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10.1371/journal.ppat.1002111 | A Dynamic Landscape for Antibody Binding Modulates Antibody-Mediated Neutralization of West Nile Virus | Neutralizing antibodies are a significant component of the host's protective response against flavivirus infection. Neutralization of flaviviruses occurs when individual virions are engaged by antibodies with a stoichiometry that exceeds a required threshold. From this “multiple-hit” perspective, the neutralizing activ... | Neutralizing antibodies are a critical aspect of protection from flavivirus infection. The primary targets of neutralizing antibodies are the envelope (E) proteins incorporated into virions. The neutralizing activity of antibodies is determined by the affinity with which they interact with the virion, and the total num... | Flaviviruses are a group of ∼70 RNA viruses that cause morbidity and mortality on a global scale, with greater than 100 million human infections annually [1]. Viruses within this genus of medical concern include yellow fever virus, tick-borne encephalitis virus, Japanese encephalitis virus, dengue virus (DENV) and West... |
10.1371/journal.pbio.1000572 | Laminar Analysis of Excitatory Local Circuits in Vibrissal Motor and Sensory Cortical Areas | Rodents move their whiskers to locate and identify objects. Cortical areas involved in vibrissal somatosensation and sensorimotor integration include the vibrissal area of the primary motor cortex (vM1), primary somatosensory cortex (vS1; barrel cortex), and secondary somatosensory cortex (S2). We mapped local excitato... | The neocortex of the mammalian brain is divided into different regions that serve specific functions. These include sensory areas for vision, hearing, and touch, and motor areas for directing aspects of movement. However, the similarities and differences in local circuit organization between these areas are not well un... | Sensation in the rodent vibrissal system relies on active whisking for interactions with the environment [1],[2]. Motor circuits control whisker movement, while sensory afferents collect information about contact with objects. Interactions between motor and sensory systems are necessary for object localization and iden... |
10.1371/journal.pbio.1001115 | A Novel Sperm-Delivered Toxin Causes Late-Stage Embryo Lethality and Transmission Ratio Distortion in C. elegans | The evolutionary fate of an allele ordinarily depends on its contribution to host fitness. Occasionally, however, genetic elements arise that are able to gain a transmission advantage while simultaneously imposing a fitness cost on their hosts. We previously discovered one such element in C. elegans that gains a transm... | Natural selection typically favors only those genetic variants that increase the overall fitness of the organism. Occasionally, however, variants arise that are able to increase their representation in future generations, while simultaneously reducing the fertility or fecundity of their hosts. Although such variants oc... | The evolutionary fate of an allele ordinarily depends on the reproductive fitness of the organisms carrying it. In some cases, however, alleles are able to increase their representation in future generations while being neutral or detrimental to the fitness of their bearers. These elements, sometimes termed “selfish” o... |
10.1371/journal.pntd.0002322 | rKLO8, a Novel Leishmania donovani – Derived Recombinant Immunodominant Protein for Sensitive Detection of Visceral Leishmaniasis in Sudan | For effective control of visceral leishmaniasis (VL) in East Africa, new rapid diagnostic tests are required to replace current tests with low sensitivity. The aim of this study is to improve diagnosis of VL in East Africa by testing a new antigen from an autochthonous L. donovani strain in Sudan.
We cloned, expressed ... | Visceral leishmaniasis (VL) is an infectious disease caused by the Leishmania donovani complex including Leishmania donovani in East Africa and India and by Leishmania infantum in the Mediterranean area and Latin America. Clinical diagnosis of VL in East Africa is difficult as maladies with similar symptoms are endemic... | Visceral leishmaniasis (VL) is a protozoan parasitic diseases caused by members of the Leishmania donovani (L. d) complex that includes L. d. donovani in East Africa and the Indian subcontinent, L. d. infantum in Europe and North Africa and L. d. chagasi in Latin America [1], [2]. However, recent molecular and enzymati... |
10.1371/journal.ppat.0030176 | Multiple Infections by the Anther Smut Pathogen Are Frequent and Involve Related Strains | Population models of host–parasite interactions predict that when different parasite genotypes compete within a host for limited resources, those that exploit the host faster will be selected, leading to an increase in parasite virulence. When parasites sharing a host are related, however, kin selection should lead to ... | Infections of one host individual by multiple genotypes of a parasite occur in many natural systems and have major consequences on the evolution of disease severity. Under such multiple infections, the parasite genotypes compete for the host's limited resources, and the faster exploiters will be advantaged over more pr... | It is generally considered that a parasite's optimal level of virulence, i.e., the decrease in host fitness induced by disease that maximizes parasite transmission, depends on several factors, such as mode of transmission, dormancy ability, host availability, and the frequency of occurrence within single hosts of multi... |
10.1371/journal.pmed.1002424 | Cardiovascular disease (CVD) and chronic kidney disease (CKD) event rates in HIV-positive persons at high predicted CVD and CKD risk: A prospective analysis of the D:A:D observational study | The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study has developed predictive risk scores for cardiovascular disease (CVD) and chronic kidney disease (CKD, defined as confirmed estimated glomerular filtration rate [eGFR] ≤ 60 ml/min/1.73 m2) events in HIV-positive people. We hypothesized that participa... | Access to combination antiretroviral therapy has increased the life expectancy of HIV-positive people.
Despite this success, there is evidence that HIV-positive people may experience an earlier onset of comorbidities (e.g., cardiovascular disease [CVD] and chronic kidney disease [CKD]) in comparison with their HIV-nega... | Combination antiretroviral therapy has transformed the lives of HIV-positive people. Over the past 20 years in high-income countries, rates of opportunistic diseases have declined and life expectancy has reached levels similar to that of the HIV-negative population [1–4]. However, there is evidence suggesting that peop... |
10.1371/journal.pntd.0001278 | The Value of Educational Messages Embedded in a Community-Based Approach to Combat Dengue Fever: A Systematic Review and Meta Regression Analysis | The effects of various dengue control measures have been investigated in previous studies. The aim of this review was to investigate the relative effectiveness (RE) of different educational messages embedded in a community-based approach on the incidence of Aedes aegypti larvae using entomological measures as outcomes.... | Dengue fever is a mosquito-borne viral infection that is widespread in the tropics. Each year there are an estimated 50 million infections worldwide. Preventing infection relies on controlling the mosquitoes that spread disease. Unfortunately it is still not clear what does and does not work in the control of the mosqu... | Dengue fever (DF) is an acute viral disease affecting all age groups. It occurs mainly in tropical and subtropical areas, the predominant vectors being the mosquitoes Aedes aegypti and albopictus, which become infected with any of the four dengue viruses and transmit the disease via a bite to humans [1]. Some 2.5 billi... |
10.1371/journal.pcbi.1003065 | Interface-Resolved Network of Protein-Protein Interactions | We define an interface-interaction network (IIN) to capture the specificity and competition between protein-protein interactions (PPI). This new type of network represents interactions between individual interfaces used in functional protein binding and thereby contains the detail necessary to describe the competition ... | Much of the work inside the cell is carried out by proteins interacting with other proteins. Each edge in a protein-protein interaction network reflects these functional interactions and each node a separate protein, creating a complex structure that nevertheless follows well-established global and local patterns relat... | Protein-protein interaction (PPI) networks aim to capture the interactions between proteins that mediate many of their molecular functions [1]–[3]. However, with one node per protein and one edge per binary interaction, PPIs provide only a coarse rendering of the nuanced molecular level interactions. With exposed surfa... |
10.1371/journal.pgen.1000832 | U87MG Decoded: The Genomic Sequence of a Cytogenetically Aberrant Human Cancer Cell Line | U87MG is a commonly studied grade IV glioma cell line that has been analyzed in at least 1,700 publications over four decades. In order to comprehensively characterize the genome of this cell line and to serve as a model of broad cancer genome sequencing, we have generated greater than 30× genomic sequence coverage usi... | Glioblastoma has a particularly dismal prognosis with median survival time of less than fifteen months. Here, we describe the broad genome sequencing of U87MG, a commonly used and thus well-studied glioblastoma cell line. One of the major features of the U87MG genome is the large number of chromosomal abnormalities, wh... | Grade IV glioma, also called glioblastoma multiforme (GBM), is the most common primary malignant brain tumor with about 16,000 new diagnoses each year in the United States. While the number of cases is relatively small, comprising only 1.35% of primary malignant cancers in the US [1], GBMs have a one-year survival rate... |
10.1371/journal.pgen.1005600 | Intermediate Levels of Bacillus subtilis CodY Activity Are Required for Derepression of the Branched-Chain Amino Acid Permease, BraB | The global transcriptional regulator, CodY, binds strongly to the regulatory region of the braB gene, which encodes a Bacillus subtilis branched-chain amino acid (BCAA) permease. However, under conditions that maximize CodY activity, braB expression was similar in wild-type and codY null mutant cells. Nonetheless, expr... | Expression of Bacillus subtilis BraB, a branched-chain amino acid permease, is under both negative and positive control by a global transcriptional regulator CodY. The negative control is direct and the positive control is indirect and mediated by another B. subtilis pleiotropic transcriptional regulator, ScoC, which, ... | BraB is one of three permeases demonstrated to be involved in the uptake of branched-chain amino acids (BCAA) in Bacillus subtilis [1]. Given the important role of BCAA in cell metabolism, it is not surprising that the synthesis of the permeases is strictly regulated and coordinated. The most efficient BCAA permease, B... |
10.1371/journal.pntd.0002333 | Imported Amoebic Liver Abscess in France | Worldwide, amoebic liver abscess (ALA) can be found in individuals in non-endemic areas, especially in foreign-born travelers.
We performed a retrospective analysis of ALA in patients admitted to French hospitals between 2002 and 2006. We compared imported ALA cases in European and foreign-born patients and assessed th... | Amœbiasis is caused by Entamoeba histolytica (E. histolytica), a protozoan specific to humans which infects humans by ingestion of contaminated food and water. According to some authors, amœbiasis could be the second leading cause of death from parasitic disease worldwide. It is endemic in tropical countries but can al... | Amœbiasis is caused by Entamoeba histolytica (E. histolytica), a protozoan specific to humans. Amœbiasis is present throughout the world, but is endemic in tropical countries where the risk of faeco-oral transmission is high [1]. The main clinical manifestations of amœbiasis are colitis and liver abscess (ALA) [1]. Ple... |
10.1371/journal.pgen.1006870 | Intestinal stem cell overproliferation resulting from inactivation of the APC tumor suppressor requires the transcription cofactors Earthbound and Erect wing | Wnt/β-catenin signal transduction directs intestinal stem cell (ISC) proliferation during homeostasis. Hyperactivation of Wnt signaling initiates colorectal cancer, which most frequently results from truncation of the tumor suppressor Adenomatous polyposis coli (APC). The β-catenin-TCF transcription complex activates b... | The identification of effective therapy for colorectal cancer, which is a leading cause of cancer-related death, is imperative. Wnt pathway components have promise as therapeutic targets, since more than 90% of colon cancers are triggered by mutations that overactivate this pathway, particularly in the tumor suppressor... | The evolutionarily conserved Wnt/β-catenin signal transduction pathway directs fundamental cellular processes across metazoans, whereas deregulation of this pathway is associated with numerous human congenital disorders and cancers [1,2]. In the absence of Wnt exposure, β-catenin, a key transcription coactivator, is ph... |
10.1371/journal.pgen.1004454 | Unraveling Genetic Modifiers in the Gria4 Mouse Model of Absence Epilepsy | Absence epilepsy (AE) is a common type of genetic generalized epilepsy (GGE), particularly in children. AE and GGE are complex genetic diseases with few causal variants identified to date. Gria4 deficient mice provide a model of AE, one for which the common laboratory inbred strain C3H/HeJ (HeJ) harbors a natural IAP r... | Absence seizures - also known as “petit-mal” - define a common form of epilepsy most prevalent in children, but also seen at other ages, and in related diseases such as juvenile myoclonic epilepsy. Absence seizures cause brief periods of unconsciousness, and are accompanied by characteristic abnormal brain waves called... | Laboratory mouse strains are well known to vary in their susceptibility to convulsive seizures, including acute experimentally induced seizures [1], [2], [3], [4], [5], [6], and spontaneous seizures induced by genetic mutation [7], [8], [9], [10], [11], [12], [13]. Most of the known strain effects have been for convuls... |
10.1371/journal.pgen.1002904 | Retrovolution: HIV–Driven Evolution of Cellular Genes and Improvement of Anticancer Drug Activation | In evolution strategies aimed at isolating molecules with new functions, screening for the desired phenotype is generally performed in vitro or in bacteria. When the final goal of the strategy is the modification of the human cell, the mutants selected with these preliminary screenings may fail to confer the desired ph... | We exploited the error-prone replication machinery of HIV-1 and its ability to stably introduce transgenes in human cells to develop a novel system, Retrovolution, to generate libraries of mutants of cellular genes. When libraries are screened to isolate variants that modify the phenotype of the human cell for biomedic... | Broadening the repertoire of natural molecules and generating variants that confer new phenotypes to human cells are appealing perspectives for the development of biomedical applications, and for understanding fundamental cellular processes. To this end, in classical procedures, libraries of mutants are generated in vi... |
10.1371/journal.pgen.1005760 | Arabidopsis ERF1 Mediates Cross-Talk between Ethylene and Auxin Biosynthesis during Primary Root Elongation by Regulating ASA1 Expression | The gaseous phytohormone ethylene participates in the regulation of root growth and development in Arabidopsis. It is known that root growth inhibition by ethylene involves auxin, which is partially mediated by the action of the WEAK ETHYLENE INSENSITIVE2/ANTHRANILATE SYNTHASE α1 (WEI2/ASA1), encoding a rate-limiting e... | Ethylene is a gaseous phytohormone that plays critical roles in plant development and defense. It is well known that ethylene inhibits primary root elongation through effects on auxin. However, it is not clear how ethylene signal is translated into auxin. In this report, the highly ethylene-responsive transcription fac... | Phytohormones are central regulators of plant root growth and development. Each root development process is determined by a network of interacting signals to give the final architecture of the root[1]. Ethylene and auxin have been shown to regulate some of the same developmental processes, including primary root elonga... |
10.1371/journal.pgen.1001263 | Signaling Role of Fructose Mediated by FINS1/FBP in Arabidopsis thaliana | Sugars are evolutionarily conserved signaling molecules that regulate the growth and development of both unicellular and multicellular organisms. As sugar-producing photosynthetic organisms, plants utilize glucose as one of their major signaling molecules. However, the details of other sugar signaling molecules and the... | Among the many plant sugar metabolites, glucose signaling has received the most attention. Although fructose is also an abundant hexose, its signaling role in plant growth and development has not been addressed clearly and systematically to date. We found that fructose functions as a regulatory sugar metabolite and int... | Myriad metabolic pathways enable cells to sustain life with basic carbon and nitrogenous compounds. Thus, the integration of metabolite status, which reflects external and internal living conditions, into cellular activities (e.g., gene expression) is a pivotal process that equips organisms with the ability to survive ... |
10.1371/journal.pcbi.1000171 | Sizing Up Allometric Scaling Theory | Metabolic rate, heart rate, lifespan, and many other physiological properties vary with body mass in systematic and interrelated ways. Present empirical data suggest that these scaling relationships take the form of power laws with exponents that are simple multiples of one quarter. A compelling explanation of this obs... | The rate at which an organism produces energy to live increases with body mass to the 3/4 power. Ten years ago West, Brown, and Enquist posited that this empirical relationship arises from the structure and dynamics of resource distribution networks such as the cardiovascular system. Using assumptions that capture phys... | Whole-organism metabolic rate, B, scales with body mass, M, across species as [1](1)where B0 is a normalization constant and α is the allometric scaling exponent, typically measured to be very close to 3/4 [2]. The empirical regularity expressed in Equation 1 with α = 3/4 is known as Kleiber's Law [3],[4].
Many other ... |
10.1371/journal.pntd.0004248 | Prevalence of and Factors Associated with Human Cysticercosis in 60 Villages in Three Provinces of Burkina Faso | Taenia solium, a zoonotic infection transmitted between humans and pigs, is considered an emerging infection in Sub-Saharan Africa, yet individual and community-level factors associated with the human infection with the larval stages (cysticercosis) are not well understood. This study aims to estimate the magnitude of ... | Taenia solium is an infection that is transmitted between pigs and humans. Humans may get infected with the larvae of Taenia solium, which results in cysticercosis, an infection common in pig farming communities where there is poor sanitation and free roaming pigs. Most published studies on this infection have included... | Taenia solium cysticercosis, a zoonotic infection transmitted between humans and pigs, is considered as an emerging infection in Sub-Saharan Africa. In the Sahel and West Africa region, the pig population has increased by 23% between 1985 and 2005, the largest increase in all animal populations during that period [1]. ... |
10.1371/journal.pcbi.1000298 | Steady-State Kinetic Modeling Constrains Cellular Resting States and Dynamic Behavior | A defining characteristic of living cells is the ability to respond dynamically to external stimuli while maintaining homeostasis under resting conditions. Capturing both of these features in a single kinetic model is difficult because the model must be able to reproduce both behaviors using the same set of molecular c... | Cells respond to extracellular signals through a complex coordination of interacting molecular components. Computational models can serve as powerful tools for prediction and analysis of signaling systems, but constructing large models typically requires extensive experimental datasets and computation. To facilitate th... | Computational models help quantify the reaction dynamics and regulatory modes in complex biochemical systems [1]–[5], particularly when a system is so intricate that its behavior cannot be predicted by intuition alone. The building blocks for constructing large reaction networks are often available in numerous database... |
10.1371/journal.pntd.0003152 | Detection of Rickettsia felis, Rickettsia typhi, Bartonella Species and Yersinia pestis in Fleas (Siphonaptera) from Africa | Little is known about the presence/absence and prevalence of Rickettsia spp, Bartonella spp. and Yersinia pestis in domestic and urban flea populations in tropical and subtropical African countries.
Fleas collected in Benin, the United Republic of Tanzania and the Democratic Republic of the Congo were investigated for ... | Fleas are associated with many bacterial diseases such as rickettsioses, bartonelloses and plague. These diseases may be severe, and little is known about their prevalence. Accordingly, we believe that our data shed light on the problem of unexplained fevers in tropical and subtropical African areas. Using molecular to... | The importance of fleas in human and animal health is largely related to their ability to transmit agents of infectious diseases [1]. The transmission of these zoonotic agents to human occurs mainly through bites or inoculation of feces into pruritic bite lesions [2], [3]. Plague is the most notorious flea-borne diseas... |
10.1371/journal.ppat.1004229 | The Frustrated Host Response to Legionella pneumophila Is Bypassed by MyD88-Dependent Translation of Pro-inflammatory Cytokines | Many pathogens, particularly those that require their host for survival, have devised mechanisms to subvert the host immune response in order to survive and replicate intracellularly. Legionella pneumophila, the causative agent of Legionnaires' disease, promotes intracellular growth by translocating proteins into its h... | Translation inhibition is a common virulence mechanism used by a number of pathogens (e.g. Diphtheria Toxin, Shiga Toxin and Pseudomonas Exotoxin A). It has been a mystery how host cells mount a pathogen-specific response and clear infection under conditions where protein synthesis is blocked by pathogens. Using Legion... | The pathogen-associated molecular pattern (PAMP) hypothesis has been developed to explain how the innate immune system recognizes foreign microbial invaders. By this model, germline-encoded receptors recognize conserved foreign ligands associated with microbes, such as nucleic acids, lipopolysaccharide (LPS), peptidogl... |
10.1371/journal.pntd.0001584 | Multiple Mitochondrial Introgression Events and Heteroplasmy in Trypanosoma cruzi Revealed by Maxicircle MLST and Next Generation Sequencing | Mitochondrial DNA is a valuable taxonomic marker due to its relatively fast rate of evolution. In Trypanosoma cruzi, the causative agent of Chagas disease, the mitochondrial genome has a unique structural organization consisting of 20–50 maxicircles (∼20 kb) and thousands of minicircles (0.5–10 kb). T. cruzi is an earl... | Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is an important public health problem in Latin America. While molecular techniques can differentiate the major T. cruzi genetic lineages, few have sufficient resolution to describe diversity among closely related strains. The online availability of thr... | Mitochondrial genes are among the most popular markers for the reconstruction of evolutionary ancestries and resolution of phylogeographic relationships [1]. Their pervasive use in population genetics can be attributed to several intrinsic characteristics, notably, their high copy number, small size (∼15–20 kb) and fas... |
10.1371/journal.ppat.1007842 | Separate domains of G3BP promote efficient clustering of alphavirus replication complexes and recruitment of the translation initiation machinery | G3BP-1 and -2 (hereafter referred to as G3BP) are multifunctional RNA-binding proteins involved in stress granule (SG) assembly. Viruses from diverse families target G3BP for recruitment to replication or transcription complexes in order to block SG assembly but also to acquire pro-viral effects via other unknown funct... | In order to repel viral infections, cells activate stress responses. One such response involves inhibition of translation and restricted availability of the translation machinery via the formation of stress granules. However, the host translation machinery is absolutely essential for synthesis of viral proteins and con... | Viral infections are inevitably accompanied by a competitive crosstalk between the host and the pathogen, engaging a complex network of protein-protein interactions. Since exploitation of host resources is crucial for the viral replication cycle, host responses aim to interfere with such measures and to clear the threa... |
10.1371/journal.pbio.2005264 | Peripherally derived macrophages modulate microglial function to reduce inflammation after CNS injury | Infiltrating monocyte-derived macrophages (MDMs) and resident microglia dominate central nervous system (CNS) injury sites. Differential roles for these cell populations after injury are beginning to be uncovered. Here, we show evidence that MDMs and microglia directly communicate with one another and differentially mo... | The immune and the central nervous systems are now thought to be inextricably linked. In response to injury, the immune system shapes CNS recovery through a complex of molecular and cellular mediators. However, it is unclear how the kinetics, magnitude, and components of this response can be harnessed to improve CNS re... | The immune system plays a pivotal role in development and homeostatic functions of the central nervous system (CNS) [1]. Immune system dysfunction can give rise to CNS disease [2] and its response to injury shapes recovery [3–5]. The cellular response to CNS injuries is stereotyped and involves the rapid reaction of ti... |
10.1371/journal.pntd.0002061 | Iron Overload Favors the Elimination of Leishmania infantum from Mouse Tissues through Interaction with Reactive Oxygen and Nitrogen Species | Iron plays a central role in host-parasite interactions, since both intervenients need iron for survival and growth, but are sensitive to iron-mediated toxicity. The host's iron overload is often associated with susceptibility to infection. However, it has been previously reported that iron overload prevented the growt... | Leishmania are important vector-borne protozoan pathogens that cause different forms of disease, ranging from cutaneous self-healing lesions to life-threatening visceral infection. L. infantum is the most common species causing visceral leishmaniasis in Europe and the Mediterranean basin. Iron plays a critical role in ... | Leishmania are trypanosomatid protozoans that alternate between two forms: the extracellular motile promastigote in the gut of phlebotomine insects and the intracellular non-motile amastigote inside the macrophages of mammalian hosts. These parasites cause leishmaniasis, a spectrum of human diseases that range from sel... |
10.1371/journal.pcbi.1004899 | HepatoDyn: A Dynamic Model of Hepatocyte Metabolism That Integrates 13C Isotopomer Data | The liver performs many essential metabolic functions, which can be studied using computational models of hepatocytes. Here we present HepatoDyn, a highly detailed dynamic model of hepatocyte metabolism. HepatoDyn includes a large metabolic network, highly detailed kinetic laws, and is capable of dynamically simulating... | Despite the key role of hepatocytes in carbohydrate and lipid homeostasis, available dynamic models of hepatocyte metabolism tend to be limited to a single pathway and/or are based on assumptions of constant concentrations of key metabolites involved in redox and energy metabolism (ATP, NAD, NADPH etc.). Furthermore, m... | No other organ performs as many physiological functions as the liver. The liver is responsible for detoxification, bile acid and blood proteins synthesis, plays a key role in the inflammatory response and, above all, it is a key regulator of glucose and lipid homeostasis in blood. Most of its functions and properties c... |
10.1371/journal.pgen.1007202 | Ras/ERK-signalling promotes tRNA synthesis and growth via the RNA polymerase III repressor Maf1 in Drosophila | The small G-protein Ras is a conserved regulator of cell and tissue growth. These effects of Ras are mediated largely through activation of a canonical RAF-MEK-ERK kinase cascade. An important challenge is to identify how this Ras/ERK pathway alters cellular metabolism to drive growth. Here we report on stimulation of ... | The Ras oncogene is one of the primary drivers of cell and tissue growth in both normal development and in diseases such as cancer. In this report, we identify the stimulation of tRNA synthesis as an important mechanism by which Ras functions. Using fruit fly genetics, we show that Ras promotes tRNA synthesis by inhibi... | The Ras small G-protein is one of the key conserved regulators of cell growth and proliferation. Over three decades of research have defined the textbook model of how Ras is activated by growth factors to stimulate a core RAF kinase, MEK (Mitogen-activated protein kinase kinase) and ERK (Extracellular signal–regulated ... |
10.1371/journal.pcbi.1000351 | Towards Prediction of Metabolic Products of Polyketide Synthases: An In Silico Analysis | Sequence data arising from an increasing number of partial and complete genome projects is revealing the presence of the polyketide synthase (PKS) family of genes not only in microbes and fungi but also in plants and other eukaryotes. PKSs are huge multifunctional megasynthases that use a variety of biosynthetic paradi... | Polyketide synthases (PKSs) form a large family of multifunctional proteins involved in the biosynthesis of diverse classes of therapeutically important natural products. These enzymes biosynthesize natural products with enormous diversity in chemical structures by combinatorial use of a limited number of catalytic dom... | It is well known that polyketide synthase (PKS) gene clusters can generate enormously diverse array of polyketide products by making use of various biosynthetic paradigms like, modular organization of sets of catalytic domains or iterative catalysis of condensation steps using single set of catalytic domains [1]. In vi... |
10.1371/journal.pgen.1005052 | A Genomic Portrait of Haplotype Diversity and Signatures of Selection in Indigenous Southern African Populations | We report a study of genome-wide, dense SNP (∼900K) and copy number polymorphism data of indigenous southern Africans. We demonstrate the genetic contribution to southern and eastern African populations, which involved admixture between indigenous San, Niger-Congo-speaking and populations of Eurasian ancestry. This fin... | Genome-wide analysis of human populations is useful in shedding light on the evolutionary history of the human genome, with a wide range of applications from reconstructing past associations between different population histories to disease mapping. In this manuscript we report on the application of genome-wide data to... | The analysis of high-throughput genotype data has revealed global patterns of human haplotype variation, casting light on the pre-history of human populations [1, 2, 3, 4, 5]. The International HapMap consortium [1,5]) and Human Genome Diversity Project (HGDP) [6], among others, have facilitated the analysis of human g... |
10.1371/journal.pgen.1007033 | The combinatorial control of alternative splicing in C. elegans | Normal development requires the right splice variants to be made in the right tissues at the right time. The core splicing machinery is engaged in all splicing events, but which precise splice variant is made requires the choice between alternative splice sites—for this to occur, a set of splicing factors (SFs) must re... | Alternative splicing (AS) is a highly regulated process that is crucial for normal development. It requires the core splicing machinery, but the specific choice of splice site during AS is controlled by splicing factors (SFs) such as ELAV or RBFOX proteins that bind to specific sequences in pre-mRNAs to regulate usage ... | Alternative splicing (AS) is highly regulated. Many genes have different splice patterns in different tissues and at different developmental stages, and splicing can also change in response to external cues (reviewed in [1]). AS plays a crucial role in the proper development of all animals [2–7] and AS is typically wid... |
10.1371/journal.pntd.0003885 | Involvement of Tetraspanin C189 in Cell-to-Cell Spreading of the Dengue Virus in C6/36 Cells | Dengue virus (DENV) is naturally transmitted by mosquitoes to humans, infecting cells of both hosts. Unlike in mammalian cells, DENV usually does not cause extremely deleterious effects on cells of mosquitoes. Despite this, clustered progeny virions were found to form infection foci in a high density cell culture. It i... | Dengue fever is one of the most important mosquito-borne viral infectious diseases in the world. Its etiological agent is naturally transmitted via blood feeding by Aedes mosquitoes. An ingested virus can replicate and be disseminated within and between tissues in mosquitoes. In this study, we found that infection of D... | Dengue virus (DENV) consists of four serotypes that manifest similar symptoms, ranging from a mild febrile illness to a life-threatening dengue hemorrhagic fever [1]. Taxonomically, DENV is one of some 70 members of the family Flaviviridae and is transmitted between humans by Aedes mosquitoes [2], particularly Aedes ae... |
10.1371/journal.pgen.0030075 | Being Pathogenic, Plastic, and Sexual while Living with a Nearly Minimal Bacterial Genome | Mycoplasmas are commonly described as the simplest self-replicating organisms, whose evolution was mainly characterized by genome downsizing with a proposed evolutionary scenario similar to that of obligate intracellular bacteria such as insect endosymbionts. Thus far, analysis of mycoplasma genomes indicates a low lev... | Mycoplasmas are cell wall–lacking prokaryotes that evolved from ancestors common to Gram-positive bacteria by way of massive losses of genetic material. With their minimal genome, mycoplasmas are considered to be the simplest free-living organisms, yet several species are successful pathogens of man and animal. In this... | Organisms belonging to the Mycoplasma genus (class Mollicutes) are commonly described as the simplest and smallest self-replicating bacteria because of their total lack of cell wall, the paucity of their metabolic pathways, and the small size of their genome [1,2]. In the 1980s, they were shown to have evolved from mor... |
10.1371/journal.pntd.0004979 | Urinary Biomarkers KIM-1 and NGAL for Detection of Chronic Kidney Disease of Uncertain Etiology (CKDu) among Agricultural Communities in Sri Lanka | Chronic Kidney Disease of uncertain etiology (CKDu) is an emerging epidemic among farming communities in rural Sri Lanka. Victims do not exhibit common causative factors, however, histopathological studies revealed that CKDu is a tubulointerstitial disease. Urine albumin or albumin-creatinine ratio is still being used ... | Chronic Kidney Disease (CKD) is a challenging global health issue around the world. Impairment of kidney function with time is eminent, but indications of CKD may not be seen until considerable damage to kidney functions. Two main causes of CKD are diabetes and high blood pressure. However recently new form of CKD has ... | Chronic Kidney Disease of unknown etiology (CKDu) is an endemic disease among dry zone farming communities in Sri Lanka. First cases were reported in early 1990s in North Central Province (NCP) predominantly among male farmers [1]. It has reached epidemic proportions with ever increasing numbers of patients and deaths,... |
10.1371/journal.pntd.0003595 | Modeling the Dynamics of Plasmodium vivax Infection and Hypnozoite Reactivation In Vivo | The dynamics of Plasmodium vivax infection is characterized by reactivation of hypnozoites at varying time intervals. The relative contribution of new P. vivax infection and reactivation of dormant liver stage hypnozoites to initiation of blood stage infection is unclear. In this study, we investigate the contribution ... | Plasmodium vivax is one of two major parasite species causing human disease. This parasite can lie dormant in the liver as a hypnozoite, before later reactivating to cause blood-stage infection. Treatment to eliminate the dormant hypnozoite stage relies mostly on a single drug—primaquine. Understanding the rate of prim... | Plasmodium vivax is one of the major agents of malaria infection, with around 2.5 billion people living in areas at risk of infection, and more than 70 million estimated annual infections [1–3]. P. vivax is generally less pathogenic than Plasmodium falciparum infection due to the absence of sequestration and cytoadhere... |
10.1371/journal.pbio.0060123 | Notch-Deficient Skin Induces a Lethal Systemic B-Lymphoproliferative Disorder by Secreting TSLP, a Sentinel for Epidermal Integrity | Epidermal keratinocytes form a highly organized stratified epithelium and sustain a competent barrier function together with dermal and hematopoietic cells. The Notch signaling pathway is a critical regulator of epidermal integrity. Here, we show that keratinocyte-specific deletion of total Notch signaling triggered a ... | Skin is the largest organ of the body, forming an elaborate barrier that prevents water loss and protects the internal environment from outside invaders. When this barrier is compromised, keratinocytes, keratin-producing epidermal cells, alert and recruit the immune cells to the site of the breach as part of an adaptiv... | The vertebrate skin is an organ in which keratinocytes, underlying mesenchymal cells, and circulating hematopoietic cells engage in reciprocal communication as they monitor organ integrity [1]. Therefore, skin is an ideal system in which to study how complex, multicompartmental networks function. Epidermal keratinocyte... |
10.1371/journal.ppat.1005961 | The Drosophila CD36 Homologue croquemort Is Required to Maintain Immune and Gut Homeostasis during Development and Aging | Phagocytosis is an ancient mechanism central to both tissue homeostasis and immune defense. Both the identity of the receptors that mediate bacterial phagocytosis and the nature of the interactions between phagocytosis and other defense mechanisms remain elusive. Here, we report that Croquemort (Crq), a Drosophila memb... | Phagocytosis is a first-line host defense mechanism against microbes. Interactions between phagocytosis and other immune mechanisms, such as the humoral response, however, remain elusive. Defective phagocytosis can lead to immune deficiencies and chronic auto-inflammation. Here, we show that Croquemort (Crq), a Drosoph... | Mounting appropriate immune responses against pathogens is critical for the survival of all animals. Mechanisms to both eliminate microbes and resolve infection by returning the immune system to basal activity are necessary to maintain an adequate and balanced immune response [1,2]. Alterations in these responses can l... |
10.1371/journal.pgen.1003205 | Next-Generation Sequencing Identifies the Danforth's Short Tail Mouse Mutation as a Retrotransposon Insertion Affecting Ptf1a Expression | The semidominant Danforth's short tail (Sd) mutation arose spontaneously in the 1920s. The homozygous Sd phenotype includes severe malformations of the axial skeleton with an absent tail, kidney agenesis, anal atresia, and persistent cloaca. The Sd mutant phenotype mirrors features seen in human caudal malformation syn... | Birth defects are the leading cause of infant mortality in the United States, accounting for 1 in 5 infant deaths annually. Birth defects that affect development of the caudal portion of the embryo can include malformations of the spine, such as spina bifida, and malformations of the kidneys and lower gastrointestinal ... | The Danforth's short tail (Sd) mouse mutation arose spontaneously in the early 1920s in an inbred mouse colony maintained in the laboratory of C.H. Danforth [1], [2]. The inbred line in which the Sd mutation arose was being maintained for study of a dominant but incompletely penetrant posterior duplication phenotype. D... |
10.1371/journal.pntd.0007139 | Water-induced strong protection against acute exposure to low subzero temperature of adult Aedes albopictus | As an important vector of dengue and Zika, Aedes albopictus has been the fastest spreading invasive mosquitoes in the world over the last 3–4 decades. Cold tolerance is important for survival and expansion of insects. Ae. albopictus adults are generally considered to be cold-intolerant that cannot survive at subzero te... | Aedes albopictus is one of two most important vectors for dengue and zika. During the last 3–4 decades, this mosquito has spread from native Asian area to all continents except Antarctica, becoming the most invasive mosquitoes which imposed extensive public health threat to human beings throughout the world. Cold toler... | Cold tolerance or cold hardiness, the ability of an insect to survive at low temperature, is important in defining the distribution and survival of insects. There are two different cold hardening in insects at present. One is accomplished by long term (weeks or months) cold acclimatization to overwinter that occurs in ... |
10.1371/journal.pcbi.1005680 | Interactions between the tumor and the blood systemic response of breast cancer patients | Although systemic immunity is critical to the process of tumor rejection, cancer research has largely focused on immune cells in the tumor microenvironment. To understand molecular changes in the patient systemic response (SR) to the presence of BC, we profiled RNA in blood and matched tumor from 173 patients. We desig... | We present a novel system (MIxT) to identify genes and pathways in the primary tumor that are tightly linked to genes and pathways in the patient systemic response (SR). These results suggest new ways to tackle and monitor the disease by looking outside the tumor and exploiting the patient SR.
| Breast cancer (BC) research has largely focused on understanding the intrinsic properties of the primary tumor in order to therapeutically target key molecular components that drive progression within the tumor epithelial cells [1]. For example, tamoxifen and trastuzumab target the estrogen and human epidermal growth f... |
10.1371/journal.pcbi.1003581 | Wikipedia Usage Estimates Prevalence of Influenza-Like Illness in the United States in Near Real-Time | Circulating levels of both seasonal and pandemic influenza require constant surveillance to ensure the health and safety of the population. While up-to-date information is critical, traditional surveillance systems can have data availability lags of up to two weeks. We introduce a novel method of estimating, in near-re... | Although influenza is largely avoidable through vaccination, between 3,000–50,000 deaths occur in the United States each year that are attributed to this disease. The Centers for Disease Control and Prevention continuously monitor the amount of influenza that is present in the American population and compiles this info... | Each year, there are an estimated 250,000–500,000 deaths worldwide that are attributed to seasonal influenza [1], with anywhere between 3,000–50,000 deaths occurring in the United States of America (US) [2]. In the US, the Centers for Disease Control and Prevention (CDC) continuously monitors the level of influenza-lik... |
10.1371/journal.pcbi.1003493 | A Novel Bayesian Method for Detection of APOBEC3-Mediated Hypermutation and Its Application to Zoonotic Transmission of Simian Foamy Viruses | Simian Foamy Virus (SFV) can be transmitted from non-human primates (NHP) to humans. However, there are no documented cases of human to human transmission, and significant differences exist between infection in NHP and human hosts. The mechanism for these between-host differences is not completely understood. In this p... | Simian Foamy Virus (SFV) is a very common retrovirus in monkeys. When an infected monkey bites a human it can transmit the virus to the human; however, there are no documented cases of human to human transmission. There also appear to be significant differences between infection in monkey and human hosts. The reason fo... | Simian foamy viruses (SFV) comprise a subfamily of retroviruses that naturally infect all primates examined with the notable exception of humans. In non-human primates (NHP), they show strong evidence of co-evolution with their hosts [1]. Persistent infection with SFV is ubiquitous in populations of free-ranging NHP [2... |
10.1371/journal.pntd.0006012 | Composition of the Schistosoma mansoni worm secretome: Identification of immune modulatory Cyclophilin A | The helminth Schistosoma mansoni modulates the infected host’s immune system to facilitate its own survival, by producing excretory/secretory molecules that interact with a variety of the host’s cell types including those of the immune system. Herein, we characterise the S. mansoni adult male worm secretome and identif... | Helminths are known for their ability to alter the host’s immune response in order to promote their survival. One such mechanism is the propensity of helminths to secrete molecules with immunomodulatory activity; such molecules alter various aspects of host immunity to the benefit of the parasite. Following detailed ch... | Schistosomiasis is one of the most prevalent parasitic diseases, with approximately 230 million people being infected globally [1]. To develop improved schistosomiasis control strategies, including new drugs and vaccines, it is important to advance our understanding of how the parasite manipulates the host’s immune sys... |
10.1371/journal.pcbi.1003446 | Leadership and Path Characteristics during Walks Are Linked to Dominance Order and Individual Traits in Dogs | Movement interactions and the underlying social structure in groups have relevance across many social-living species. Collective motion of groups could be based on an “egalitarian” decision system, but in practice it is often influenced by underlying social network structures and by individual characteristics. We inves... | How does a group of family dogs decide the direction of their collective movements? Is there a leader, or is decision-making based on an egalitarian system? Is leadership related to social dominance status? We collected GPS trajectory data from an owner and her six dogs during several walks. We found that dogs adjusted... | Groups that are not able to coordinate their actions and cannot reach a consensus on important events, such as where to go, will destabilise, and individuals will lose the benefits associated with being part of a group [1], [2]. Decision-making usually involves some form of leadership, i.e. ‘the initiation of new direc... |
10.1371/journal.ppat.1000898 | The Type III Effectors NleE and NleB from Enteropathogenic E. coli and OspZ from Shigella Block Nuclear Translocation of NF-κB p65 | Many bacterial pathogens utilize a type III secretion system to deliver multiple effector proteins into host cells. Here we found that the type III effectors, NleE from enteropathogenic E. coli (EPEC) and OspZ from Shigella, blocked translocation of the p65 subunit of the transcription factor, NF-κB, to the host cell n... | Bacterial intestinal pathogens have evolved distinct ways of colonizing the gut and causing disease. Enteropathogenic E. coli (EPEC) and its close relative enterohemorrhagic E. coli O157:H7 (EHEC) are extracellular pathogens that cause a characteristic lesion on the intestinal mucosa known as an attaching and effacing ... | Many bacterial pathogens have the ability to “inject” virulence effector proteins into the host cell using a type III secretion system (T3SS). The effector proteins perform a variety of functions that allow the pathogen to persist in the host and cause disease [1]. Enteropathogenic Escherichia coli (EPEC) and enterohem... |
10.1371/journal.pgen.1004831 | The Global Regulatory Architecture of Transcription during the Caulobacter Cell Cycle | Each Caulobacter cell cycle involves differentiation and an asymmetric cell division driven by a cyclical regulatory circuit comprised of four transcription factors (TFs) and a DNA methyltransferase. Using a modified global 5′ RACE protocol, we globally mapped transcription start sites (TSSs) at base-pair resolution, m... | The generation of diverse cell types occurs through two fundamental processes; asymmetric cell division and cell differentiation. Cells progress through these developmental changes guided by complex and layered genetic programs that lead to differential expression of the genome. To explore how a genetic program directs... | The regulation of timing and ordered progression of cell cycle events is central to the survival of any organism and is one of the fundamental processes of life. The gram-negative α-proteobacterium Caulobacter crescentus (Caulobacter, hereafter) is an important model organism for the study of the regulation of cell cyc... |
10.1371/journal.pgen.1005026 | Recombination between Homologous Chromosomes Induced by Unrepaired UV-Generated DNA Damage Requires Mus81p and Is Suppressed by Mms2p | DNA lesions caused by UV radiation are highly recombinogenic. In wild-type cells, the recombinogenic effect of UV partially reflects the processing of UV-induced pyrimidine dimers into DNA gaps or breaks by the enzymes of the nucleotide excision repair (NER) pathway. In this study, we show that unprocessed pyrimidine d... | Ultraviolet (UV) light is a ubiquitous agent of exogenous DNA damage. In normal cells, the nucleotide excision repair (NER) pathway is the primary mechanism for repair of UV-induced DNA lesions. Defects in the NER pathway are associated with the human disease xeroderma pigmentosum (XP), and XP patients are prone to ski... | The primary types of DNA lesions caused by UV radiation are pyrimidine dimers [1]. Although UV strongly stimulates recombination in wild-type yeast cells [2–5], it is unclear whether this stimulation in wild-type cells primarily reflects unexcised dimers, or single-stranded DNA gaps and double-stranded DNA breaks (DSBs... |
10.1371/journal.pbio.1000204 | The Mechanochemistry of Endocytosis | Endocytic vesicle formation is a complex process that couples sequential protein recruitment and lipid modifications with dramatic shape transformations of the plasma membrane. Although individual molecular players have been studied intensively, how they all fit into a coherent picture of endocytosis remains unclear. T... | Endocytosis is a complex and efficient process that cells utilize to take up nutrients and communicate with other cells. Eukaryotes have diverse endocytic pathways with two common features, mechanical and chemical. Proper mechanical forces are necessary to deform the plasma membrane and, eventually, pinch off the cargo... | During clathrin-mediated endocytosis, cells regulate plasma membrane molecular composition and internalize essential nutrients. This process involves coordination of biochemical activities with membrane shape changes [1],[2]. Multicolor real-time fluorescence microscopy studies in mammalian cells and yeast established ... |
10.1371/journal.pgen.1000883 | Multiple Signals Converge on a Differentiation MAPK Pathway | An important emerging question in the area of signal transduction is how information from different pathways becomes integrated into a highly coordinated response. In budding yeast, multiple pathways regulate filamentous growth, a complex differentiation response that occurs under specific environmental conditions. To ... | Signal integration is an essential feature of information flow through signal transduction pathways. The mechanisms by which signals from multiple pathways become integrated into a coordinated response remain unclear. We show that multiple pathways that regulate filamentous growth converge on a differentiation-dependen... | Signal transduction pathways regulate the response to extracellular stimuli. Complex behaviors frequently require the action of multiple pathways that act in concert to reprogram cell fate. In metazoan development for example, a highly regulated network of interactions between evolutionarily conserved pathways like Not... |
10.1371/journal.pgen.1005274 | The Human Blood Metabolome-Transcriptome Interface | Biological systems consist of multiple organizational levels all densely interacting with each other to ensure function and flexibility of the system. Simultaneous analysis of cross-sectional multi-omics data from large population studies is a powerful tool to comprehensively characterize the underlying molecular mecha... | Biological systems operate on multiple, intertwined organizational layers that can nowadays be accesses by high-throughput measurement methods, the so-called ‘omics’ technologies. A major aim in the field of systems biology is to understand the flow of biological information between the different layers at a systems le... | Blood is a connective tissue, which not only ensures nutrient and oxygen supply of all organs of the human body, but also the communication between them. Among the variety of key tasks performed by blood are immunological functions through white blood cells. Due to its diverse functionality, blood is heterogeneous and ... |
10.1371/journal.pcbi.1006236 | Optimal multi-source forecasting of seasonal influenza | Forecasting the emergence and spread of influenza viruses is an important public health challenge. Timely and accurate estimates of influenza prevalence, particularly of severe cases requiring hospitalization, can improve control measures to reduce transmission and mortality. Here, we extend a previously published mach... | In the United States, seasonal influenza causes thousands of deaths and hundreds of thousands of hospitalizations. The annual timing and burden of the flu season vary considerably with the severity of the circulating viruses. Epidemic forecasting can inform early and effective countermeasures to limit the human toll of... | Seasonal influenza epidemics annually result in significant global morbidity and mortality [1], and influenza pandemics can cause catastrophic levels of death, social disruption, and economic loss [2]. Early detection and forecasting of both emergence and peak epidemic activity can inform an effective allocation of res... |
10.1371/journal.pcbi.1002294 | Probabilistic Inference in General Graphical Models through Sampling in Stochastic Networks of Spiking Neurons | An important open problem of computational neuroscience is the generic organization of computations in networks of neurons in the brain. We show here through rigorous theoretical analysis that inherent stochastic features of spiking neurons, in combination with simple nonlinear computational operations in specific netw... | Experimental data from neuroscience have provided substantial knowledge about the intricate structure of cortical microcircuits, but their functional role, i.e. the computational calculus that they employ in order to interpret ambiguous stimuli, produce predictions, and derive movement plans has remained largely unknow... | We show in this article that noisy networks of spiking neurons are in principle able to carry out a quite demanding class of computations: probabilistic inference in general graphical models. More precisely, they are able to carry out probabilistic inference for arbitrary probability distributions over discrete random ... |
10.1371/journal.pgen.1004751 | Notch3 Interactome Analysis Identified WWP2 as a Negative Regulator of Notch3 Signaling in Ovarian Cancer | The Notch3 signaling pathway is thought to play a critical role in cancer development, as evidenced by the Notch3 amplification and rearrangement observed in human cancers. However, the molecular mechanism by which Notch3 signaling contributes to tumorigenesis is largely unknown. In an effort to identify the molecular ... | Notch pathway is important for many cellular activities, and its dysregulation leads to several diseases in humans, including cancer. Although Notch hyperactivity has been observed in many types of cancers, the interactome of Notch receptor remains largely unknown, especially for Notch3, which is involved in ovarian ca... | Notch signaling is a highly conserved cell-cell communication system present in multicellular organisms, and has been shown to be involved in cell fate decision, cell lineage specification, cell proliferation, and survival. Dysregulation of Notch signaling has been known to play a significant role in many diseases incl... |
10.1371/journal.pcbi.1004926 | Novel Computational Protocols for Functionally Classifying and Characterising Serine Beta-Lactamases | Beta-lactamases represent the main bacterial mechanism of resistance to beta-lactam antibiotics and are a significant challenge to modern medicine. We have developed an automated classification and analysis protocol that exploits structure- and sequence-based approaches and which allows us to propose a grouping of seri... | Beta-lactamases are bacterial proteins largely responsible for resistance to beta-lactam antibiotics and so pose a significant challenge to modern medicine. Whilst there are many studies cataloguing beta-lactamases, antibiotic screening has not always been consistent or comprehensive, causing confusion in the classific... | In this article we demonstrate the value of different clustering and analysis platforms for classifying an important superfamily of bacterial proteins, the beta-lactamases. Our approaches are based largely on the sequence properties of the relatives although structural information is considered for some analyses. The p... |
10.1371/journal.pgen.1008377 | BZU2/ZmMUTE controls symmetrical division of guard mother cell and specifies neighbor cell fate in maize | Intercellular communication in adjacent cell layers determines cell fate and polarity, thus orchestrating tissue specification and differentiation. Here we use the maize stomatal apparatus as a model to investigate cell fate determination. Mutations in ZmBZU2 (bizui2, bzu2) confer a complete absence of subsidiary cells... | In the grasses, individual stomatal complexes comprise a pair of dumbbell-shaped guard cells associated with two subsidiary cells and the pore, which together play essential roles in the exchange of CO2 and O2, in xylem transport, and in transpiration. However, little is known about grass stomatal complex development. ... | The development of the stomatal complex in maize (Zea mays), consisting of a pair of dumbbell-shaped guard cells (GCs) flanked by two subsidiary cells (SCs), provides an excellent model system to study the signals controlling fate determination of adjacent cells by intercellular communication. Unlike the two kidney-sha... |
10.1371/journal.pcbi.1002400 | Comparison of Insertional RNA Editing in Myxomycetes | RNA editing describes the process in which individual or short stretches of nucleotides in a messenger or structural RNA are inserted, deleted, or substituted. A high level of RNA editing has been observed in the mitochondrial genome of Physarum polycephalum. The most frequent editing type in Physarum is the insertion ... | RNA is an important biomolecule that is deeply involved in all aspects of molecular biology, such as protein production, gene regulation, and viral replication. However, many significant aspects such as the mechanism of RNA editing are not well understood. RNA editing is the process in which an organism's RNA is modifi... | RNA editing describes the process in which individual or short stretches of nucleotides in a messenger or structural RNA are inserted, deleted, or substituted. As a consequence, the final RNA product translated into a protein or functional by itself is different from its genomic template in organisms with RNA editing. ... |
10.1371/journal.pcbi.1004699 | Josephin Domain Structural Conformations Explored by Metadynamics in Essential Coordinates | The Josephin Domain (JD), i.e. the N-terminal domain of Ataxin 3 (At3) protein, is an interesting example of competition between physiological function and aggregation risk. In fact, the fibrillogenesis of Ataxin 3, responsible for the spinocerebbellar ataxia 3, is strictly related to the JD thermodynamic stability. Wh... | Proteins are fascinating molecular machines capable of organizing themselves into well-defined hierarchical structures through a huge number of conformational changes to accomplish a wide range of cellular functions. Protein conformational changes may be characterized by transitions from a low-energy conformation to an... | Proteins are fascinating molecular machines capable of organizing themselves into well-defined hierarchical structures through a huge number of conformational changes, in order to accomplish a wide range of cellular physiological functions. From an energy landscape point of view, protein conformational changes may be c... |
10.1371/journal.ppat.1003647 | Transcriptional Regulation of Culex pipiens Mosquitoes by Wolbachia Influences Cytoplasmic Incompatibility | Cytoplasmic incompatibility (CI) induced by the endosymbiont Wolbachia pipientis causes complex patterns of crossing sterility between populations of the Culex pipiens group of mosquitoes. The molecular basis of the phenotype is yet to be defined. In order to investigate what host changes may underlie CI at the molecul... | Wolbachia are maternally inherited bacteria that manipulate invertebrate reproduction. Cytoplasmic incompatibility is embryo death that occurs when males carrying Wolbachia mate with females that do not, or that carry a different Wolbachia variant; its mechanism is poorly understood. In Culex mosquitoes, in the presenc... | The intracellular maternally inherited bacterium Wolbachia pipientis, a widespread endosymbiont of invertebrates [1], can influence reproduction in arthropods. The most common manipulation is cytoplasmic incompatibility (CI). Sperm from Wolbachia-infected males are modified during maturation, prior to the loss of Wolba... |
10.1371/journal.ppat.1007050 | Isolation of a natural DNA virus of Drosophila melanogaster, and characterisation of host resistance and immune responses | Drosophila melanogaster has played a key role in our understanding of invertebrate immunity. However, both functional and evolutionary studies of host-virus interaction in Drosophila have been limited by a dearth of native virus isolates. In particular, despite a long history of virus research, DNA viruses of D. melano... | The fruit fly Drosophila melanogaster is a useful model species to study host-virus interaction and innate immunity. However, few natural viruses of Drosophila have been available for experiments, and no natural DNA viruses of Drosophila melanogaster have been available at all. Although infecting flies with viruses fro... | Studies of Drosophila melanogaster are central to our understanding of infection and immunity in insects. Moreover, many components of the Drosophila immune response, including parts of the JAK-STAT, IMD, and Toll (and perhaps RNA interference; RNAi) pathways are conserved from flies to mammals [1–8], making Drosophila... |
10.1371/journal.pntd.0006219 | Caregivers’ views on stigmatization and discrimination of people affected by leprosy in Ghana | Leprosy is a condition that has long been associated with stigma and discrimination, even when infected persons have been cured. This paper describes stigma and discrimination as viewed by caregivers who are associated with people affected by leprosy in Ghana.
A qualitative interview with semi-structured interviews wer... | In Ghana, the social interpretation of leprosy regardless of the language, culture and tradition engenders stigmatization and discrimination that leads to social rejection and exclusion of persons who have been cured of the disease. Often, these persons are cared for by relatives who happen to live with them in a confi... | The understanding and management of leprosy has seen tremendous improvement over the years. This accomplishment can be attributed to the increasing availability of the Multi-Drug Therapy (MDT) that has enabled many sufferers globally to be cured of the disease. Over the years in Ghana, efforts put in place have realize... |
10.1371/journal.pgen.1006183 | Overexpression of Mitochondria Mediator Gene TRIAP1 by miR-320b Loss Is Associated with Progression in Nasopharyngeal Carcinoma | The therapeutic strategy for advanced nasopharyngeal carcinoma (NPC) is still challenging. It is an urgent need to uncover novel treatment targets for NPC. Therefore, understanding the mechanisms underlying NPC tumorigenesis and progression is essential for the development of new therapeutic strategies. Here, we showed... | The therapeutic strategy for advanced nasopharyngeal carcinoma (NPC) is still challenging. The most urgent need for NPC is novel treatment targets. Therefore, understanding the mechanisms underlying NPC tumorigenesis and progression is essential for the development of new therapeutic strategies. Here, we identified TRI... | Nasopharyngeal carcinoma (NPC) is the most prevalent head and neck malignancy in Southeast Asia, especially in Southern China [1]. A majority of NPC patients are diagnosed at advanced stages, leading to approximately 30% of NPC patients developing treatment failure [2]. Although NPC is a heterogeneous disease, a combin... |
10.1371/journal.ppat.1004040 | Regulation of Human T-Lymphotropic Virus Type I Latency and Reactivation by HBZ and Rex | Human T lymphotropic virus type I (HTLV-I) infection is largely latent in infected persons. How HTLV-1 establishes latency and reactivates is unclear. Here we show that most HTLV-1-infected HeLa cells become senescent. By contrast, when NF-κB activity is blocked, senescence is averted, and infected cells continue to di... | Most HTLV-1-infected individuals are asymptomatic. It is thought that the proviral DNA is transcriptionally inert and HTLV-1 replicates through mitotic expansion of host cells. The evolving provirus integration patterns in HTLV-1 carriers, however, suggest new infection occurs continuously. Whether or how HTLV-1 establ... | Human T-lymphotropic virus type 1 (HTLV-1) is a complex human retrovirus that infect approximately 10–20 million people worldwide [1]. In 3–5% of infected individuals a malignancy of CD4+ T cells known as adult T-cell leukemia/lymphoma (ATL) develops over a course of several decades [2], [3]. Other diseases caused by H... |
10.1371/journal.pgen.1004177 | miR-100 Induces Epithelial-Mesenchymal Transition but Suppresses Tumorigenesis, Migration and Invasion | Whether epithelial-mesenchymal transition (EMT) is always linked to increased tumorigenicity is controversial. Through microRNA (miRNA) expression profiling of mammary epithelial cells overexpressing Twist, Snail or ZEB1, we identified miR-100 as a novel EMT inducer. Surprisingly, miR-100 inhibits the tumorigenicity, m... | Induction of epithelial-mesenchymal transition (EMT) in epithelial tumor cells has been shown to enhance migration, invasion and cancer ‘stemness’. Here we demonstrate that a miRNA downregulated in human breast tumors, miR-100, can simultaneously induce EMT and inhibit tumorigenesis, migration and invasion through dire... | Epithelial-mesenchymal transition (EMT) is regulated by transcription factors [1], [2], extracellular ligands [3] and microRNAs (miRNAs) [4]–[9]. It has been proposed that inducing EMT in epithelial tumor cells enhances migration, invasion and dissemination, whereas the mesenchymal-epithelial transition (MET) process f... |
10.1371/journal.pmed.1002322 | Long-term health status and trajectories of seriously injured patients: A population-based longitudinal study | Improved understanding of the quality of survival of patients is crucial in evaluating trauma care, understanding recovery patterns and timeframes, and informing healthcare, social, and disability service provision. We aimed to describe the longer-term health status of seriously injured patients, identify predictors of... | Improvements in trauma care have improved the chances of surviving serious injury, requiring a shift in focus to better understanding how well people recover from injury and how long this takes.
Longitudinal studies of the long-term health outcomes of seriously injured people are few. This study was undertaken to close... | The implementation of organised trauma systems has enabled considerable reductions in injury-related mortality in high-income countries [1–3]. With improving survival rates comes the potential for greater numbers of people living with long-term injury impacts, including reduced health status or health-related quality o... |
10.1371/journal.ppat.1000418 | Molecular Mechanisms of Recombination Restriction in the Envelope Gene of the Human Immunodeficiency Virus | The ability of pathogens to escape the host's immune response is crucial for the establishment of persistent infections and can influence virulence. Recombination has been observed to contribute to this process by generating novel genetic variants. Although distinctive recombination patterns have been described in many... | Recombination allows mixing portions of genomes of different origins, generating chimeric genes and genomes. With respect to the random generation of new mutations, it can lead to the simultaneous insertion of several substitutions, introducing more drastic changes in the genome. Furthermore, recombination is expected ... | Pathogens, and viruses in particular, are subject to strong selective pressures during infection and often have characteristically high degrees of genetic variation [1]. Recombination is an important evolutionary mechanism that contributes to this genetic diversification. By creating novel combinations of pre-existing ... |
10.1371/journal.pgen.1003693 | QTL Analysis of High Thermotolerance with Superior and Downgraded Parental Yeast Strains Reveals New Minor QTLs and Converges on Novel Causative Alleles Involved in RNA Processing | Revealing QTLs with a minor effect in complex traits remains difficult. Initial strategies had limited success because of interference by major QTLs and epistasis. New strategies focused on eliminating major QTLs in subsequent mapping experiments. Since genetic analysis of superior segregants from natural diploid strai... | Most traits of organisms are determined by an interplay of different genes interacting in a complex way. For instance, nearly all industrially-important traits of the yeast Saccharomyces cerevisiae are complex traits. We have analyzed high thermotolerance, which is important for industrial fermentations, reducing cooli... | Many genetic traits are quantitative and show complex inheritance. Because these traits are so prevalent in nature, understanding the underlying factors is important for various biological fields and for applications like industrial biotechnology and agricultural practice [1]. Recently, baker's yeast Saccharomyces cere... |
10.1371/journal.pntd.0002847 | In Vitro and In Vivo Trypanocidal Activity of H2bdtc-Loaded Solid Lipid Nanoparticles | The parasite Trypanosoma cruzi causes Chagas disease, which remains a serious public health concern and continues to victimize thousands of people, primarily in the poorest regions of Latin America. In the search for new therapeutic drugs against T. cruzi, here we have evaluated both the in vitro and the in vivo activi... | The protozoan parasite Trypanosoma cruzi causes Chagas disease, a condition that affects the poorest regions of Latin America mainly. The chronic phase of this disease disables thousands of patients, constituting an important public health issue. The pharmacotherapy that is currently applied to treat the disease emerge... | T. cruzi parasites are transmitted by insect vectors (triatomine bugs). T.cruzi is the causative agent of Chagas disease, which is silent and can remain asymptomatic for years [1], [2], [3]. A century after its discovery, this disease remains a serious public health issue—it is closely associated with human poverty and... |
10.1371/journal.pgen.1004650 | Topoisomerase II Is Required for the Proper Separation of Heterochromatic Regions during Drosophila melanogaster Female Meiosis | Heterochromatic homology ensures the segregation of achiasmate chromosomes during meiosis I in Drosophila melanogaster females, perhaps as a consequence of the heterochromatic threads that connect achiasmate homologs during prometaphase I. Here, we ask how these threads, and other possible heterochromatic entanglements... | Proper chromosome segregation during egg and sperm development is crucial to prevent birth defects and miscarriage. During chromosome replication, DNA entanglements are created that must be resolved before chromosomes can fully separate. In the oocytes of the fruit fly Drosophila melanogaster, DNA entanglements persist... | In most organisms, crossing over between homologs during meiosis ensures their faithful segregation at the first meiotic division. However, in Drosophila melanogaster females, the 4th chromosomes are always achiasmate, and the X chromosomes normally fail to crossover in 6–10% of oocytes [1]. Nonetheless, Drosophila fem... |
10.1371/journal.pntd.0005272 | The Antiviral RNAi Response in Vector and Non-vector Cells against Orthobunyaviruses | Vector arthropods control arbovirus replication and spread through antiviral innate immune responses including RNA interference (RNAi) pathways. Arbovirus infections have been shown to induce the exogenous small interfering RNA (siRNA) and Piwi-interacting RNA (piRNA) pathways, but direct antiviral activity by these ho... | A number of orthobunyaviruses such as Oropouche virus, La Crosse virus and Schmallenberg virus are important global human or animal pathogens transmitted by arthropod vectors. Further understanding of the antiviral control mechanisms in arthropod vectors is key to developing novel prevention strategies based on prevent... | Orthobunyaviruses are endemic in tropical and subtropical regions worldwide and are transmitted by mosquitoes, midges, ticks or other arthropods. The Orthobunyavirus genus within the Bunyaviridae family comprises at least 30 viruses that can cause disease in humans, including Oropouche virus (OROV; febrile illness), La... |
10.1371/journal.ppat.1002747 | Proteomic Profiling of the TRAF3 Interactome Network Reveals a New Role for the ER-to-Golgi Transport Compartments in Innate Immunity | Tumor Necrosis Factor receptor-associated factor-3 (TRAF3) is a central mediator important for inducing type I interferon (IFN) production in response to intracellular double-stranded RNA (dsRNA). Here, we report the identification of Sec16A and p115, two proteins of the ER-to-Golgi vesicular transport system, as novel... | In response to pathogens, such as viruses and bacteria, infected cells defend themselves by generating a set of cytokines called type I interferon (IFN). Since Type I IFN (namely IFN alpha and beta) are potent antiviral agents, understanding the cellular mechanisms by which infected cells produce type I IFN is required... | Following exposure to pathogen-associated molecular patterns (PAMPs), the innate immune response and the subsequent inflammatory reaction rely on evolutionarily conserved receptors termed pattern-recognition receptors (PRRs) [1]. These signalling receptors can be expressed at the cellular membrane (Toll-like receptors ... |
10.1371/journal.pbio.1000494 | Chromosomal Redistribution of Male-Biased Genes in Mammalian Evolution with Two Bursts of Gene Gain on the X Chromosome | Mammalian X chromosomes evolved under various mechanisms including sexual antagonism, the faster-X process, and meiotic sex chromosome inactivation (MSCI). These forces may contribute to nonrandom chromosomal distribution of sex-biased genes. In order to understand the evolution of gene content on the X chromosome and ... | Some evolutionary theories predict that the X chromosome will be enriched for genes with male functions. However, recent studies showed there had been gene traffic in which autosomal male-biased genes were retroposed from X-linked parental genes. A question remains about whether this pattern also holds for all types of... | In mammals and Drosophila, the X chromosome usually differs dramatically from autosomes since it is hemizygous in males [1]. Sexual antagonism (beneficial for one sex, but deleterious for the other) enriches male-biased genes on the X chromosome, if alleles are generally recessive, and on the autosome if they are gener... |
10.1371/journal.pcbi.0030141 | A Balanced Memory Network | A fundamental problem in neuroscience is understanding how working memory—the ability to store information at intermediate timescales, like tens of seconds—is implemented in realistic neuronal networks. The most likely candidate mechanism is the attractor network, and a great deal of effort has gone toward investigatin... | A critical component of cognition is memory—the ability to store information, and to readily retrieve it on cue. Existing models postulate that recalled items are represented by self-sustained activity; that is, they are represented by activity that can exist in the absence of input. These models, however, are incomple... | A critical component of any cognitive system is working memory—a mechanism for storing information about past events, and for accessing that information at later times. Without such a mechanism, even simple tasks, such as deciding whether to wear a heavy jacket or a light sweater after hearing the weather report, would... |
10.1371/journal.pmed.1002203 | Zika Virus Infection as a Cause of Congenital Brain Abnormalities and Guillain–Barré Syndrome: Systematic Review | The World Health Organization (WHO) stated in March 2016 that there was scientific consensus that the mosquito-borne Zika virus was a cause of the neurological disorder Guillain–Barré syndrome (GBS) and of microcephaly and other congenital brain abnormalities based on rapid evidence assessments. Decisions about causali... | In 2015, the mosquito-borne Zika virus caused epidemics of a mild viral illness for the first time in Brazil and then other countries in Latin America and the Caribbean.
In mid to late 2015, clinicians in northeastern Brazil reported unexpected increases in the numbers of babies born with abnormally small heads (microc... | An “explosive pandemic of Zika virus infection” [1] in 2015 caught the world by surprise. The Pan American Health Organization (PAHO) and World Health Organization (WHO) published an alert about a possible association with increases in reports of congenital abnormalities and Guillain–Barré syndrome (GBS) on December 1,... |
10.1371/journal.pntd.0006272 | Management of severe strongyloidiasis attended at reference centers in Spain | Strongyloides stercoralis is a globally distributed nematode that causes diverse clinical symptoms in humans. Spain, once considered an endemic country, has experienced a recent increase in imported cases. The introduction of serology helps diagnosis and is currently replacing microbiological techniques in some setting... | Strongyloides stercoralis is a globally distributed worm. It has a free living cycle in wet moist soils, and an autoinfecting cycle affecting humans in their lungs, bowels and skin. Strongyloidiasis is the name of the infection caused by S.stercoralis and it can vary from an indolent state, with no symptoms at all, to ... | Strongyloidiasis is an infection caused by Strongyloides stercoralis. Other Strongyloides spp. include S. fuelleborni, which infects some non-human primates and may cause self-limited disease in humans. S.stercoralis is widely distributed, affecting up to 370 million people worldwide according to recent estimates [1, 2... |
10.1371/journal.pntd.0004135 | Seasonal and Spatial Dynamics of the Primary Vector of Plasmodium knowlesi within a Major Transmission Focus in Sabah, Malaysia | The simian malaria parasite Plasmodium knowlesi is emerging as a public health problem in Southeast Asia, particularly in Malaysian Borneo where it now accounts for the greatest burden of malaria cases and deaths. Control is hindered by limited understanding of the ecology of potential vector species.
We conducted a on... | The first natural infection of Plasmodium knowlesi was reported 40 years ago. At that time it was perceived that the infection would not affect humans. However, now P. knowlesi is the predominant malaria species (38% of the cases) infecting people in Malaysia and is a notable obstacle to malaria elimination in the coun... | Significant progress has been made fighting malaria in the last decade, decreasing the incidence of cases and mortality by 30% and 47% respectively on a global scale [1] and reducing cases by 76% in Asia Pacific countries [2]. The development and use of better tools for diagnostics and treatment [3] coupled with substa... |
10.1371/journal.pbio.1001666 | Hypoxic Regulation of Hand1 Controls the Fetal-Neonatal Switch in Cardiac Metabolism | Cardiomyocytes are vulnerable to hypoxia in the adult, but adapted to hypoxia in utero. Current understanding of endogenous cardiac oxygen sensing pathways is limited. Myocardial oxygen consumption is determined by regulation of energy metabolism, which shifts from glycolysis to lipid oxidation soon after birth, and is... | Regulation of oxygen usage in cardiomyocytes is of great medical interest, because adult cardiac tissue is extremely vulnerable to hypoxia during myocardial infarction and cardiac surgery. While some progress has been made toward protecting cardiomyocytes from hypoxia in these circumstances, it has been limited by a la... | Adult cardiomyocytes are particularly vulnerable to hypoxia, which can result in cellular dysfunction and death. While some progress has been made towards protecting cardiomyocytes from the deleterious effects of low oxygen levels, cardiac ischaemia continues to result in high mortality and remains a clinical challenge... |
10.1371/journal.pbio.1001685 | Coevolution and the Effects of Climate Change on Interacting Species | Recent studies suggest that environmental changes may tip the balance between interacting species, leading to the extinction of one or more species. While it is recognized that evolution will play a role in determining how environmental changes directly affect species, the interactions among species force us to conside... | Recent studies suggest that environmental changes may tip the balance between species that interact with each other, leading to the extinction of one or more species. While it is recognized that evolution will alter the way environmental changes directly affect individual species, the interactions between species force... | Climatic changes, or indeed any change in the environment, have the potential to cause the local extinction of species, and to alter community composition and ecosystem functioning [1]. Numerous models have been used to predict how the density and geographical range of species will be affected by climate change, with m... |
10.1371/journal.pcbi.1002365 | Novel Approach to Meta-Analysis of Microarray Datasets Reveals Muscle Remodeling-related Drug Targets and Biomarkers in Duchenne Muscular Dystrophy | Elucidation of new biomarkers and potential drug targets from high-throughput profiling data is a challenging task due to a limited number of available biological samples and questionable reproducibility of differential changes in cross-dataset comparisons. In this paper we propose a novel computational approach for dr... | Comparison of gene expression in diseased and normal tissue is a powerful tool of studying processes involved in pathogenesis and searching for potential drug targets and biomarkers of the disease's progression and treatment outcome. We have developed a novel approach for systematic knowledge-driven analysis of gene ex... | Microarray-based expression profiling is a widely used, quick and inexpensive method to obtain information about the specific diseases. A traditional approach when searching for drug targets or candidate biomarkers for a specific disease is to look for genes differentially expressed between the disease and appropriate ... |
10.1371/journal.ppat.1002618 | Modeling of the N-Glycosylated Transferrin Receptor Suggests How Transferrin Binding Can Occur within the Surface Coat of Trypanosoma brucei | The transferrin receptor of bloodstream form Trypanosoma brucei is a heterodimer encoded by expression site associated genes 6 and 7. This low-abundance glycoprotein with a single glycosylphosphatidylinositol membrane anchor and eight potential N-glycosylation sites is located in the flagellar pocket. The receptor is e... | The tsetse fly transmitted parasite that causes human African trypanosomiasis, or sleeping sickness, scavenges iron from the bloodstream of the infected individual so that it can live, multiply and ultimately cause disease. To do this, it places a glycoprotein (a protein with carbohydrate chains attached) called the tr... | The tsetse-transmitted Trypanosoma brucei group of parasites cause human African trypanosomiasis and nagana in cattle and constitute a serious health problem for people and livestock in 36 countries of sub-Saharan Africa. T. brucei exists in the mammalian host as the bloodstream form trypomastigote and in the midgut of... |
10.1371/journal.ppat.0030139 | Hepatitis C Virus Induces E6AP-Dependent Degradation of the Retinoblastoma Protein | Hepatitis C virus (HCV) is a positive-strand RNA virus that frequently causes persistent infections and is uniquely associated with the development of hepatocellular carcinoma. While the mechanism(s) by which the virus promotes cancer are poorly defined, previous studies indicate that the HCV RNA-dependent RNA polymera... | Persons infected with hepatitis C virus (HCV) are at increased risk for liver cancer. This is remarkable because HCV is an RNA virus with replication confined to the cytoplasm and no potential for integration of its genome into host cell DNA. While it is likely that chronic inflammation contributes to liver cancer, pri... | Among viruses that infect the human liver, hepatitis C virus (HCV) is a leading cause of morbidity and mortality worldwide [1]. Chronic infection with HCV is a major risk factor for the development of cirrhosis as well as hepatocellular carcinoma (HCC) [2,3]. The incidence of this cancer has increased dramatically in r... |
10.1371/journal.pbio.2004538 | Functional characterization of adaptive variation within a cis-regulatory element influencing Drosophila melanogaster growth | Gene expression variation is a major contributor to phenotypic diversity within species and is thought to play an important role in adaptation. However, examples of adaptive regulatory polymorphism are rare, especially those that have been characterized at both the molecular genetic level and the organismal level. In t... | Much of the phenotypic variation that is observed within species is thought to be caused by variation in gene expression. Variants within cis-regulatory elements, which affect the expression of nearby genes within the same DNA strand, are thought to be an abundant resource upon which natural selection can act. Understa... | Gene expression variation is extensive both within and between species and is believed to underlie much of the phenotypic diversity observed among species, as well as among populations of the same species [1–2]. Furthermore, expression variation is thought to provide an abundant source of material for adaptation, as al... |
10.1371/journal.pmed.1002217 | Patient Safety Incidents Involving Sick Children in Primary Care in England and Wales: A Mixed Methods Analysis | The UK performs poorly relative to other economically developed countries on numerous indicators of care quality for children. The contribution of iatrogenic harm to these outcomes is unclear. As primary care is the first point of healthcare contact for most children, we sought to investigate the safety of care provide... | Children receive most of their healthcare in the community setting rather than the hospital setting, but very little is known about the safety of this care.
There are signs from previous research that the UK is providing poorer quality pediatric care than its similarly economically developed counterparts.
The purpose o... | The United Kingdom (UK) has one of the highest child mortality rates in Western Europe: the 2,000 excess child deaths that occur annually compare unfavorably with Sweden, which is the best performing country in this region [1–3]. Intercountry variability in rates of child mortality is a well-described global problem. D... |
10.1371/journal.pgen.1007418 | Yeast heterochromatin regulators Sir2 and Sir3 act directly at euchromatic DNA replication origins | Most active DNA replication origins are found within euchromatin, while origins within heterochromatin are often inactive or inhibited. In yeast, origin activity within heterochromatin is negatively controlled by the histone H4K16 deacetylase, Sir2, and at some heterochromatic loci also by the nucleosome binding protei... | When a cell divides, it must copy or “replicate” its DNA. DNA replication starts at chromosomal regions called origins when a collection of replication proteins gains local access to unwind the two DNA strands. Chromosomal DNA is packaged into a protein-DNA complex called chromatin and there are two major structurally ... | In eukaryotic cells, efficient genome duplication requires the function of multiple DNA replication origins distributed over the length of each chromosome [1–5]. Origins are selected by a series of steps in late M- to G1-phase during which the origin recognition complex (ORC) binds directly to DNA and recruits the Cdc6... |
10.1371/journal.pcbi.1007225 | β-Methylamino-L-alanine substitution of serine in SOD1 suggests a direct role in ALS etiology | Exposure to the environmental toxin β-methylamino-L-alanine (BMAA) is linked to amyotrophic lateral sclerosis (ALS), but its disease-promoting mechanism remains unknown. We propose that incorporation of BMAA into the ALS-linked protein Cu,Zn superoxide dismutase (SOD1) upon translation promotes protein misfolding and a... | The environmental toxin β-methylamino-L-alanine (BMAA) has been linked to cases of amyotrophic lateral sclerosis (ALS), but the role of this compound in disease is unknown. We propose that BMAA becomes incorporated into the ALS-linked protein Cu,Zn superoxide dismutase (SOD1), destabilizing it and promoting formation o... | Amyotrophic lateral sclerosis (ALS) is a motor neurodegenerative disease that affects 2–9 individuals per 100,000 every year [1]. More than 150 mutations to Cu,Zn superoxide dismutase (SOD1) have been associated with ALS. Misfolded and aggregated SOD1 has been found in motor neurons in both sporadic and familial ALS [2... |
10.1371/journal.pntd.0000238 | Trypanosoma brucei rhodesiense Transmitted by a Single Tsetse Fly Bite in Vervet Monkeys as a Model of Human African Trypanosomiasis | We have investigated the pathogenicity of tsetse (Glossina pallidipes)-transmitted cloned strains of Trypanosoma brucei rhodesiense in vervet monkeys. Tsetse flies were confirmed to have mature trypanosome infections by xenodiagnosis, after which nine monkeys were infected via the bite of a single infected fly. Chancre... | Sleeping sickness is caused by a species of trypanosome blood parasite that is transmitted by tsetse flies. To understand better how infection with this parasite leads to disease, we provide here the most detailed description yet of the course of infection and disease onset in vervet monkeys. One infected tsetse fly wa... | In human African trypanosomiasis (HAT), the use of animal models has contributed enormously to what is currently known about the relationships between disease duration, parasite invasion of different body systems and the potential of resultant host clinical and biological changes as diagnostic and disease staging marke... |
10.1371/journal.pbio.1000376 | A Neuromedin U Receptor Acts with the Sensory System to Modulate Food Type-Dependent Effects on C. elegans Lifespan | The type of food source has previously been shown to be as important as the level of food intake in influencing lifespan. Here we report that different Escherichia coli food sources alter Caenorhabditis elegans lifespan. These effects are modulated by different subsets of sensory neurons, which act with nmur-1, a homol... | Work on the model organisms C. elegans and D. melanogaster has contributed important and often surprising insights into the factors that determine lifespan. One intriguing finding is that lifespan in both animals can be extended or shortened by interfering with the function of neurons that smell or taste food. Indeed, ... | The sensory systems of Caenorhabditis elegans and Drosophila melanogaster have been shown to modulate the lifespan of these animals [1]–[4]. This sensory influence involves subsets of gustatory and olfactory neurons [2],[3] that either shorten or lengthen lifespan, which suggests that (i) some of the cues that affect l... |
10.1371/journal.ppat.1004934 | Pseudomonas aeruginosa ExoT Induces Atypical Anoikis Apoptosis in Target Host Cells by Transforming Crk Adaptor Protein into a Cytotoxin | Previously, we demonstrated that Pseudomonas aeruginosa ExoT induces potent apoptosis in host epithelial cells in a manner that primarily depends on its ADP-ribosyltransferase domain (ADPRT) activity. However, the mechanism underlying ExoT/ADPRT-induced apoptosis remains undetermined. We now report that ExoT/ADPRT disr... | We have previously demonstrated that ExoT is both necessary and sufficient to induce potent apoptosis in host epithelial cells in a manner that depends primarily on its ADP-ribosyltransferase (ADPRT) domain activity. However, the molecular basis underlying ExoT/ADPRT-induced apoptosis remains unknown. In this study, we... | Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen that targets immunocompromised individuals and those with injured epithelia, making it one of the leading causes of nosocomial infections and the leading cause of morbidity and mortality in cystic fibrosis patients [1–3]. P. aeruginosa boasts a large arse... |
10.1371/journal.ppat.1006123 | EV71 3D Protein Binds with NLRP3 and Enhances the Assembly of Inflammasome Complex | Activation of NLRP3 inflammasome is important for effective host defense against invading pathogen. Together with apoptosis-associated speck-like protein containing CARD domain (ASC), NLRP3 induces the cleavage of caspase-1 to facilitate the maturation of interleukin-1beta (IL-1β), an important pro-inflammatory cytokin... | The immune system protects the infected host and clears the invading pathogens. An important part of the innate immune response is the activation of NLRP3 inflammasome, which is induced upon exposure to pathogens. Activated inflammasome subsequently regulates the maturation of IL-1β that plays an important role in infl... | The innate immune system is a highly conserved signaling network important for protection of the infected host and clearance of the invading pathogen [1]. Recognition of the pathogen-associate molecular patterns (PAMPS) is dependent on host pattern recognition receptors (PRRs), whose activation results in the productio... |
10.1371/journal.pbio.1000349 | Pro-Survival Role for Parkinson's Associated Gene DJ-1 Revealed in Trophically Impaired Dopaminergic Neurons | The mechanisms underlying the selective death of substantia nigra (SN) neurons in Parkinson disease (PD) remain elusive. While inactivation of DJ-1, an oxidative stress suppressor, causes PD, animal models lacking DJ-1 show no overt dopaminergic (DA) neuron degeneration in the SN. Here, we show that aging mice lacking ... | The major pathological event in Parkinson disease is the loss of dopaminergic neurons in a midbrain structure, the substantia nigra. The study of familial Parkinson disease has uncovered several disease-associated genes, including DJ-1. Subsequent studies have suggested that the DJ-1 protein is a suppressor of oxidativ... | Specific and progressive loss of substantia nigra (SN) neurons is the central pathogenic event in Parkinson disease (PD), the most common movement neurodegenerative disorder, characterized by tremor, rigidity, and bradykinesia. A second pathological feature of PD is the presence of aggregated alpha-synuclein (Lewy Bodi... |
10.1371/journal.pntd.0000895 | Elimination of Active Trachoma after Two Topical Mass Treatments with Azithromycin 1.5% Eye Drops | Following an epidemiological study carried out in 2006 showing a high prevalence of blinding trachoma in the Far North Region of Cameroon, a trachoma elimination programme using the SAFE strategy was initiated: three yearly trachoma mass treatments were to be performed.
The entire district population (120,000 persons) ... | Trachoma is the leading cause of infectious blindness worldwide, accounting for 1.3 million cases of blindness. Although it has disappeared in many regions of the world, trachoma is still endemic in Africa, Eastern Mediterranean, Latin America, Asia, and Australia. The WHO has currently set a target of 2020 for control... | Trachoma is caused by Chlamydia trachomatis and it is spread by direct contact with eye, nose, and throat secretions from affected individuals or by contact with objects, such as towels and/or washcloths, which have had similar contact with these secretions [1], [2]. Flies can also be a route of mechanical transmission... |
10.1371/journal.pgen.1002302 | Insights into Hox Protein Function from a Large Scale Combinatorial Analysis of Protein Domains | Protein function is encoded within protein sequence and protein domains. However, how protein domains cooperate within a protein to modulate overall activity and how this impacts functional diversification at the molecular and organism levels remains largely unaddressed. Focusing on three domains of the central class D... | Proteins perform essential regulatory functions, including control of gene transcription, a process central to development, evolution, and disease. While protein domains important for protein activity have been identified, how they act together to define the activity of a protein remains poorly explored. The predominan... | How the diversity of animal body plans is established remains a central question in developmental and evolutionary biology [1], [2]. A key step towards understanding the molecular basis underlying diversity is to decipher mechanisms controlling proper genome expression, and how variations in these mechanisms have been ... |
10.1371/journal.pcbi.1007090 | Connecting signaling and metabolic pathways in EGF receptor-mediated oncogenesis of glioblastoma | As malignant transformation requires synchronization of growth-driving signaling (S) and metabolic (M) pathways, defining cancer-specific S-M interconnected networks (SMINs) could lead to better understanding of oncogenic processes. In a systems-biology approach, we developed a mathematical model for SMINs in mutated E... | Complex and highly dynamic interconnected networks allow cancer to take different routes and circumvent chemotherapy. Therefore, understanding these context-specific networks and their dynamics of molecular interactions driven by different oncogenic signaling and metabolic pathways is very much needed to predict drug t... | Diseases like cancer involve a large range of components that interact via complex and highly dynamic networks [1–3], and are interconnected with biochemical pathways [4–7]. These multipath interconnections may allow cancer and other diseases to take alternate routes and bypass the effects of therapeutic interventions.... |
10.1371/journal.pcbi.1003162 | Viral Proteins Originated De Novo by Overprinting Can Be Identified by Codon Usage: Application to the “Gene Nursery” of Deltaretroviruses | A well-known mechanism through which new protein-coding genes originate is by modification of pre-existing genes, e.g. by duplication or horizontal transfer. In contrast, many viruses generate protein-coding genes de novo, via the overprinting of a new reading frame onto an existing (“ancestral”) frame. This mechanism ... | How does novelty originate in nature? It is commonly thought that new genes are generated mainly by modifications of existing genes (the “tinkering” model). In contrast, we have shown recently that in viruses, numerous genes are generated entirely de novo (“from scratch”). The role of these genes remains underexplored,... | Modification of existing genes, such as by duplication or fusion, is a common and well-understood mechanism by which protein-coding genes originate [1], [2]. In contrast, we have shown that viruses generate many proteins de novo (hereafter called “de novo proteins”) [3], [4]. Preliminary observations indicate that thes... |
10.1371/journal.ppat.1002143 | The Cost of Virulence: Retarded Growth of Salmonella Typhimurium Cells Expressing Type III Secretion System 1 | Virulence factors generally enhance a pathogen's fitness and thereby foster transmission. However, most studies of pathogen fitness have been performed by averaging the phenotypes over large populations. Here, we have analyzed the fitness costs of virulence factor expression by Salmonella enterica subspecies I serovar ... | Pathogenic bacteria require virulence factors to foster growth and survival of the pathogen within the host. Therefore, virulence factor expression is generally assumed to enhance the pathogen's fitness. However, most studies of pathogen fitness have been performed by averaging the phenotypes over large pathogen popula... | The ability to infect a host and elicit disease is dictated by the virulence factors expressed by a given pathogen. This may include, but is not limited to, protective factors neutralizing antibacterial defenses, enzymes involved in nutrient acquisition within the host, regulators of virulence factor expression and tox... |
10.1371/journal.pgen.1002142 | A Two-Stage Meta-Analysis Identifies Several New Loci for Parkinson's Disease | A previous genome-wide association (GWA) meta-analysis of 12,386 PD cases and 21,026 controls conducted by the International Parkinson's Disease Genomics Consortium (IPDGC) discovered or confirmed 11 Parkinson's disease (PD) loci. This first analysis of the two-stage IPDGC study focused on the set of loci that passed g... | This paper describes the largest case-control analysis of Parkinson's disease to date, with a combined sample set of over 12,000 cases and 21,000 controls. After combining our findings with an independent replication dataset of more than 3,000 cases and 29,000 controls, we found five additional PD risk loci in addition... | Until the recent developments of high throughput genotyping and genome-wide association (GWA) studies, little was known of the genetics of typical Parkinson's disease (PD). Studies of the genetic basis of familial forms of PD first identified rare highly penetrant mutations in LRKK2 [1], [2], PINK1 [3], SNCA [4], PARK2... |
10.1371/journal.pgen.1004729 | Identification of Rare Causal Variants in Sequence-Based Studies: Methods and Applications to VPS13B, a Gene Involved in Cohen Syndrome and Autism | Pinpointing the small number of causal variants among the abundant naturally occurring genetic variation is a difficult challenge, but a crucial one for understanding precise molecular mechanisms of disease and follow-up functional studies. We propose and investigate two complementary statistical approaches for identif... | Sequencing technologies allow identification of genetic variants down to single base resolution for a whole human genome. The vast majority of these variants (over 90%) are rare, with population frequencies less than 1%. Furthermore, in a specific study, many of the variants identified are not associated with the disea... | The tremendous progress in massively parallel sequencing (aka ‘next generation’ sequencing) technologies enables investigators to obtain genetic information down to single base resolution on a genome-wide scale in a rapid and cost efficient manner [1], [2], [3]. The resulting datasets are high dimensional and very spar... |
10.1371/journal.ppat.1004870 | Sigma Factor SigB Is Crucial to Mediate Staphylococcus aureus Adaptation during Chronic Infections | Staphylococcus aureus is a major human pathogen that causes a range of infections from acute invasive to chronic and difficult-to-treat. Infection strategies associated with persisting S. aureus infections are bacterial host cell invasion and the bacterial ability to dynamically change phenotypes from the aggressive wi... | Staphylococcus aureus is a frequent pathogen of severe invasive infections that can develop into chronicity and become extremely difficult to eradicate. Chronic infections have been highly associated with altered bacterial phenotypes, i.e., the small colony variants (SCVs) that dynamically appear after bacterial host c... | S. aureus is a major human pathogen that can infect almost every organ in the body and cause destructive infections [1]. Besides tissue damage the ability to develop persisting and therapy-refractory infections poses a major problem in clinical practice, such as endovascular and bone infections [2,3]. Chronic infection... |
10.1371/journal.ppat.1000790 | Lethal Antibody Enhancement of Dengue Disease in Mice Is Prevented by Fc Modification | Immunity to one of the four dengue virus (DV) serotypes can increase disease severity in humans upon subsequent infection with another DV serotype. Serotype cross-reactive antibodies facilitate DV infection of myeloid cells in vitro by promoting virus entry via Fcγ receptors (FcγR), a process known as antibody-dependen... | Dengue is the most common vector-borne viral disease of humans, with over 3 billion people at risk for infection and 50–100 million infections in tropical and subtropical regions each year. Dengue virus (DV) causes a spectrum of clinical disease ranging from an acute debilitating, self-limited febrile illness (DF) to a... | The four serotypes of dengue virus (DV) are mosquito-borne flaviviruses responsible for 50–100 million human infections annually. Primary infection in individuals over the age of one year with any DV serotype is usually asymptomatic or results in self-limited dengue fever (DF), but secondary infection with another DV s... |
10.1371/journal.pntd.0001419 | In Vivo Expression of Salmonella enterica Serotype Typhi Genes in the Blood of Patients with Typhoid Fever in Bangladesh | Salmonella enterica serotype Typhi is the cause of typhoid fever. It is a human-restricted pathogen, and few data exist on S. Typhi gene expression in humans.
We applied an RNA capture and amplification technique, Selective Capture of Transcribed Sequences (SCOTS), and microarray hybridization to identify S. Typhi tran... | Salmonella enterica serotype Typhi is the cause of typhoid fever and infects over 21 million cases and causes 200,000 deaths each year. S. Typhi only infects humans and this has greatly limited studies of S. Typhi pathogenesis. To study bacterial gene expression in human hosts, we used Selective Capture of Transcribed ... | Salmonella enterica serotype Typhi is a Gram-negative bacterium and the cause of typhoid fever. Typhoid fever affects over 21 million people each year, killing 200,000 [1]. S. Typhi is a human-restricted pathogen and this has greatly limited studies of S. Typhi pathogenesis. Our current understanding of S. Typhi respon... |
10.1371/journal.pcbi.1002094 | A Dynamical Model Reveals Gene Co-Localizations in Nucleus | Co-localization of networks of genes in the nucleus is thought to play an important role in determining gene expression patterns. Based upon experimental data, we built a dynamical model to test whether pure diffusion could account for the observed co-localization of genes within a defined subnuclear region. A simple s... | Transcription is a fundamental step in gene expression, yet it remains poorly understood at cellular level. Textbooks are full of descriptions of promoter-bound transcription factors recruiting RNA polymerase, which initiates transcription before sliding along the transcription unit. However, increasing evidence suppor... | A central theme in the regulation of transcription is the binding of transcription factor proteins to specific sites along the DNA. Though these sites can be several tens or hundreds of kilobases from a target gene promoter, regulation is achieved by the formation of chromatin loops that bring the sites together to for... |
10.1371/journal.ppat.1005761 | CD4+ T Cells Expressing PD-1, TIGIT and LAG-3 Contribute to HIV Persistence during ART | HIV persists in a small pool of latently infected cells despite antiretroviral therapy (ART). Identifying cellular markers expressed at the surface of these cells may lead to novel therapeutic strategies to reduce the size of the HIV reservoir. We hypothesized that CD4+ T cells expressing immune checkpoint molecules wo... | The persistence of HIV in a small pool of long-lived latently infected resting CD4+ T cells is a major barrier to viral eradication. Identifying cellular markers that are preferentially expressed at the surface of latently infected cells may lead to novel therapeutic strategies to cure HIV infection. We identified PD-1... | Although antiretroviral therapy (ART) is highly effective at suppressing HIV replication, viral reservoirs persist despite treatment and lead to rapid viral rebound when ART is interrupted [1–4]. A major step to achieve natural control of HIV replication after ART cessation would be to eliminate, or at least reduce, th... |
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