and are among the most successful and widespread parasitic protozoa. They include Neospora caninum which is a leading cause of abortion in cattle and one of its nearest relatives, Toxoplasma gondii. Despite its close phylogenetic relationship... | Toxoplasma gondii and Neospora caninum are closely related tissue-dwelling Coccidia – intracellular protozoan parasites of the phylum Apicomplexa. T. gondii can infect essentially any warm-blooded vertebrate and is found in nearly one third of humans, arguably being the world's most successful zoonotic parasite [1]; it... |
10.1371/journal.pcbi.1000226 | Neutrality and Robustness in Evo-Devo: Emergence of Lateral Inhibition | Embryonic development is defined by the hierarchical dynamical process that translates genetic information (genotype) into a spatial gene expression pattern (phenotype) providing the positional information for the correct unfolding of the organism. The nature and evolutionary implications of genotype–phenotype mapping ... | The diversity of life is a consequence of changes in the genotype (genes and their interdependence), but it is upon the observable organism's morphology (phenotype) that natural selection acts. Thus, the study of genotype–phenotype mapping can reveal key mechanisms driving life's capacity of continuous evolution and re... | The evolution of life forms on our planet has led to the generation of an enormous variety of living structures. How such patterns of organization emerge [1]–[3], how contingency [4] and constraints [5],[6] shape them and how they acquire robustness [7] are unanswered questions that have been at the forefront of biolog... |
10.1371/journal.pmed.1002471 | Cell salvage and donor blood transfusion during cesarean section: A pragmatic, multicentre randomised controlled trial (SALVO) | Excessive haemorrhage at cesarean section requires donor (allogeneic) blood transfusion. Cell salvage may reduce this requirement.
We conducted a pragmatic randomised controlled trial (at 26 obstetric units; participants recruited from 4 June 2013 to 17 April 2016) of routine cell salvage use (intervention) versus curr... | Given that cesarean section rates are rising worldwide, the need for promoting alternatives to blood transfusion in cesareans, such as harnessing the patient’s own reserves where feasible, is well recognised.
While cell salvage in operations outside of obstetrics has been shown to reduce the need for donor blood transf... | Childbirth by cesarean section is on the rise worldwide [1]. Excessive blood loss (haemorrhage) is an important cause of maternal death [2], emergency hysterectomy [3], and maternal critical care admission [4] among women undergoing a cesarean birth [5]. The treatment of major haemorrhage, in addition to optimising red... |
10.1371/journal.pntd.0005187 | Engineered Aedes aegypti JAK/STAT Pathway-Mediated Immunity to Dengue Virus | We have developed genetically modified Ae. aegypti mosquitoes that activate the conserved antiviral JAK/STAT pathway in the fat body tissue, by overexpressing either the receptor Dome or the Janus kinase Hop by the blood feeding-induced vitellogenin (Vg) promoter. Transgene expression inhibits infection with several de... | Dengue has represented a significant public health burden for a number of decades, and given the lack of dengue-specific drugs and limited availability of licensed vaccine, new methods for prevention and control are urgently needed. Here, we investigated whether genetic manipulation of the mosquitoes’ native JAK/STAT p... | Despite decades of attempts at disease control, dengue remains a major mosquito-borne arboviral disease, causing an estimated 390 million infections annually [1]. Without drugs and with only limited availability of a licensed vaccine, vector control has remained the most important approach to reduce disease transmissio... |
10.1371/journal.ppat.1002442 | Nef Decreases HIV-1 Sensitivity to Neutralizing Antibodies that Target the Membrane-proximal External Region of TMgp41 | Primate lentivirus nef is required for sustained virus replication in vivo and accelerated progression to AIDS. While exploring the mechanism by which Nef increases the infectivity of cell-free virions, we investigated a functional link between Nef and Env. Since we failed to detect an effect of Nef on the quantity of ... | Nef is a pathogenic factor expressed by primate lentiviruses. HIV-1 virions produced by cells that express Nef acquire unknown modifications that allow them to infect new target cells with higher efficiency. We hypothesized that Nef might alter the structure or function of the HIV-1 Env glycoproteins. In this study we ... | Nef is a multifunctional pathogenicity factor expressed by primate lentiviruses. Disruption of nef is associated with defective virus replication in vivo and delayed pathology [1]–[3]. At the cellular level, Nef has well-documented activities that include the ability to downregulate cell-surface molecules CD4 [4]–[6] a... |
10.1371/journal.ppat.1006304 | Fatty acid DSF binds and allosterically activates histidine kinase RpfC of phytopathogenic bacterium Xanthomonas campestris pv. campestris to regulate quorum-sensing and virulence | As well as their importance to nutrition, fatty acids (FA) represent a unique group of quorum sensing chemicals that modulate the behavior of bacterial population in virulence. However, the way in which full-length, membrane-bound receptors biochemically detect FA remains unclear. Here, we provide genetic, enzymologica... | Besides roles in nutrition, lipids also function as important signals in the regulation of prokaryotic and eukaryotic cells. In bacteria, fatty acids are part of the language of cell-cell communication known as quorum sensing for a decade. However, how bacteria detect these signals and regulate virulence remains elusiv... | Quorum-sensing is a process that bacterial cells communicate with each other to elicit specific physiological responses, including virulence against hosts [1,2]. How single-celled bacteria detect and respond to population density is a fundamental question in studying quorum sensing. Previous studies have reported that ... |
10.1371/journal.pbio.1000294 | Rare Variants Create Synthetic Genome-Wide Associations | Genome-wide association studies (GWAS) have now identified at least 2,000 common variants that appear associated with common diseases or related traits (http://www.genome.gov/gwastudies), hundreds of which have been convincingly replicated. It is generally thought that the associated markers reflect the effect of a nea... | It has long been assumed that common genetic variants of modest effect make an important contribution to common human diseases, such as most forms of cardiovascular disease, asthma, and neuropsychiatric disease. Genome-wide scans evaluating the role of common variation have now been completed for all common disease usi... | Efforts to fine map the causal variants responsible for genome-wide association studies (GWAS) signals have been largely predicated on the common disease common variant theory, postulating a common variant as the culprit for observed associations. This has led to extensive resequencing efforts that have been largely un... |
10.1371/journal.ppat.1005990 | Mechanistic Studies and Modeling Reveal the Origin of Differential Inhibition of Gag Polymorphic Viruses by HIV-1 Maturation Inhibitors | HIV-1 maturation inhibitors (MIs) disrupt the final step in the HIV-1 protease-mediated cleavage of the Gag polyprotein between capsid p24 capsid (CA) and spacer peptide 1 (SP1), leading to the production of infectious virus. BMS-955176 is a second generation MI with improved antiviral activity toward polymorphic Gag v... | HIV-1 continues to be a serious health threat, with nearly 40 million infected individuals worldwide. Despite effective treatment options, issues with resistance and drug toxicities illustrate the need for new drugs with novel mechanisms. Maturation inhibitors (MIs) block a key protease cleavage within its target, prev... | Currently there are more than 1.2 million individuals (age 13 years older) in the United States (CDC data)[1] and more than 35 million worldwide infected with HIV, with 39 million people already having died from the disease and 2.3 million new cases reported in 2013.[2] There are presently >35 FDA-approved HIV therapie... |
10.1371/journal.pgen.1005618 | Allelic Variation of Cytochrome P450s Drives Resistance to Bednet Insecticides in a Major Malaria Vector | Scale up of Long Lasting Insecticide Nets (LLINs) has massively contributed to reduce malaria mortality across Africa. However, resistance to pyrethroid insecticides in malaria vectors threatens its continued effectiveness. Deciphering the detailed molecular basis of such resistance and designing diagnostic tools is cr... | Scale up of Long Lasting Insecticide Nets has massively reduced malaria mortality across Africa. However, resistance to pyrethroid insecticides in malaria vectors threatens its continued effectiveness. Here, we established that allelic variation in two CYP450s is the most important driver of pyrethroid resistance in th... | Despite the recent decrease in malaria mortality (47%) [1], the disease remains a serious public health burden in the tropical world, with 584,000 deaths globally in 2013, of which 90% occurred in WHO African region, and mostly in children under the age of 5. Malaria control relies heavily on the use of insecticide-imp... |
10.1371/journal.pgen.1000477 | Designing Genome-Wide Association Studies: Sample Size, Power, Imputation, and the Choice of Genotyping Chip | Genome-wide association studies are revolutionizing the search for the genes underlying human complex diseases. The main decisions to be made at the design stage of these studies are the choice of the commercial genotyping chip to be used and the numbers of case and control samples to be genotyped. The most common meth... | Genome-wide association studies are a powerful and now widely-used method for finding genetic variants that increase the risk of developing particular diseases. These studies are complex and must be planned carefully in order to maximize the probability of finding novel associations. The main design choices to be made ... | The International HapMap project [1],[2] documented the strong correlations between alleles at polymorphic loci in close physical proximity along human chromosomes. As a consequence it is necessary to genotype only a subset of loci to capture much of the common variation in the genome. Combined with recent technologica... |
10.1371/journal.pgen.1005985 | Intermittent Stem Cell Cycling Balances Self-Renewal and Senescence of the C. elegans Germ Line | Self-renewing organs often experience a decline in function in the course of aging. It is unclear whether chronological age or external factors control this decline, or whether it is driven by stem cell self-renewal—for example, because cycling cells exhaust their replicative capacity and become senescent. Here we assa... | Stem cell cycling is expected to be beneficial because it helps delay aging, by ensuring organ self-renewal. Yet stem cell cycling is best used sparingly: cycling likely causes mutation accumulation—increasing the likelihood of cancer—and may eventually cause stem cells to senesce and thus stop contributing to organ se... | An important goal of aging research is not just to extend lifespan—which in C. elegans can be simply achieved by a pause in developmental and reproductive activities in the “dauer” state [1]—but to do so in a way that increases “healthspan” without diminishing organ activity. To this end, it is critical to understand w... |
10.1371/journal.pcbi.1003421 | A Multi-Scale Model of Hepcidin Promoter Regulation Reveals Factors Controlling Systemic Iron Homeostasis | Systemic iron homeostasis involves a negative feedback circuit in which the expression level of the peptide hormone hepcidin depends on and controls the iron blood levels. Hepcidin expression is regulated by the BMP6/SMAD and IL6/STAT signaling cascades. Deregulation of either pathway causes iron-related diseases such ... | The nutritional iron uptake is tightly regulated because the body has limited capacity of iron excretion. Mammals maintain iron homeostasis by a negative feedback loop, in which the peptide hepcidin senses the iron blood level and controls iron resorption. Molecular perturbations in the homeostasis loop lead to iron-re... | Hepcidin is a humoral polypeptide that plays a central role in systemic iron homeostasis (reviewed in [1]). One main function of hepcidin is to maintain constant levels of iron circulating in the blood despite imbalances in external iron availability: Iron overload in the blood stimulates hepcidin transcription in hepa... |
10.1371/journal.pntd.0006630 | Field evaluation of a 0.005% fipronil bait, orally administered to Rhombomys opimus, for control of fleas (Siphonaptera: Pulicidae) and phlebotomine sand flies (Diptera: Psychodidae) in the Central Asian Republic of Kazakhstan | Plague (Yersinia pestis) and zoonotic cutaneous leishmaniasis (Leishmania major) are two rodent-associated diseases which are vectored by fleas and phlebotomine sand flies, respectively. In Central Asia, the great gerbil (Rhombomys opimus) serves as the primary reservoir for both diseases in most natural foci. The syst... | Plague and cutaneous leishmaniasis are two diseases transmissible to humans vectored by fleas and sand flies, respectively. Although the diseases are vectored by two different insect types, the primary reservoir host for both diseases in desert foci in Central Asia is the great gerbil. Therefore, a promising strategy f... | Vector-borne diseases transmissible to humans were responsible for more human disease and death than all other causes combined between the 17th and 20th centuries [1] and since the 1970s a global reemergence of several vector borne diseases has occurred [2]. Vector-borne diseases occur most frequently in areas of extre... |
10.1371/journal.pntd.0004073 | Syndromic Approach to Arboviral Diagnostics for Global Travelers as a Basis for Infectious Disease Surveillance | Arboviruses have overlapping geographical distributions and can cause symptoms that coincide with more common infections. Therefore, arbovirus infections are often neglected by travel diagnostics. Here, we assessed the potential of syndrome-based approaches for diagnosis and surveillance of neglected arboviral diseases... | Physicians attending travelers with particular symptoms often neglect those infections that are transmitted by arthropods like ticks and mosquitoes (arboviruses) or don’t test for the appropriate arboviruses. This is because arboviruses cause symptoms that are similar to more common infections and because there is a ge... | Globalization has resulted in a steep increase in travel and trade.[1, 2] In recent decades it has contributed to the spread of diseases that traditionally emerged only regionally but now threaten populations across the globe, stressing the need for global health surveillance.[1, 2] Among these emerging threats, arbovi... |
10.1371/journal.pntd.0000444 | Community Management of Endemic Scabies in Remote Aboriginal Communities of Northern Australia: Low Treatment Uptake and High Ongoing Acquisition | Scabies and skin infections are endemic in many Australian Aboriginal communities. There is limited evidence for effective models of scabies treatment in high prevalence settings. We aimed to assess the level of treatment uptake amongst clinically diagnosed scabies cases and amongst their household contacts. In additio... | Like many impoverished areas around the world, Aboriginal communities in Australia experience an unacceptably high burden of scabies, skin infections, and secondary complications. Young children are most at risk. Our study investigated scabies in a remote setting with very high rates of skin disease, a high level of ho... | Skin infections are a significant cause of morbidity in disadvantaged settings around the world [1],[2]. Scabies and pyoderma are endemic in many Aboriginal communities in northern Australia. These conditions cause local morbidity and contribute substantially to clinic workload and costs [3]. Moreover, the primary bact... |
10.1371/journal.pcbi.1001059 | A Computational and Experimental Study of the Regulatory Mechanisms of the Complement System | The complement system is key to innate immunity and its activation is necessary for the clearance of bacteria and apoptotic cells. However, insufficient or excessive complement activation will lead to immune-related diseases. It is so far unknown how the complement activity is up- or down- regulated and what the associ... | The complement system, which is the frontline immune defense, constitutes proteins that flow freely in the blood. It quickly detects invading microbes and alerts the host by sending signals into immune responsive cells to eliminate the hostile substances. Inadequate or excessive complement activities harm the host and ... | The complement system is pivotal to defending against invading microorganisms. The complement proteins recognize conserved pathogen-associated molecular patterns (PAMPs) on the surface of the invading pathogens [1] to initiate the innate immunity response. The complement activity also enhances adaptive immunity [2], [3... |
10.1371/journal.pcbi.1003258 | Predictive Coding of Dynamical Variables in Balanced Spiking Networks | Two observations about the cortex have puzzled neuroscientists for a long time. First, neural responses are highly variable. Second, the level of excitation and inhibition received by each neuron is tightly balanced at all times. Here, we demonstrate that both properties are necessary consequences of neural networks th... | Two observations about the cortex have puzzled and fascinated neuroscientists for a long time. First, neural responses are highly variable. Second, the level of excitation and inhibition received by each neuron is tightly balanced at all times. Here, we demonstrate that both properties are necessary consequences of neu... | Neural systems need to integrate, store, and manipulate sensory information before acting upon it. Various neurophysiological and psychophysical experiments have provided examples of how these feats are accomplished in the brain, from the integration of sensory stimuli to decision-making [1], from the short-term storag... |
10.1371/journal.ppat.1002734 | Structure and Functional Analysis of the RNA- and Viral Phosphoprotein-Binding Domain of Respiratory Syncytial Virus M2-1 Protein | Respiratory syncytial virus (RSV) protein M2-1 functions as an essential transcriptional cofactor of the viral RNA-dependent RNA polymerase (RdRp) complex by increasing polymerase processivity. M2-1 is a modular RNA binding protein that also interacts with the viral phosphoprotein P, another component of the RdRp compl... | Premature termination of transcription by the RNA-dependent RNA polymerase (RdRp) complex of respiratory syncytial virus (RSV) is prevented by the M2-1 protein. This transcription factor interacts with both RNA and viral phosphoprotein P, the main RdRp cofactor, through a specific “core” domain. Using NMR, we solved th... | Human respiratory syncytial virus (RSV), a pneumovirus of the Paramyxoviridae family in the Mononegavirales order, is an important respiratory pathogen and the major cause of bronchiolitis and pneumonia in children [1]. Bovine RSV on the other hand represents an important economic issue due to the high morbidity and mo... |
10.1371/journal.pntd.0002447 | A Review of Factors That Influence Individual Compliance with Mass Drug Administration for Elimination of Lymphatic Filariasis | The success of programs to eliminate lymphatic filariasis (LF) depends in large part on their ability to achieve and sustain high levels of compliance with mass drug administration (MDA). This paper reports results from a comprehensive review of factors that affect compliance with MDA.
Papers published between 2000 and... | Lymphatic filariasis (LF, also known as “elephantiasis”) is a deforming and disabling disease that is caused by roundworm parasites that are transmitted by mosquitoes. The Global Programme to Eliminate Lymphatic Filariasis is the largest public health intervention program attempted to date based on mass drug administra... | The Global Programme to Eliminate Lymphatic Filariasis (GPELF) is one of the most ambitious, exciting, and challenging public health programs of our time. Part of the challenge is in the large numbers of people that either have lymphatic filariasis (LF) (an estimated 120 million) or who are at risk for the disease (1.3... |
10.1371/journal.pntd.0006891 | The ectodomains of the lymphocyte scavenger receptors CD5 and CD6 interact with tegumental antigens from Echinococcus granulosus sensu lato and protect mice against secondary cystic echinococcosis | Scavenger Receptors (SRs) from the host’s innate immune system are known to bind multiple ligands to promote the removal of non-self or altered-self targets. CD5 and CD6 are two highly homologous class I SRs mainly expressed on all T cells and the B1a cell subset, and involved in the fine tuning of activation and diffe... | Scavenger Receptors (SRs) are constituents of host’s innate immune system able to sense and remove altered-self and/or pathogen components. Data on their interaction with helminth parasites is scarce. In this work, we describe that CD5 and CD6 -two lymphoid SRs previously reported to interact with conserved structures ... | The mammalian innate immune system relies on a limited number of germline-encoded and non-clonally distributed receptors for pathogen recognition, which have evolved to identify the so called pathogen associated molecular patterns (PAMPs): conserved microbial structures, essential for their survival and not shared by t... |
10.1371/journal.pntd.0000154 | Household Transmission of Leptospira Infection in Urban Slum Communities | Leptospirosis, a spirochaetal zoonotic disease, is the cause of epidemics associated with high mortality in urban slum communities. Infection with pathogenic Leptospira occurs during environmental exposures and is traditionally associated with occupational risk activities. However, slum inhabitants reside in close prox... | Leptospirosis has emerged to become an urban slum health problem. Epidemics of severe leptospirosis, characterized by jaundice, acute renal failure and haemorrhage, are now reported in cities throughout the developing world due to rapid expansion of slum settlements, which in turn has produced the ecological conditions... | Leptospirosis is an important zoonotic health problem because of its life-threatening clinical manifestations, Weil's disease and severe pulmonary haemorrhage syndrome, for which fatality is 10 to 50% [1]. Moreover there has been growing awareness of the large under-recognized disease burden that leptospirosis imparts ... |
10.1371/journal.ppat.1003441 | Multifunctional Double-negative T Cells in Sooty Mangabeys Mediate T-helper Functions Irrespective of SIV Infection | Studying SIV infection of natural host monkey species, such as sooty mangabeys, has provided insights into the immune changes associated with these nonprogressive infections. Mangabeys maintain immune health despite high viremia or the dramatic CD4 T cell depletion that can occur following multitropic SIV infection. He... | SIV infection of sooty mangabeys is generally characterized by maintained CD4 T cell levels and a lack of disease progression despite active virus replication. We have previously shown however, that dramatic loss of CD4 T cells can occur during SIV infection of mangabeys. This study investigates the potential for doubl... | While simian immunodeficiency virus (SIV) infection of Asian macaques generally results in progression to simian AIDS, SIV infection of African monkey species is typically associated with a nonpathogenic outcome. These African monkeys, including sooty mangabeys, are found naturally infected with SIV and are thought to ... |
10.1371/journal.pcbi.1003792 | VASP-E: Specificity Annotation with a Volumetric Analysis of Electrostatic Isopotentials | Algorithms for comparing protein structure are frequently used for function annotation. By searching for subtle similarities among very different proteins, these algorithms can identify remote homologs with similar biological functions. In contrast, few comparison algorithms focus on specificity annotation, where the i... | Proteins, the ubiquitous worker molecules of the cell, are a diverse class of molecules that perform very specific tasks. Understanding how proteins achieve specificity is a critical step towards understanding biological systems and a key prerequisite for rationally engineering new proteins. To examine electrostatic in... | Software for comparing protein structures is widely used to make inferences about protein function. These methods assist in function annotation by revealing proteins that perform similar biological functions despite vast evolutionary differences. Many methods focus on the discovery of subtle structural similarities amo... |
10.1371/journal.pbio.1001923 | Inhibitor of the Tyrosine Phosphatase STEP Reverses Cognitive Deficits in a Mouse Model of Alzheimer's Disease | STEP (STriatal-Enriched protein tyrosine Phosphatase) is a neuron-specific phosphatase that regulates N-methyl-D-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking, as well as ERK1/2, p38, Fyn, and Pyk2 activity. STEP is overactive in several neuropsychiatri... | A series of recent studies have found that the levels of the enzyme striatal-enriched protein tyrosine phosphatase (STEP) are raised in several different neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease, fragile X syndrome, and schizophrenia. STEP normally opposes the development of synap... | STriatal-Enriched protein tyrosine Phosphatase (STEP) (PTPN5) is a brain-enriched protein tyrosine phosphatase (PTP) targeted in part to postsynaptic terminals of excitatory glutamatergic synapses [1]–[4]. Recent studies indicate that STEP is overactive in Alzheimer's disease (AD), schizophrenia, and fragile X syndrome... |
10.1371/journal.ppat.1002579 | HMOX1 Gene Promoter Alleles and High HO-1 Levels Are Associated with Severe Malaria in Gambian Children | Heme oxygenase 1 (HO-1) is an essential enzyme induced by heme and multiple stimuli associated with critical illness. In humans, polymorphisms in the HMOX1 gene promoter may influence the magnitude of HO-1 expression. In many diseases including murine malaria, HO-1 induction produces protective anti-inflammatory effect... | HO-1 is an important anti-inflammatory enzyme induced by several stimuli associated with critical illness. In humans, the amount of HO-1 produced is influenced by a genetic polymorphism in the gene promoter region. Using Plasmodium falciparum malaria that can cause a sepsis-like syndrome as an example, we characterize ... | Heme oxygenase (HO) is the rate limiting enzyme that catabolizes free heme into carbon monoxide (CO), ferrous iron, and biliverdin/bilirubin [1]. To date, two functional isoforms (HO-1, HO-2) have been described. While HO-2 is constitutively produced by most cells, HO-1 protein is induced by its substrate heme and a br... |
10.1371/journal.pgen.1000069 | An Inducible and Reversible Mouse Genetic Rescue System | Inducible and reversible regulation of gene expression is a powerful approach for uncovering gene function. We have established a general method to efficiently produce reversible and inducible gene knockout and rescue in mice. In this system, which we named iKO, the target gene can be turned on and off at will by treat... | We describe a technology for the creation of inducible and reversible gene inactivation in mice. It combines two genetically modified mouse lines: a knock-out line with a tetracycline transactivator replacing the endogenous target gene, and a line in which a tetracycline-inducible cDNA of the target gene has been inser... | In the post-genome era, a major challenge is deciphering the function of thousands of newly identified genes. One of the main approaches for studying gene function involves inactivation of genes in cells or animals using random (chemical or insertional) mutagenesis or gene targeting. A common problem with these methods... |
10.1371/journal.pcbi.1005924 | Mathematical modeling identifies optimum lapatinib dosing schedules for the treatment of glioblastoma patients | Human primary glioblastomas (GBM) often harbor mutations within the epidermal growth factor receptor (EGFR). Treatment of EGFR-mutant GBM cell lines with the EGFR/HER2 tyrosine kinase inhibitor lapatinib can effectively induce cell death in these models. However, EGFR inhibitors have shown little efficacy in the clinic... | In vivo inhibition of tumor expansion requires a sufficient amount of therapeutic agent to be present in the tumor tissue. A number of factors affect drug concentrations including the maximum tolerated dose, pharmacokinetics and pharmacodynamics profiles. We present a computational modeling platform incorporating both ... | Glioblastoma is the most common and aggressive form of brain tumors in adults, characterized by short survival and poor treatment response [1]. Currently, the standard of care for glioblastoma patients includes surgery followed by radiotherapy and adjuvant chemotherapy with temozolomide [2]. However, the addition of ch... |
10.1371/journal.ppat.1005753 | Rabies Internalizes into Primary Peripheral Neurons via Clathrin Coated Pits and Requires Fusion at the Cell Body | The single glycoprotein (G) of rabies virus (RABV) dictates all viral entry steps from receptor engagement to membrane fusion. To study the uptake of RABV into primary neuronal cells in culture, we generated a recombinant vesicular stomatitis virus in which the G protein was replaced with that of the neurotropic RABV C... | Rabies virus is the causative agent of a generally fatal and incurable disease of the central nervous system (CNS). Rabies lethality requires that the virus invade the brain, a feat accomplished by neuronal transmission from the site of infection to the CNS. Using cultures of peripheral neurons and chemicals that pertu... | Rabies virus (RABV), a member of the Rhabdoviridae family, is a neurotropic pathogen that causes fatal encephalitis in animals and humans. The neurotropism of RABV is conferred by its single attachment and fusion glycoprotein (G) [1]. Virulence of specific RABV strains correlates with the neuroinvasiveness of their G p... |
10.1371/journal.pgen.1003711 | Neuronal Reprograming of Protein Homeostasis by Calcium-Dependent Regulation of the Heat Shock Response | Protein quality control requires constant surveillance to prevent misfolding, aggregation, and loss of cellular function. There is increasing evidence in metazoans that communication between cells has an important role to ensure organismal health and to prevent stressed cells and tissues from compromising lifespan. Her... | The protein quality control machinery is responsible for preventing the accumulation of misfolded and damaged proteins and loss of cellular function. The capacity of cellular surveillance is limited however, leading to increased appearance of protein aggregates and risk for age-associated diseases. Here, we show that u... | Cellular health and organismal lifespan are critically dependent upon the fidelity of the proteome and the proteostasis network [1]. What are the molecular events that control proteostasis across tissues to activate protective responses at the cellular level to ensure organismal health? At the cellular level the heat s... |
10.1371/journal.pcbi.1000878 | Lysine120 Interactions with p53 Response Elements can Allosterically Direct p53 Organization | p53 can serve as a paradigm in studies aiming to figure out how allosteric perturbations in transcription factors (TFs) triggered by small changes in DNA response element (RE) sequences, can spell selectivity in co-factor recruitment. p53-REs are 20-base pair (bp) DNA segments specifying diverse functions. They may be ... | p53-response elements (p53-REs) are 20 base pairs (bps) DNA segments recognized by the p53 transcription factor (TF). They are found in promoters and enhancers across the genome and are associated with genes that have diverse functions. Because the DNA sequences of p53-REs can be very similar to each other, differing b... | p53-response elements (p53-REs) are two 10-bp palindromic DNA segments with the consensus sequence of 5′-Pu1Pu2Pu3C4(A/T)5(A/T)5′G4′Py3′Py2′Py1′-3′ for each of the two half sites, where Pu and Py stand for purine and pyrimidine bases, respectively [1], [2]. The two half sites can be separated by as many as 20 bps [1]–[... |
10.1371/journal.pcbi.1006557 | Representations of regular and irregular shapes by deep Convolutional Neural Networks, monkey inferotemporal neurons and human judgments | Recent studies suggest that deep Convolutional Neural Network (CNN) models show higher representational similarity, compared to any other existing object recognition models, with macaque inferior temporal (IT) cortical responses, human ventral stream fMRI activations and human object recognition. These studies employed... | The primate inferior temporal (IT) cortex is considered to be the final stage of visual processing that allows for object recognition, identification and categorization of objects. Electrophysiology studies suggest that an object’s shape is a strong determinant of the neuronal response patterns in IT. Here we examine w... | Recently, several studies compared the representations of visual images in deep Convolutional Neural Networks (CNN) with those of biological systems, such as the primate ventral visual stream [1–4]. These studies showed that the representation of visual objects in macaque inferior temporal (IT) cortex corresponds bette... |
10.1371/journal.pntd.0004688 | Tegument Glycoproteins and Cathepsins of Newly Excysted Juvenile Fasciola hepatica Carry Mannosidic and Paucimannosidic N-glycans | Recently, the prevalence of Fasciola hepatica in some areas has increased considerably and the availability of a vaccine to protect livestock from infection would represent a major advance in tools available for controlling this disease. To date, most vaccine-target discovery research on this parasite has concentrated ... | Fasciola hepatica is a parasite responsible for the zoonotic disease fasciolosis, prevalence of which has increased in recent years because of the emergence of triclabendazole-resistant strains as well as changing climatic conditions. A number of F. hepatica protein antigens are used for assessing the immune response o... | The trematode Fasciola hepatica, commonly known as the liver fluke, is widely distributed across five continents and is responsible for fasciolosis in livestock and humans. It has a large economic impact on the livestock industry, causing production losses in terms of reduced milk yield, liver condemnation and problems... |
10.1371/journal.ppat.1002397 | The Splicing Factor Proline-Glutamine Rich (SFPQ/PSF) Is Involved in Influenza Virus Transcription | The influenza A virus RNA polymerase is a heterotrimeric complex responsible for viral genome transcription and replication in the nucleus of infected cells. We recently carried out a proteomic analysis of purified polymerase expressed in human cells and identified a number of polymerase-associated cellular proteins. H... | The influenza A viruses cause annual epidemics and occasional pandemics of respiratory infections that may be life threatening. The viral genome contains 8 RNA molecules forming ribonucleoproteins that replicate and transcribe in the nucleus of infected cells. Influenza viruses are intracellular parasites that need the... | The influenza A viruses belong to the family Orthomyxoviridae and contain a segmented, single-stranded RNA genome of negative polarity (for a review see [1]. Each of the genomic RNA segments is encapsidated in a ribonucleoprotein particle (RNP) containing the polymerase complex and a number of nucleoprotein (NP) monome... |
10.1371/journal.pcbi.1002282 | Collective Animal Behavior from Bayesian Estimation and Probability Matching | Animals living in groups make movement decisions that depend, among other factors, on social interactions with other group members. Our present understanding of social rules in animal collectives is mainly based on empirical fits to observations, with less emphasis in obtaining first-principles approaches that allow th... | Animals need to act on uncertain data and with limited cognitive abilities to survive. It is well known that our sensory and sensorimotor processing uses probabilistic estimation as a means to counteract these limitations. Indeed, the way animals learn, forage or select mates is well explained by probabilistic estimati... | Animals need to make decisions without certainty in which option is best. This uncertainty is due to the ambiguity of sensory data but also to limited processing capabilities, and is an intrinsic and general property of the representation that animals can build about the world. A general way to make decisions in uncert... |
10.1371/journal.pgen.1005731 | dbl-1/TGF-β and daf-12/NHR Signaling Mediate Cell-Nonautonomous Effects of daf-16/FOXO on Starvation-Induced Developmental Arrest | Nutrient availability has profound influence on development. In the nematode C. elegans, nutrient availability governs post-embryonic development. L1-stage larvae remain in a state of developmental arrest after hatching until they feed. This “L1 arrest” (or "L1 diapause") is associated with increased stress resistance,... | Animals must cope with feast and famine in the wild. Environmental fluctuations require a balancing act between development in favorable conditions and survival during starvation. Disruption of the pathways that govern this balance can lead to cancer, where cells proliferate when they should not, and metabolic diseases... | C. elegans L1-stage larvae must feed upon hatching in order to exit developmental arrest. Larvae in L1 arrest have increased stress resistance and can survive for weeks, initiating postembryonic development when food is available [1]. C. elegans larvae can also arrest development during the dauer stage, an alternative ... |
10.1371/journal.pgen.1006791 | USP9X counteracts differential ubiquitination of NPHP5 by MARCH7 and BBS11 to regulate ciliogenesis | Ciliogenesis is a fundamental biological process central to human health. Precisely how this process is coordinated with the cell cycle remains an open question. We report that nephrocystin-5 (NPHP5/IQCB1), a positive regulator of ciliogenesis, is a stable and low turnover protein subjected to cycles of ubiquitination ... | Centrosomes are non-membrane bound organelles that modulate a variety of cellular processes including cell division and formation of hair-like protrusions called primary cilia. Primary cilia function as cellular antennae to sense a wide variety of signals important for growth, development and differentiation. Defects i... | Primary cilia, microtubule-based protrusions found on the surface of most eukaryotic cells, are derived from centrosomes and possess sensory function such as chemosensation and mechanosensation[1,2]. Formation of primary cilia is tightly regulated during the cell cycle: they assemble primarily during the G0 phase and u... |
10.1371/journal.pcbi.1003101 | PUMA: A Unified Framework for Penalized Multiple Regression Analysis of GWAS Data | Penalized Multiple Regression (PMR) can be used to discover novel disease associations in GWAS datasets. In practice, proposed PMR methods have not been able to identify well-supported associations in GWAS that are undetectable by standard association tests and thus these methods are not widely applied. Here, we presen... | Genome-wide association studies (GWAS) have identified hundreds of regions of the human genome that are associated with susceptibility to common diseases. Yet many lines of evidence indicate that many susceptibility loci, which cannot be detected by standard statistical methods, remain to be discovered. We have develop... | Genome-wide association studies (GWAS) have identified many susceptibility loci underlying the molecular etiology of complex diseases [1]. These studies have been responsible for the discovery of many individual genes that contribute to disease risk [2]–[10], for discoveries on the front line of personalized medicine [... |
10.1371/journal.ppat.1005378 | Functional Interplay between Type I and II Interferons Is Essential to Limit Influenza A Virus-Induced Tissue Inflammation | Host control of influenza A virus (IAV) is associated with exuberant pulmonary inflammation characterized by the influx of myeloid cells and production of proinflammatory cytokines including interferons (IFNs). It is unclear, however, how the immune system clears the virus without causing lethal immunopathology. Here, ... | Influenza A virus (IAV) is a leading cause of respiratory infection and induces a strong acute inflammation manifested by the recruitment of monocytes and neutrophils as well as the production of proinflammatory cytokines in infected lungs. The interferons (IFNs) are strongly induced by IAV and are known to mediate hos... | Influenza A virus (IAV) is a leading cause of respiratory infection and an ongoing threat to global health. Host clearance of IAV, which infects primarily airway epithelial cells, requires the development of both innate and adaptive immune responses [1,2]. Interestingly, recent studies have suggested that the host immu... |
10.1371/journal.pcbi.1001019 | Modeling Mechanisms of In Vivo Variability in Methotrexate Accumulation and Folate Pathway Inhibition in Acute Lymphoblastic Leukemia Cells | Methotrexate (MTX) is widely used for the treatment of childhood acute lymphoblastic leukemia (ALL). The accumulation of MTX and its active metabolites, methotrexate polyglutamates (MTXPG), in ALL cells is an important determinant of its antileukemic effects. We studied 194 of 356 patients enrolled on St. Jude Total XV... | One of the primary agents used in the treatment of childhood acute lymphoblastic leukemia (ALL) is methotrexate (MTX). By better understanding its intracellular disposition, we are able to better design treatments that circumvent drug resistance and thus help improve ALL cure rates. In this study, we develop a system o... | Methotrexate (MTX) is one of the primary anticancer agents used for the treatment of acute lymphoblastic leukemia (ALL) [1]–[3]. The ability of cells to accumulate intracellular polyglutamate metabolites of MTX (MTXPG) is an important factor in its antileukemic effects [4]. Specifically, MTXPG inhibits the folate pathw... |
10.1371/journal.pntd.0000927 | Factors Associated with the Prevalence of Circulating Antigens to Porcine Cysticercosis in Three Villages of Burkina Faso | Little is known about porcine cysticercosis in Burkina Faso. We conducted a pilot study to estimate the prevalence of antigens of Taenia solium cysticercosis and to identify associated factors in pigs of three villages in Burkina Faso, selected to represent different pig management practices: one village where pigs are... | Taenia solium cysticercosis is a neglected tropical infection transmitted between humans and pigs. This infection is particularly common in areas where sanitation, hygiene and pig management practices are poor, and can sometimes lead to epilepsy in humans. There is very little information about the importance of this i... | Burkina Faso is one of the poorest countries in the world ranking 177th out of 182 according to the Human Development Index (HDI) [1]. Its economy relies predominantly on agriculture (40% of GDP), with cotton production being the most important, followed by livestock production, accounting for 12% of the GDP [2]. The m... |
10.1371/journal.pcbi.1000992 | Finding the Way with a Noisy Brain | Successful navigation is fundamental to the survival of nearly every animal on earth, and achieved by nervous systems of vastly different sizes and characteristics. Yet surprisingly little is known of the detailed neural circuitry from any species which can accurately represent space for navigation. Path integration is... | The ability to navigate allows animals to vastly increase the action space for finding resources, mates, and to avoid predators. The benefits are many and it is commonly believed that modern brain functions have emerged from ancestral forms evolved for effective navigation. Since the time of Charles Darwin, it has been... | In nature, successful navigation is vital for survival. It follows that neural circuitry capable of carrying out navigation must be ubiquitous in the animal kingdom. The study of animal navigation, therefore, is not only important in its own right, but may offer general insights into the architecture, computational alg... |
10.1371/journal.ppat.1004937 | TNF-α Induced by Hepatitis C Virus via TLR7 and TLR8 in Hepatocytes Supports Interferon Signaling via an Autocrine Mechanism | Invasion by infectious pathogens can elicit a range of cytokine responses from host cells. These cytokines provide the initial host defense mechanism. In this report, we demonstrate that TNF-α, a pro-inflammatory cytokine, can be induced by hepatitis C virus (HCV) in its host cells in a biphasic manner. The initial ind... | Hepatitis C virus (HCV) patients have increased levels of circulating tumor necrosis factor-α (TNF-α). In this report, we demonstrate that HCV can directly induce the expression of TNF-α in hepatocytes in a biphasic manner via NF-κB. The induction of TNF-α by HCV in the first phase is prompt, requires no HCV gene expre... | Hepatitis C virus (HCV) is an enveloped virus with a single-stranded RNA genome of 9.6-Kb [1]. After binding to its receptors on hepatocytes, HCV is internalized by receptor-mediated endocytosis, and its genomic RNA is subsequently released into the cytosol to direct the synthesis of viral proteins using the internal r... |
10.1371/journal.pntd.0000436 | Cholera Epidemics, War and Disasters around Goma and Lake Kivu: An Eight-Year Survey | During the last eight years, North and South Kivu, located in a lake area in Eastern Democratic Republic of Congo, have been the site of a major volcano eruption and of numerous complex emergencies with population displacements. These conditions have been suspected to favour emergence and spread of cholera epidemics.
I... | With the number of cholera cases up to 73,000 during the last eight years and successive wars that have persisted for fifteen years, the North and South Kivu provinces of the Democratic Republic of Congo are currently heavily hit by both cholera outbreaks and war-related population displacements. Prior to this study, n... | Numerous factors have been postulated to increase the risk of cholera outbreaks in a given area where cholera is already circulating among the population. The main environmental risk factors identified include heavy rainfall, blooms of plankton, and an increase in sea surface temperatures [1]. However, most studies hav... |
10.1371/journal.pbio.1001537 | Transsynaptic Coordination of Synaptic Growth, Function, and Stability by the L1-Type CAM Neuroglian | The precise control of synaptic connectivity is essential for the development and function of neuronal circuits. While there have been significant advances in our understanding how cell adhesion molecules mediate axon guidance and synapse formation, the mechanisms controlling synapse maintenance or plasticity in vivo r... | The function of neuronal circuits relies on precise connectivity, and processes like learning and memory involve refining this connectivity through the selective formation and elimination of synapses. Cell adhesion molecules (CAMs) that directly mediate cell–cell interactions at synaptic contacts are thought to mediate... | Transsynaptic interactions mediated by cell adhesion molecules (CAMs) control the formation, function, and stability of synaptic connections within neuronal circuits. While a large number of synaptogenic CAMs controlling the initial steps of synapse formation have been identified [1],[2], we have only limited knowledge... |
10.1371/journal.pgen.1003531 | PARP-1 Regulates Metastatic Melanoma through Modulation of Vimentin-induced Malignant Transformation | PARP inhibition can induce anti-neoplastic effects when used as monotherapy or in combination with chemo- or radiotherapy in various tumor settings; however, the basis for the anti-metastasic activities resulting from PARP inhibition remains unknown. PARP inhibitors may also act as modulators of tumor angiogenesis. Pro... | Metastasis is the spread of malignant tumor cells from their original site to other parts of the body and is responsible for the vast majority of solid cancer-related mortality. PARP inhibitors are emerging as promising anticancer therapeutics and are currently undergoing clinical trials. It is therefore important to e... | Metastatic melanoma is a fatal malignancy that is remarkably resistant to treatment; however, the mechanisms regulating the transition from the primary local tumor growth to distant metastasis remain poorly understood. Metastasis, defined as the spread of malignant tumor cells from the primary tumor mass to distant sit... |
10.1371/journal.pntd.0007494 | Functional illiteracy burden in soil-transmitted helminth (STH) endemic regions of the Philippines: An ecological study and geographical prediction for 2017 | Soil-transmitted helminth (STH) infections remain highly endemic across the Philippines, and are believed to be important contributors to delayed cognitive development of school-aged children. Identification of communities where children are at risk of functional illiteracy is important for the attainment of Sustainabl... | While previous studies in the Philippines indicated an association between STH infection and cognitive development measured by memory and school performance, the contribution of STH infections on the overall functional illiteracy burden in the Philippines is unknown. This study presents the first use of geographical ri... | Functional literacy is one of the targets of the Sustainable Development Goals (SDG) of the United Nations, launched in September 2015 [1]. Functional literacy is a key indicator of cognitive function, especially information processing and comprehension, and it has been used to measure cognitive function in school-aged... |
10.1371/journal.ppat.1003834 | An In-Depth Comparison of Latent HIV-1 Reactivation in Multiple Cell Model Systems and Resting CD4+ T Cells from Aviremic Patients | The possibility of HIV-1 eradication has been limited by the existence of latently infected cellular reservoirs. Studies to examine control of HIV latency and potential reactivation have been hindered by the small numbers of latently infected cells found in vivo. Major conceptual leaps have been facilitated by the use ... | HIV establishes a state of latency in vivo and this latent reservoir, although small, is difficult to eradicate. To be able to better understand this state of latency, and to develop strategies to eliminate it, many groups have developed in vitro models of HIV latency. However, notable differences exist among cell mode... | The possibility to achieve HIV eradication has been limited, at least in part, by the existence of latently infected cellular reservoirs [1]–[3]. The major known cellular reservoir is established in quiescent memory CD4+ T cells, providing an extremely long-lived set of cells in which the virus can remain transcription... |
10.1371/journal.pbio.1000620 | Extinction Risk and Diversification Are Linked in a Plant
Biodiversity Hotspot | It is widely recognized that we are entering an extinction event on a scale
approaching the mass extinctions seen in the fossil record. Present-day rates of
extinction are estimated to be several orders of magnitude greater than
background rates and are projec... | The rapid loss of biodiversity is the most significant ecological challenge we
face today. Over the past few years, the International Union for Conservation of
Nature has published Red Lists documenting the inexorable slide
towards extinction of species; recen... | The rapid and accelerating loss of biodiversity is the most significant ecological
challenge we face today. Current rates of extinction are already estimated to be
several orders of magnitude greater than background rates [1] and are projected to increase
another order of... |
10.1371/journal.pgen.1000631 | The Ataxia (axJ) Mutation Causes Abnormal GABAA Receptor Turnover in Mice | Ataxia represents a pathological coordination failure that often involves functional disturbances in cerebellar circuits. Purkinje cells (PCs) characterize the only output neurons of the cerebellar cortex and critically participate in regulating motor coordination. Although different genetic mutations are known that ca... | Cerebellar ataxia describes a combination of motor symptoms and uncoordinated movements that originates from various hereditary and non-hereditary diseases. Although functional disturbances of cerebellar inhibitory output signals are thought to cause ataxia, the underlying molecular mechanisms are barely understood and... | A number of heterogeneous hereditary and non-hereditary disorders lead to ataxia characterized by coordination failures [1],[2],[3]. The spontaneous axJ mutation affects the locomotory system, causing an ataxic phenotype in mice [4]. The mutated gene encodes the deubiquitinating enzyme (DUB) Usp14 [5], a member of the ... |
10.1371/journal.pbio.1002549 | Short Time-Scale Sensory Coding in S1 during Discrimination of Whisker Vibrotactile Sequences | Rodent whisker input consists of dense microvibration sequences that are often temporally integrated for perceptual discrimination. Whether primary somatosensory cortex (S1) participates in temporal integration is unknown. We trained rats to discriminate whisker impulse sequences that varied in single-impulse kinematic... | Sensory input is rich in temporal patterns, but how the brain processes this temporal information is not well understood. This process is important in the whisker tactile system of rodents, in which active whisking on objects generates dense streams of stick-slip and contact events. Rats can discriminate vibrotactile s... | Natural sensory input comprises dense temporal series of discrete events, which animals often temporally integrate to guide perceptual decisions. The temporal integration process has been studied in primate somatosensation and vision [1,2], but less in rodents, in which modern tools could reveal the underlying circuit ... |
10.1371/journal.pgen.1006152 | A High Temperature-Dependent Mitochondrial Lipase EXTRA GLUME1 Promotes Floral Phenotypic Robustness against Temperature Fluctuation in Rice (Oryza sativa L.) | The sessile plants have evolved diverse intrinsic mechanisms to control their proper development under variable environments. In contrast to plastic vegetative development, reproductive traits like floral identity often show phenotypic robustness against environmental variations. However, it remains obscure about the m... | Various mechanisms have evolved to ensure proper organ formation under variable environments in order to complete one organism’s life cycle. In angiosperms, vegetative and reproductive organs show a differential plastic development between varied environments, with a low plasticity or high robustness for flower formati... | The sessile plants have evolved various exquisite adaptive strategies to cope with environmental changes [1,2]. Among them, phenotypic plasticity is the ability of a single genotype capable of producing different phenotypes in response to varying environments [3–6]. For an integral high fitness, morphologies of vegetat... |
10.1371/journal.pntd.0002315 | Mycobacterium ulcerans Disease: Experience with Primary Oral Medical Therapy in an Australian Cohort | Mycobacterium ulcerans (MU) is responsible for disfiguring skin lesions and is endemic on the Bellarine peninsula of southeastern Australia. Antibiotics have been shown to be highly effective in sterilizing lesions and preventing disease recurrences when used alone or in combination with surgery. Our practice has evolv... | Mycobacterium ulcerans (MU) is responsible for disfiguring skin infections which are challenging to treat. The recommended treatment for MU has continued to evolve from surgery to remove all involved tissue, to the use of effective combination oral antibiotics with surgery as required. Our study describes the oral medi... | Buruli ulcer, also known as Bairnsdale ulcer, Daintree ulcer, or Mossman ulcer is a necrotising infection of skin and subcutaneous tissue caused by Mycobacterium ulcerans (MU) [1]. The major burden of disease is found in tropical climates, but cases have been reported from 33 countries worldwide [2]. M.ulcerans infecti... |
10.1371/journal.pntd.0005716 | A leprosy clinical severity scale for erythema nodosum leprosum: An international, multicentre validation study of the ENLIST ENL Severity Scale | We wished to validate our recently devised 16-item ENLIST ENL Severity Scale, a clinical tool for measuring the severity of the serious leprosy associated complication of erythema nodosum leprosum (ENL). We also wished to assess the responsiveness of the ENLIST ENL Severity Scale in detecting clinical change in patient... | Erythema nodosum leprosum (ENL) is a severe, painful complication of leprosy, which can occur before, during or after successful treatment of the infection. ENL is characterised by severe pain and the development of new painful skin lesions. Other organ systems are often affected. ENL may continue to affect people for ... | Erythema nodosum leprosum (ENL) is a severe inflammatory complication of borderline lepromatous (BL) leprosy and lepromatous leprosy (LL). ENL affects up to 50% of individuals with LL and 5–10% of BL leprosy patients [1, 2]. A bacterial index of four or more is also a risk factor for developing ENL. ENL may occur befor... |
10.1371/journal.pgen.1007998 | Evolution of an insect immune barrier through horizontal gene transfer mediated by a parasitic wasp | Genome sequencing data have recently demonstrated that eukaryote evolution has been remarkably influenced by the acquisition of a large number of genes by horizontal gene transfer (HGT) across different kingdoms. However, in depth-studies on the physiological traits conferred by these accidental DNA acquisitions are la... | Parasitic wasps are important insect biocontrol agents. These insects are beneficial for the ecological service they provide, which largely contributes to the control of natural populations of their hosts. Paradoxically, they can be beneficial also for non-host individuals attacked by mistake, if these survive after pa... | Horizontal gene transfer (HGT) is a mechanism of accidental acquisition of genetic material by means other than reproduction, which in some evolutionary lineages, such as prokaryotes, is considered the major driving force in genome evolution [1]. In theory, all genes may undergo HGT, however current evidence on prokary... |
10.1371/journal.pgen.1004888 | Notch Signaling Mediates the Age-Associated Decrease in Adhesion of Germline Stem Cells to the Niche | Stem cells have an innate ability to occupy their stem cell niche, which in turn, is optimized to house stem cells. Organ aging is associated with reduced stem cell occupancy in the niche, but the mechanisms involved are poorly understood. Here, we report that Notch signaling is increased with age in Drosophila female ... | Aging is frequently associated with a decline in the size of stem cell pools, but little is known regarding the molecular mechanisms underlying this process. Here, we report that Notch signaling is increased in GSCs as they age, and this promotes their removal from the niche in an E-cadherin dependent manner. In contra... | Age-associated depletion of stem cell pools has been reported for mammalian satellite stem cells, Drosophila male and female GSCs, and C. elegans GSCs [1]–[4]; however, the mechanisms underlying such depletion remain unknown. The stem cell niche houses stem cells and maintains their cell identity, by providing physical... |
10.1371/journal.pntd.0005518 | Rapid mapping of urinary schistosomiasis: An appraisal of the diagnostic efficacy of some questionnaire-based indices among high school students in Katsina State, northwestern Nigeria | In sub-Saharan Africa, over 200 million individuals are estimated to be infected with urinary and intestinal schistosomiasis. In a bid to lay a foundation for effective future control programme, this study was carried out with the aim of assessing the diagnostic efficacy of some questionnaire-based rapid assessment ind... | Schistosomiasis is a water-borne neglected infectious disease of poverty that has consistently plagued over 200 million helpless inhabitants of the tropics, particularly, sub-Sahara Africa. Under the auspices of different nomenclatures and affiliations, many control programmes based on Praziquantel have been inaugurate... | Schistosomiasis, a water-borne neglected tropical disease (NTD), has been reported as the second most prevalent parasitic disease after malaria [1]. The causative agent of human schistosomiasis is a digenetic trematode blood fluke of the genus Schistosoma with a complex, indirect life cycle involving different species ... |
10.1371/journal.pgen.1004723 | ZTF-8 Interacts with the 9-1-1 Complex and Is Required for DNA Damage Response and Double-Strand Break Repair in the C. elegans Germline | Germline mutations in DNA repair genes are linked to tumor progression. Furthermore, failure in either activating a DNA damage checkpoint or repairing programmed meiotic double-strand breaks (DSBs) can impair chromosome segregation. Therefore, understanding the molecular basis for DNA damage response (DDR) and DSB repa... | Proper response to DNA damage and repair of DNA double-strand breaks (DSBs) is important to maintain genomic integrity and promote both accurate chromosome segregation and tumor suppression. Here we define the roles of a previously uncharacterized and conserved protein, ZTF-8, which is required for proper DNA damage ch... | Genome instability is a hallmark of cancer cells and a critical feature that enables tumor progression. Instability allows cells to break and reform chromosomes, generate new oncogene fusions, inactivate tumor suppressor genes, amplify drug resistance genes, and therefore increase their malignancy. This whole progressi... |
10.1371/journal.ppat.1000534 | The Two-Domain LysX Protein of Mycobacterium tuberculosis Is Required for Production of Lysinylated Phosphatidylglycerol and Resistance to Cationic Antimicrobial Peptides | The well-recognized phospholipids (PLs) of Mycobacterium tuberculosis (Mtb) include several acidic species such as phosphatidylglycerol (PG), cardiolipin, phosphatidylinositol and its mannoside derivatives, in addition to a single basic species, phosphatidylethanolamine. Here we demonstrate that an additional basic PL,... | The human pathogen Mycobacterium tuberculosis (Mtb) survives in the hostile intracellular environment, in part, by withstanding the actions of host-induced cationic antimicrobial peptides (CAMPs). Membrane phospholipid composition and the resultant charge could play an important role in Mtb survival within the host. Ac... | Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is a successful human pathogen that has infected more than one-third of the world's population. The success of Mtb as an infectious agent relies, in part, on its ability to modulate the expression of bacterial factors in response to infection so tha... |
10.1371/journal.pcbi.1005600 | Rosetta:MSF: a modular framework for multi-state computational protein design | Computational protein design (CPD) is a powerful technique to engineer existing proteins or to design novel ones that display desired properties. Rosetta is a software suite including algorithms for computational modeling and analysis of protein structures and offers many elaborate protocols created to solve highly spe... | Protein engineering, i. e. the targeted modification or design of proteins has tremendous potential for medical and industrial applications. One generally applicable strategy for protein engineering is rational protein design: based on detailed knowledge of structure and function, computer programs like Rosetta propose... | Since the 1990s, computational protein design (CPD) has been a powerful tool of protein engineering. For example, CPD has been successfully utilized to increase thermostability of proteins [1–3] and to design new or altered binding specificities for metals [4], DNA [5] or other ligands [6, 7]. Additionally, CPD was app... |
10.1371/journal.pcbi.1006548 | Dilution and titration of cell-cycle regulators may control cell size in budding yeast | The size of a cell sets the scale for all biochemical processes within it, thereby affecting cellular fitness and survival. Hence, cell size needs to be kept within certain limits and relatively constant over multiple generations. However, how cells measure their size and use this information to regulate growth and div... | Proliferating cells need to coordinate the initiation of genome replication and cell division with cell growth. In particular, the average time between two division events must precisely allow for a doubling in cell volume. Any systematic deviation from this balance would lead to progressive changes in cell size over c... | Balanced growth of proliferating cells requires some coordination between the increasing size of a growing cell and its probability of undergoing DNA synthesis and division. In particular, the average time between two successive cell divisions must allow for a doubling in cell mass (or volume, which we will use interch... |
10.1371/journal.pgen.1005634 | EGFR/Ras Signaling Controls Drosophila Intestinal Stem Cell Proliferation via Capicua-Regulated Genes | Epithelial renewal in the Drosophila intestine is orchestrated by Intestinal Stem Cells (ISCs). Following damage or stress the intestinal epithelium produces ligands that activate the epidermal growth factor receptor (EGFR) in ISCs. This promotes their growth and division and, thereby, epithelial regeneration. Here we ... | Studies suggest that epidermal growth factor receptor (EGFR) signaling activation is a causal driver of many stem cell-derived epithelial cancers, including colorectal cancer. As in the human intestine, epithelial renewal in Drosophila intestine is orchestrated by intestinal stem cells (ISCs). EGFR signaling also plays... | EGFR/Ras/MAPK signaling has diverse functions in regulating cell proliferation, growth, differentiation and survival in most animal cells [1]. Abundant studies also indicate that epidermal growth factor receptor (EGFR) activation is a causal driver of many cancers, including breast, lung, brain, and colorectal cancer [... |
10.1371/journal.ppat.1006786 | eCD4-Ig promotes ADCC activity of sera from HIV-1-infected patients | Antibody-dependent cell-mediated cytotoxity (ADCC) can eliminate HIV-1 infected cells, and may help reduce the reservoir of latent virus in infected patients. Sera of HIV-1 positive individuals include a number of antibodies that recognize epitopes usually occluded on HIV-1 envelope glycoprotein (Env) trimers. We have ... | Antibodies can bind HIV-1-infected cells by recognizing the viral envelope glycoprotein (Env) on the cell surface. Antibody-bound cells then recruit natural killer cells to eliminate these infected cells. Here we demonstrate the unique properties of eCD4-Ig, a potent and exceptionally broad antibody-like HIV-1 entry in... | Natural killer (NK) cells and other Fc-gamma receptor (FcγR)-expressing cells can eliminate HIV-1 infected cells through antibody-dependent cell-mediated cytotoxicity (ADCC) [1–3]. These ADCC activities depend on the antibody isotype [4,5]. For example, IgG1 and IgG3 mediate efficient ADCC, whereas the IgG2 and IgG4 do... |
10.1371/journal.pcbi.1004569 | An Ovol2-Zeb1 Mutual Inhibitory Circuit Governs Bidirectional and Multi-step Transition between Epithelial and Mesenchymal States | Reversible epithelial-to-mesenchymal transition (EMT) is central to tissue development, epithelial stemness, and cancer metastasis. While many regulatory elements have been identified to induce EMT, the complex process underlying such cellular plasticity remains poorly understood. Utilizing a systems biology approach i... | Cumulative evidence reveals remarkable lineage plasticity of somatic cells. Epithelial-to-mesenchymal transition (EMT) represents a prime example of such plasticity where an epithelial cell is converted into a mesenchymal cell. This process is used in normal development to generate crucial cell types, and is hijacked b... | Epithelial-to-mesenchymal transition (EMT) represents an extreme form of cellular plasticity where an epithelial cell is converted into a mesenchymal cell. Complete EMT is essential during embryogenesis to generate crucial developmental cell types [1], whereas partial EMT occurs in committed epithelial tissues with yet... |
10.1371/journal.pcbi.1004337 | Impact of School Cycles and Environmental Forcing on the Timing of Pandemic Influenza Activity in Mexican States, May-December 2009 | While a relationship between environmental forcing and influenza transmission has been established in inter-pandemic seasons, the drivers of pandemic influenza remain debated. In particular, school effects may predominate in pandemic seasons marked by an atypical concentration of cases among children. For the 2009 A/H1... | An influenza pandemic virus emerged in North America in 2009. Although the virus spread worldwide within months of its emergence, the timing of peak pandemic activity varied by nearly a year across global populations. In fact, the most intense period of pandemic activity occurred earlier in temperate countries of the s... | There is strong evidence that seasonal influenza activity around the world is modulated by environmental variability [1]. Temperate regions are characterized by annual winter epidemics [2,3] that may result from seasonal decreases in specific humidity and subsequent increases in virus survival and transmission [4–6]. S... |
10.1371/journal.pgen.1005346 | TopBP1 Governs Hematopoietic Stem/Progenitor Cells Survival in Zebrafish Definitive Hematopoiesis | In vertebrate definitive hematopoiesis, nascent hematopoietic stem/progenitor cells (HSPCs) migrate to and reside in proliferative hematopoietic microenvironment for transitory expansion. In this process, well-established DNA damage response pathways are vital to resolve the replication stress, which is deleterious for... | The rapidly proliferating hematopoietic stem/progenitor cells (HSPCs) require well-established DNA damage response/repair pathways to resolve the DNA replication stress-induced DNA damage, which is deleterious for the genome stability and cell survival. Impairment of these pathways could lead to the progressive bone ma... | Hematopoietic stem/progenitor cells (HSPCs) possess the capabilities of self-renewal and differentiation into all lineages of mature blood cells [1]. Dysregulated self-renewal of HSPCs is tightly associated with the human blood diseases including leukemia and bone marrow failure (BMF) syndrome [2–4]. Previous studies h... |
10.1371/journal.pgen.1004509 | Wnt-Mediated Repression via Bipartite DNA Recognition by TCF in the Drosophila Hematopoietic System | The Wnt/β-catenin signaling pathway plays many important roles in animal development, tissue homeostasis and human disease. Transcription factors of the TCF family mediate many Wnt transcriptional responses, promoting signal-dependent activation or repression of target gene expression. The mechanism of this specificity... | During development and in adult tissues, cells communicate with each other through biochemical cascades known as signaling pathways. In this report, we study the Wnt signaling pathway, using the fruit fly Drosophila as a model system. This pathway is known to activate gene expression in cells receiving the Wnt signal, ... | It is a common theme in gene regulation that the same transcription factor (TF) can directly activate or repress target gene expression, increasing the transcriptional complexity these TFs can achieve [1], [2]. There are several mechanisms by which TFs exhibit this dual regulation. These include TFs interfering with th... |
10.1371/journal.pgen.1003254 | An Evolutionarily Conserved Synthetic Lethal Interaction Network Identifies FEN1 as a Broad-Spectrum Target for Anticancer Therapeutic Development | Harnessing genetic differences between cancerous and noncancerous cells offers a strategy for the development of new therapies. Extrapolating from yeast genetic interaction data, we used cultured human cells and siRNA to construct and evaluate a synthetic lethal interaction network comprised of chromosome instability (... | Anticancer therapeutic discovery is a major challenge in cancer research. Because cancer is a disease caused by somatic genetic mutations, the search for anticancer therapeutics is often driven by the ability to exploit genetic differences specific to tumor cells. Recently, cancer therapeutic development has sought to ... | Cancerous cells carry somatic mutations that genotypically distinguish them from surrounding noncancerous cells, and this provides an opportunity that can be exploited for therapeutic development. One strategy for the specific targeting of cancer genotypes relative to nonmutated somatic cells is to exploit synthetic le... |
10.1371/journal.pcbi.1004201 | Bacterial Temporal Dynamics Enable Optimal Design of Antibiotic Treatment | There is a critical need to better use existing antibiotics due to the urgent threat of antibiotic resistant bacteria coupled with the reduced effort in developing new antibiotics. β-lactam antibiotics represent one of the most commonly used classes of antibiotics to treat a broad spectrum of Gram-positive and -negativ... | Antibiotic resistance is a growing problem that the World Health Organization describes as “one of the top three threats to global health.” To date, bacteria have developed resistance to all antibiotics used in clinical settings. Unfortunately, the evolution of antibiotic resistant bacteria is accelerating, as antibiot... | Bacteria eventually develop resistance to all antibiotics they encounter [1–3]. Unfortunately, the evolution of antibiotic resistant bacteria is accelerating due to the widespread use of antibiotics [4,5]. As the antibiotic pipeline is drying up and the threat of antibiotic resistance is becoming more urgent [6,7], it ... |
10.1371/journal.pntd.0005274 | Whole Genome Sequence Analysis of Salmonella Typhi Isolated in Thailand before and after the Introduction of a National Immunization Program | Vaccines against Salmonella Typhi, the causative agent of typhoid fever, are commonly used by travellers, however, there are few examples of national immunization programs in endemic areas. There is therefore a paucity of data on the impact of typhoid immunization programs on localised populations of S. Typhi. Here we ... | Typhoid fever is a systemic infection caused by the bacterium Salmonella Typhi. Typhoid fever is associated with inadequate hygiene in low-income settings and a lack of sanitation infrastructure. A sustained outbreak of typhoid fever occurred in Thailand in the 1970s, which peaked in 1975–1976. In response to this typh... | Salmonella enterica subspecies enterica serovar Typhi (S. Typhi) is a human restricted bacterial pathogen and the etiological agent of typhoid fever. S. Typhi is transmitted faeco-orally and can establish asymptomatic carriage in a small subset of an exposed population [1]. Recent estimates [2–4] place the global burde... |
10.1371/journal.pcbi.1005014 | Modeling Electrophysiological Coupling and Fusion between Human Mesenchymal Stem Cells and Cardiomyocytes | Human mesenchymal stem cell (hMSC) delivery has demonstrated promise in preclinical and clinical trials for myocardial infarction therapy; however, broad acceptance is hindered by limited understanding of hMSC-human cardiomyocyte (hCM) interactions. To better understand the electrophysiological consequences of direct h... | Myocardial infarction—better known as a heart attack—strikes on average every 43 seconds in America. An emerging approach to treat myocardial infarction patients involves the delivery of human mesenchymal stem cells (hMSCs) to the damaged heart. While clinical trials of this therapeutic approach have yet to report adve... | Ischemic heart disease, which results from reduced coronary flow of oxygenated blood, is a leading cause of myocardial infarction and heart failure. This insufficient oxygenation results in the death of cardiomyocytes, which are normally incapable of substantial regeneration. Therefore, despite tremendous advancements ... |
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