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10.1371/journal.ppat.1005086 | A Non-enveloped Virus Hijacks Host Disaggregation Machinery to Translocate across the Endoplasmic Reticulum Membrane | Mammalian cytosolic Hsp110 family, in concert with the Hsc70:J-protein complex, functions as a disaggregation machinery to rectify protein misfolding problems. Here we uncover a novel role of this machinery in driving membrane translocation during viral entry. The non-enveloped virus SV40 penetrates the endoplasmic ret... | How non-enveloped viruses penetrate a host membrane to enter cells and cause disease remains an enigmatic step. To infect cells, the non-enveloped SV40 must transport across the ER membrane to reach the cytosol. In this study, we report that a cellular Hsp105-powered disaggregation machinery pulls SV40 into the cytosol... | Protein misfolding and aggregation compromise cellular integrity. Cells in turn deploy powerful molecular chaperones to promote protein folding, prevent aggregation, and in some instances, re-solubilize the aggregated toxic species to rectify these problems and maintain proper cellular function [1–3]. A cell’s ability ... |
10.1371/journal.pgen.1006427 | Human Oocyte-Derived Methylation Differences Persist in the Placenta Revealing Widespread Transient Imprinting | Thousands of regions in gametes have opposing methylation profiles that are largely resolved during the post-fertilization epigenetic reprogramming. However some specific sequences associated with imprinted loci survive this demethylation process. Here we present the data describing the fate of germline-derived methyla... | Differences in gamete DNA methylation is subject to genome-wide reprogramming during preimplantation development to establish an embryo with an epigenetic state compatible with totipotency. DNA sequences associated with imprinted differentially methylated regions (DMRs) are largely protected from this process, retainin... | In mammals, DNA methylation of CpG dinucleotides has been shown to play critical roles in many developmental processes including cellular differentiation, X chromosome inactivation and genomic imprinting. DNA methylation patterns are initially established by the de novo DNA methyltransferase DNMT3A [1], with the methyl... |
10.1371/journal.pntd.0000200 | DNA-Sequence Variation Among Schistosoma mekongi Populations and Related Taxa; Phylogeography and the Current Distribution of Asian Schistosomiasis | Schistosomiasis in humans along the lower Mekong River has proven a persistent public health problem in the region. The causative agent is the parasite Schistosoma mekongi (Trematoda: Digenea). A new transmission focus is reported, as well as the first study of genetic variation among S. mekongi populations. The aim is... | Schistosomiasis is a disease caused by parasitic worms of the genus Schistosoma. In the lower Mekong river, schistosomiasis in humans is called Mekong schistosomiasis and is caused by Schistosoma mekongi. In the past, Mekong schistosomiasis was known only from the lower Mekong river. Here DNA-sequence variation is used... | Schistosomiasis in humans along the lower Mekong river (specifically Cambodia and southern Laos) was first recognized in 1957 [1] and has proven a persistent public health problem in the region [2]. The species involved is the parasitic blood fluke Schistosoma mekongi Voge, Buckner & Bruce 1978, which uses the caenogas... |
10.1371/journal.pntd.0006163 | Seroprevalence of antibodies against chikungunya virus in Singapore resident adult population | We determined the seroprevalence of chikungunya virus (CHIKV) infection in the adult resident population in Singapore following local outbreaks of chikungunya fever (CHIKF) in 2008–2009.
Our cross-sectional study involved residual sera from 3,293 adults aged 18–79 years who had participated in the National Health Surve... | The prevalence of neutralizing antibodies against chikungunya virus (CHIKV) was low at 1.9% among resident adults in Singapore after local outbreaks in 2008–2009. Adults aged 30–39 years and 70–79 years, men, those of Indian ethnicity and ethnic minority groups, and residence on ground floor of public and private housi... | Chikungunya fever (CHIKF) has re-emerged as an important mosquito-borne disease caused by the Chikungunya virus (CHIKV), an Alphavirus belonging to the Togaviridae family [1], and transmitted by two main vectors, Aedes aegypti and Aedes albopictus in the urban cycle [2]. It is characterized by fever, joint pain, headac... |
10.1371/journal.pntd.0001824 | Age-Related Patterns in Human Myeloid Dendritic Cell Populations in People Exposed to Schistosoma haematobium Infection | Urogenital schistosomiasis is caused by the helminth parasite Schistosoma haematobium. In high transmission areas, children acquire schistosome infection early in life with infection levels peaking in early childhood and subsequently declining in late childhood. This age-related infection profile is thought to result f... | A characteristic feature of most helminth infections is the convex age infection profile, where infection levels rise to peak in early childhood and decline in adulthood, a pattern thought to result from the development of protective acquired immunity. Thus, several investigations characterizing protective responses to... | Schistosoma haematobium helminth parasites cause urogenital schistosomiasis which affects about 112 million people mainly in rural areas of subtropical countries [1]. Infections with S. haematobium are most common in school-age children. Populations in endemic areas show a characteristic age-infection profile with infe... |
10.1371/journal.pcbi.1005942 | What drives the perceptual change resulting from speech motor adaptation? Evaluation of hypotheses in a Bayesian modeling framework | Shifts in perceptual boundaries resulting from speech motor learning induced by perturbations of the auditory feedback were taken as evidence for the involvement of motor functions in auditory speech perception. Beyond this general statement, the precise mechanisms underlying this involvement are not yet fully understo... | Experimental evidence suggest that motor learning influences categories in speech perception. These observations are consistent with studies of arm motor control showing that motor learning alters the perception of the arm location in the space, and that these perceptual changes are associated with increased connectivi... | The fact that perception has an influence on motor learning is known and has been the focus of a large number of studies. The converse, i.e. that motor learning would influence perception, seems more intriguing and unclear. For speech, shifts in perceptual boundaries have been shown to result from motor learning induce... |
10.1371/journal.pntd.0006749 | Community-based prevalence of typhoid fever, typhus, brucellosis and malaria among symptomatic individuals in Afar Region, Ethiopia | In sub-Saharan Africa, where there is the scarcity of proper diagnostic tools, febrile illness related symptoms are often misdiagnosed as malaria. Information on causative agents of febrile illness related symptoms among pastoral communities in Ethiopia have rarely been described.
In this a community based cross-sectio... | Many diseases such as typhoid fever, typhus, brucellosis and malaria show common symptoms such as fever, headache, joint pain and back pain. Hence, in countries where there is a problem of appropriate laboratory based diagnostic tools, health workers cannot properly diagnose these diseases and provide appropriate treat... | Sub-Saharan Africa is plagued by a myriad of infectious diseases posing significant public health and economic challenges. In addition, the often non-specific clinical signs of these diseases and the scarcity of proper diagnostic tools are the major challenges for health professionals in properly diagnosing and treatin... |
10.1371/journal.pbio.1002103 | A Voltage-Gated Calcium Channel Regulates Lysosomal Fusion with Endosomes and Autophagosomes and Is Required for Neuronal Homeostasis | Autophagy helps deliver sequestered intracellular cargo to lysosomes for proteolytic degradation and thereby maintains cellular homeostasis by preventing accumulation of toxic substances in cells. In a forward mosaic screen in Drosophila designed to identify genes required for neuronal function and maintenance, we iden... | Autophagy is a cellular process used by cells to prevent the accumulation of toxic substances. It delivers misfolded proteins and damaged organelles by fusing autophagosomes—organelles formed by a double membrane that surrounds the “debris” to be eliminated—with lysosomes. How this fusion process is regulated during au... | Autophagy is an evolutionarily conserved, lysosome-mediated degradation process required to maintain cellular homeostasis [1,2]. In eukaryotic cells, autophagy is a ubiquitous process that is important for several physiological processes. It occurs at a basal level in most cells to remove damaged organelles and is requ... |
10.1371/journal.pntd.0001054 | Rabies-Related Knowledge and Practices Among Persons At Risk of Bat Exposures in Thailand | Rabies is a fatal encephalitis caused by lyssaviruses. Evidence of lyssavirus circulation has recently emerged in Southeast Asian bats. A cross-sectional study was conducted in Thailand to assess rabies-related knowledge and practices among persons regularly exposed to bats and bat habitats. The objectives were to iden... | Rabies is a fatal encephalitis caused by lyssaviruses. Evidence of lyssavirus circulation has recently emerged in Southeast Asian bats. We surveyed persons regularly exposed to bats and bat habitats in Thailand to assess rabies‐related knowledge and practices. Targeted groups included guano miners, bat hunters, game wa... | Rabies is an exceptionally fatal encephalitis caused by Rhabdoviruses in the Lyssavirus genus. Transmission typically occurs when broken skin is contaminated with saliva from an infected mammal—usually in association with a bite but in rare instances by scratches. The most well-known and ubiquitous lyssavirus is the ra... |
10.1371/journal.ppat.1000288 | Disruption of the Toxoplasma gondii Parasitophorous Vacuole by IFNγ-Inducible Immunity-Related GTPases (IRG Proteins) Triggers Necrotic Cell Death | Toxoplasma gondii is a natural intracellular protozoal pathogen of mice and other small mammals. After infection, the parasite replicates freely in many cell types (tachyzoite stage) before undergoing a phase transition and encysting in brain and muscle (bradyzoite stage). In the mouse, early immune resistance to the t... | Toxoplasma gondii infects many warm-blooded animals, including approximately one quarter of the world's human population, residing life-long, usually asymptomatically, in cysts in the brain. If, however, the immune system is weakened for any reason, T. gondii can break out and cause life-threatening disease. Furthermor... | The mouse is a natural intermediate host for Toxoplasma gondii, an apicomplexan parasite whose definitive host is the cat. Most T. gondii strains are not virulent for normal mice at low infective doses [1],[2]. Following the development of a strongly IFNγ-dependent primary immunity, rapidly replicating tachyzoites conv... |
10.1371/journal.ppat.1000827 | Serological Profiling of a Candida albicans Protein Microarray Reveals Permanent Host-Pathogen Interplay and Stage-Specific Responses during Candidemia | Candida albicans in the immunocompetent host is a benign member of the human microbiota. Though, when host physiology is disrupted, this commensal-host interaction can degenerate and lead to an opportunistic infection. Relatively little is known regarding the dynamics of C. albicans colonization and pathogenesis. We de... | Candida albicans has both a benign and pathogenic association with the human host. Previous to this study, little was known in regard to how the host humoral system responds to the commensal colonization of C. albicans, as well as the development of hematogenously disseminated candidiasis. We show using a C. albicans c... | The yeast Candida albicans exists in a dichotomist relationship with the human host. C. albicans is frequently found as a commensal organism on the human skin, gastrointestinal (GI) tract and the vulvovaginal tract [1]. Close to 60% of healthy individuals carry C. albicans as a commensal in the oral cavity. Colonic and... |
10.1371/journal.pgen.1006898 | Notch-dependent epithelial fold determines boundary formation between developmental fields in the Drosophila antenna | Compartment boundary formation plays an important role in development by separating adjacent developmental fields. Drosophila imaginal discs have proven valuable for studying the mechanisms of boundary formation. We studied the boundary separating the proximal A1 segment and the distal segments, defined respectively by... | During development, boundary formation between adjacent developmental fields is important to maintain the integrity of complex organs and tissues. We examined how boundaries become established between adjacent developmental fields—which are defined by expression of distinct selector genes and developmental fates—using ... | During development, an organism is progressively divided into discrete fields that develop into different organs or parts of an organ. In many cases, the adjacent developmental fields develop distinct morphological, functional and molecular characteristics and are often divided by a sharp boundary that function to prev... |
10.1371/journal.pgen.1008177 | A mutation in the endonuclease domain of mouse MLH3 reveals novel roles for MutLγ during crossover formation in meiotic prophase I | During meiotic prophase I, double-strand breaks (DSBs) initiate homologous recombination leading to non-crossovers (NCOs) and crossovers (COs). In mouse, 10% of DSBs are designated to become COs, primarily through a pathway dependent on the MLH1-MLH3 heterodimer (MutLγ). Mlh3 contains an endonuclease domain that is cri... | Meiosis is a specialized cell division whereby a diploid cell undergoes one round of DNA replication followed by two rounds of division, yielding up to four haploid gametes. This process depends on tethering of maternal and paternal homologous chromosomes, and by the formation of crossovers (COs) between homologs durin... | Meiosis is a specialized cell division process in which a diploid parental cell undergoes one round of DNA replication followed by two rounds of division, resulting in up to four haploid gametes. Successful halving of the genome during meiosis I depends on the tethering of maternal and paternal homologous chromosomes d... |
10.1371/journal.pntd.0005819 | Widespread Trypanosoma cruzi infection in government working dogs along the Texas-Mexico border: Discordant serology, parasite genotyping and associated vectors | Chagas disease, caused by the vector-borne protozoan Trypanosoma cruzi, is increasingly recognized in the southern U.S. Government-owned working dogs along the Texas-Mexico border could be at heightened risk due to prolonged exposure outdoors in habitats with high densities of vectors. We quantified working dog exposur... | Chagas disease, a potentially deadly cardiac disease of humans, canines and other mammals is caused by the parasite Trypanosoma cruzi. The parasite is primarily transmitted to dogs by ingestion of infected triatomine ‘kissing bug’ vectors or through contact with the insect’s feces. Previous studies concluded that stray... | Chagas disease, a potentially deadly cardiac disease of humans and dogs, is caused by the flagellated protozoan parasite Trypanosoma cruzi. The parasite is transmitted by infected hematophagous triatomine insects, commonly known as ‘kissing bugs’. Chagas disease is estimated to infect nearly 6 million people throughout... |
10.1371/journal.pbio.0050237 | High-Throughput In Vivo Analysis of Gene Expression in Caenorhabditis elegans | Using DNA sequences 5′ to open reading frames, we have constructed green fluorescent protein (GFP) fusions and generated spatial and temporal tissue expression profiles for 1,886 specific genes in the nematode Caenorhabditis elegans. This effort encompasses about 10% of all genes identified in this organism. GFP-expres... | Knowing where a protein is expressed provides an important clue about its potential function. As critical as this information is, we have complete developmental expression profiles for only a small fraction of all genes expressed in any metazoan. Here, we have generated spatial and temporal tissue expression profiles f... | Determining when and where genes are expressed is often key to determining their function. Although expression profiling of genes using Serial Analysis of Gene Expression (SAGE) and microarrays is now routine, we still have complete developmental expression profiles for only a small fraction of all genes expressed in a... |
10.1371/journal.ppat.0030190 | A Cellular Basis for Wolbachia Recruitment to the Host Germline | Wolbachia are among the most widespread intracellular bacteria, carried by thousands of metazoan species. The success of Wolbachia is due to efficient vertical transmission by the host maternal germline. Some Wolbachia strains concentrate at the posterior of host oocytes, which promotes Wolbachia incorporation into pos... | This study focuses on Wolbachia, a genus of intracellular bacteria carried by insect and nematode host species. It was recently shown that Wolbachia carried into the human body by the host nematode Onchocerca volvulus trigger an immune response that leads to African river blindness. Findings like these raise fundamenta... | Wolbachia are among the most widespread intracellular bacteria, carried by an estimated 15%–76% of insect species as well as by some crustaceans, mites, and filarial nematodes [1,2]. Wolbachia are closely related to the Rickettsia family, a collection of tick-borne pathogens known for causing typhus and spotted fevers ... |
10.1371/journal.pcbi.1005786 | Machine learning to design integral membrane channelrhodopsins for efficient eukaryotic expression and plasma membrane localization | There is growing interest in studying and engineering integral membrane proteins (MPs) that play key roles in sensing and regulating cellular response to diverse external signals. A MP must be expressed, correctly inserted and folded in a lipid bilayer, and trafficked to the proper cellular location in order to functio... | A protein’s amino acid sequence determines how it will fold, traffic to subcellular locations, and carry out specific functions within the cell. Understanding this process would enable the design of protein sequences capable of useful functions; unfortunately, we cannot predict in detail how sequence encodes function. ... | As crucial components of regulatory and transport pathways, integral membrane proteins (MPs) are important pharmaceutical and engineering targets [1]. To be functional, MPs must be expressed and localized through a series of elaborate sub-cellular processes that include co-translational insertion, rigorous quality cont... |
10.1371/journal.pntd.0006088 | Turning poop into profit: Cost-effectiveness and soil transmitted helminth infection risk associated with human excreta reuse in Vietnam | Human excreta is a low cost source of nutrients vital to plant growth, but also a source of pathogens transmissible to people and animals. We investigated the cost-savings and infection risk of soil transmitted helminths (STHs) in four scenarios where farmers used either inorganic fertilizer or fresh/composted human ex... | Each year, hundreds of millions of people worldwide are infected with intestinal worms spread by contaminated soil, also known as soil transmitted helminths (STHs). These worms are most common in tropical climates in areas lacking good hygiene and sanitation, and negatively impact child development, quality of life, an... | Application of human excreta onto rice paddies as fertilizer is a common practice in northern Vietnam, where many farmers use single or double vault latrines, lack access to wastewater infrastructure, and have variable access to commercial inorganic fertilizers [1]. Using organic waste to fertilize fields has clear ben... |
10.1371/journal.pgen.1005354 | Silencing of DNase Colicin E8 Gene Expression by a Complex Nucleoprotein Assembly Ensures Timely Colicin Induction | Colicins are plasmid-encoded narrow spectrum antibiotics that are synthesized by strains of Escherichia coli and govern intraspecies competition. In a previous report, we demonstrated that the global transcriptional factor IscR, co dependently with the master regulator of the DNA damage response, LexA, delays induction... | Colicins are considered model proteins for studying bacterial toxins. These narrow spectrum antibiotics can kill by a variety of mechanisms, e.g. by forming pores in the membranes of susceptible cells or by degrading their nucleic acids. Colicin genes are plasmid-encoded and repressed by the master regulator of the DNA... | Colicins are high-molecular-weight toxic proteins that are produced by and specifically target Escherichia coli and its close relatives [1]. These narrow-spectrum antibiotics kill by either targeting the DNA, RNA or cell membranes of susceptible cells. Cytoplasmic colicins are released upon the synthesis of a lysis pro... |
10.1371/journal.pgen.1006231 | Linking Core Promoter Classes to Circadian Transcription | Circadian rhythms in transcription are generated by rhythmic abundances and DNA binding activities of transcription factors. Propagation of rhythms to transcriptional initiation involves the core promoter, its chromatin state, and the basal transcription machinery. Here, I characterize core promoters and chromatin stat... | Circadian rhythms switch gene expression on and off with a daily rhythm in most tissues in mammals and other animals. Typically, thousands of genes are affected, and the functions of these rhythms include preparing and adjusting various physiological functions in tissues to meet time-of-day dependent requirements optim... | In many metazoans, transcription of numerous genes in most cell types occurs in a rhythmic fashion with a period of ~24 hours, also if the organism is held under constant conditions; these rhythms are termed circadian transcriptional rhythms [1]. They are to a large extent orchestrated by the cellular circadian clock, ... |
10.1371/journal.pbio.1000095 | Reawakening Retrocyclins: Ancestral Human Defensins Active Against HIV-1 | Human alpha and beta defensins contribute substantially to innate immune defenses against microbial and viral infections. Certain nonhuman primates also produce theta-defensins—18 residue cyclic peptides that act as HIV-1 entry inhibitors. Multiple human theta-defensin genes exist, but they harbor a premature terminati... | Defensins are a large family of small antimicrobial peptides that contribute to host defense against a broad spectrum of pathogens. In primates, defensins are divided into three subfamilies—alpha, beta, and theta—on the basis of their disulfide bonding pattern. Theta-defensins were the most recently identified defensin... | Nearly 33 million people are infected with HIV worldwide [1,2], and despite extensive efforts there are no effective vaccines or other countermeasures to protect against HIV transmission [3]. In our attempts to find effective anti-HIV agents, our group determined that certain synthetic θ-defensins called “retrocyclins”... |
10.1371/journal.pntd.0002169 | Uncertainty Surrounding Projections of the Long-Term Impact of Ivermectin Treatment on Human Onchocerciasis | Recent studies in Mali, Nigeria, and Senegal have indicated that annual (or biannual) ivermectin distribution may lead to local elimination of human onchocerciasis in certain African foci. Modelling-based projections have been used to estimate the required duration of ivermectin distribution to reach elimination. A cru... | Studies in Mali, Nigeria, and Senegal suggest that, in some settings, it is possible to eliminate onchocerciasis after 15–17 years of ivermectin distribution. Computer models have been used to estimate the required duration of ivermectin distribution to reach elimination. Some models assume that annual ivermectin treat... | Human onchocerciasis, caused by Onchocerca volvulus and transmitted by Simulium blackflies, is a parasitic disease leading to ocular (vision loss, blindness) and cutaneous (itching, dermatitis, depigmentation) pathology [1], [2], as well as to increased host mortality [3], [4], [5].
The Onchocerciasis Control Pr... |
10.1371/journal.pgen.1002283 | Atypical AT Skew in Firmicute Genomes Results from Selection and Not from Mutation | The second parity rule states that, if there is no bias in mutation or selection, then within each strand of DNA complementary bases are present at approximately equal frequencies. In bacteria, however, there is commonly an excess of G (over C) and, to a lesser extent, T (over A) in the replicatory leading strand. The ... | When considering a single strand of DNA, it is not necessarily the case that the frequency of each base should equal its complementary partner, such that A = T and G = C. For the leading strand, it is typically the case that Gs are more common than Cs, and Ts more common than As. This bias is widely thought to arise du... | Skews in nucleotide usage (compositional asymmetries) are of interest as they provide a window into fundamental processes operating within genomes. Under conditions of equal mutation bias and random gene orientation, the two complementary strands of a bacterial chromosome should be subject to the same sets of substitut... |
10.1371/journal.pcbi.1002721 | Probability Fluxes and Transition Paths in a Markovian Model Describing Complex Subunit Cooperativity in HCN2 Channels | Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels are voltage-gated tetrameric cation channels that generate electrical rhythmicity in neurons and cardiomyocytes. Activation can be enhanced by the binding of adenosine-3′,5′-cyclic monophosphate (cAMP) to an intracellular cyclic nucleotide binding d... | The activation of a receptor protein by a small molecule (ligand) can be quantified by Markovian models. These models, which are widely used in natural sciences, consist of distinct states and transitions between them. In nature receptor proteins are often formed by the assembly of more than one subunit and each subuni... | In a protein the time scale of conformational changes ranges from picoseconds for the thermal vibration of the atoms to seconds, or even more, for structural arrangements [1]. Since proteins consist typically of hundreds to several thousand amino acids and each amino acid consists of seven or more atoms, the complete s... |
10.1371/journal.pcbi.1001088 | Self-Organization of Muscle Cell Structure and Function | The organization of muscle is the product of functional adaptation over several length scales spanning from the sarcomere to the muscle bundle. One possible strategy for solving this multiscale coupling problem is to physically constrain the muscle cells in microenvironments that potentiate the organization of their in... | How muscle is organized impacts its function. However, understanding how muscle organizes is challenging, as the process occurs over several length scales. We approach this multiscale coupling problem by constraining the overall shapes of muscle cells to indirectly control the organization of their intracellular space.... | During biological development, evolving forms are marked by distinct functionalities. An interesting example is the organization of myofibrils in striated muscle cells. As the myocyte matures, the myofibrils are rearranged from an irregularly dispersed pattern into tightly organized bundles spanning the length, rather ... |
10.1371/journal.pgen.1002188 | Ongoing Phenotypic and Genomic Changes in Experimental Coevolution of RNA Bacteriophage Qβ and Escherichia coli | According to the Red Queen hypothesis or arms race dynamics, coevolution drives continuous adaptation and counter-adaptation. Experimental models under simplified environments consisting of bacteria and bacteriophages have been used to analyze the ongoing process of coevolution, but the analysis of both parasites and t... | To examine the ongoing changes driven by host–parasite interactions, we have constructed a coevolution model consisting of Escherichia coli and the lytic RNA bacteriophage Qβ (Qβ) in a spatially unstructured environment. In coevolution through 54 daily copropagations of the parasite and its host, E. coli first evolved ... | Host–parasite coevolution has been a topic of intense research interest in various fields from basic science of molecular evolution to agricultural and medical applications [1]–[5]. According to the Red Queen hypothesis or arms race dynamics, coevolution leads to complex but continuous change, adaptation, and counter-a... |
10.1371/journal.pgen.0030056 | Lifespan Regulation by Evolutionarily Conserved Genes Essential for Viability | Evolutionarily conserved mechanisms that control aging are predicted to have prereproductive functions in order to be subject to natural selection. Genes that are essential for growth and development are highly conserved in evolution, but their role in longevity has not previously been assessed. We screened 2,700 genes... | The lifespan of an animal is determined by both environmental and genetic factors, and many of the mechanisms identified to increase lifespan are evolutionarily conserved across organisms. Previous longevity screens in C. elegans have identified over 100 genes, but ∼2,700 essential for normal development were excluded ... | The lifespan of an organism is regulated by both genetic and environmental influences in many species [1]. Recent work has identified specific components from a variety of cellular processes that regulate lifespan. In C. elegans loss-of-function mutations in the insulin/insulin-like growth factor-1/daf-2 signaling path... |
10.1371/journal.pntd.0004555 | Trypanosoma cruzi Needs a Signal Provided by Reactive Oxygen Species to Infect Macrophages | During Trypanosoma cruzi infection, macrophages produce reactive oxygen species (ROS) in a process called respiratory burst. Several works have aimed to elucidate the role of ROS during T. cruzi infection and the results obtained are sometimes contradictory. T. cruzi has a highly efficiently regulated antioxidant machi... | The parasite Trypanosoma cruzi is the causative agent of Chagas’ disease, which affects 10 million people, mainly in Latin American. Macrophages are one of the first cellular actors facing the invasion of pathogens and during T. cruzi infection, produce reactive oxygen species (ROS). To deal with oxidative stress, T. c... | Macrophages are one of the first lines of defense against intracellular pathogens [1]. During Trypanosoma cruzi infection, these cells are activated to produce ROS, a process called respiratory burst [2–4]. The detection of infectious agents leads to activation of the membrane bound NADPH oxidase, a multi-subunit compl... |
10.1371/journal.ppat.1002376 | EBV Tegument Protein BNRF1 Disrupts DAXX-ATRX to Activate Viral Early Gene Transcription | Productive infection by herpesviruses involve the disabling of host-cell intrinsic defenses by viral encoded tegument proteins. Epstein-Barr Virus (EBV) typically establishes a non-productive, latent infection and it remains unclear how it confronts the host-cell intrinsic defenses that restrict viral gene expression. ... | Persistent infection by Epstein-Barr virus (EBV) is associated with a variety of diseases, including lymphoid and epithelial tumors. Despite a wealth of information on the mechanism of viral persistence, relatively little is known about the early steps of EBV infection and viral gene activation. Host cells actively mou... | Epstein-Barr virus (EBV) is a member of the human gammaherpesvirus subfamily that infects over 90% of the global adult population [1], [2]. EBV preferentially establishes latent infection in B-lymphocytes but can also infect epithelial cells [3], [4]. EBV primary infection is one of the main causes of infectious mononu... |
10.1371/journal.pgen.1004844 | A Drosophila ABC Transporter Regulates Lifespan | MRP4 (multidrug resistance-associated protein 4) is a member of the MRP/ABCC subfamily of ATP-binding cassette (ABC) transporters that are essential for many cellular processes requiring the transport of substrates across cell membranes. Although MRP4 has been implicated as a detoxification protein by transport of stru... | The drug transporters are often known for their ability to transport different physiological-related compounds across cell membranes. Although the abnormal up-regulation of some these transporters is believed to be the common cause of the clinic problem called drug resistance, the biological functions of these transpor... | In Drosophila, one important feature of the aging process appears to be the similarity between the changes in gene expression that occur during aging and oxidative stress response [1], [2], [3]. For instance, the up-regulation of genes encoding for some chaperones and/or detoxification agents in response to oxidative s... |
10.1371/journal.pgen.1003457 | Reference-Free Population Genomics from Next-Generation Transcriptome Data and the Vertebrate–Invertebrate Gap | In animals, the population genomic literature is dominated by two taxa, namely mammals and drosophilids, in which fully sequenced, well-annotated genomes have been available for years. Data from other metazoan phyla are scarce, probably because the vast majority of living species still lack a closely related reference ... | The analysis of genomic variation between individuals of a given species has so far been restricted to a small number of model organisms, such as human and fruitfly, for which a fully sequenced, well-annotated reference genome was available. Here we show that, thanks to next-generation high-throughput sequencing techno... | Population genomics, the analysis of within-species, genome-wide patterns of molecular variation, is a promising area of research, both applied and fundamental [1]. So far such studies have essentially been restricted to model organisms such as yeast [2] and Arabidopsis [3], in which a well-annotated, completely sequen... |
10.1371/journal.pcbi.1005857 | Automated visualization of rule-based models | Frameworks such as BioNetGen, Kappa and Simmune use “reaction rules” to specify biochemical interactions compactly, where each rule specifies a mechanism such as binding or phosphorylation and its structural requirements. Current rule-based models of signaling pathways have tens to hundreds of rules, and these numbers ... | Signaling in living cells is mediated through a complex network of chemical interactions. Current predictive models of signal pathways have hundreds of reaction rules that specify chemical interactions, and a comprehensive model of a stem cell or cancer cell would be expected to have many more. Visualizations of rules ... | Rule-based frameworks such as BioNetGen [1–3], Kappa [4–6] and Simmune [7,8] have been used to build detailed kinetic models of signaling pathways (e.g., FcεRI [9–11], TCR [12], EGFR [13,14], and p53 [15]). A rule-based model is composed of multiple “reaction rules”, where each rule specifies a reaction mechanism and i... |
10.1371/journal.pgen.1000344 | Organised Genome Dynamics in the Escherichia coli Species Results in Highly Diverse Adaptive Paths | The Escherichia coli species represents one of the best-studied model organisms, but also encompasses a variety of commensal and pathogenic strains that diversify by high rates of genetic change. We uniformly (re-) annotated the genomes of 20 commensal and pathogenic E. coli strains and one strain of E. fergusonii (the... | Although abundant knowledge has been accumulated regarding the E. coli laboratory strain K-12, little is known about the evolutionary trajectories that have driven the high diversity observed among natural isolates of the species, which encompass both commensal and highly virulent intestinal and extraintestinal pathoge... | Escherichia coli was brought into laboratories almost a century ago to become one of the most important model organisms and by far the best-studied prokaryote. Major findings in phage genetics, bacterial conjugation, recombination, genetic regulation and chromosome replication involved the use of E. coli, especially la... |
10.1371/journal.pgen.1004573 | Genome Wide Association Studies Using a New Nonparametric Model Reveal the Genetic Architecture of 17 Agronomic Traits in an Enlarged Maize Association Panel | Association mapping is a powerful approach for dissecting the genetic architecture of complex quantitative traits using high-density SNP markers in maize. Here, we expanded our association panel size from 368 to 513 inbred lines with 0.5 million high quality SNPs using a two-step data-imputation method which combines i... | Genotype imputation has been used widely in the analysis of genome-wide association studies (GWAS) to boost power and fine-map associations. We developed a two-step data imputation method to meet the challenge of large proportion missing genotypes. GWAS have uncovered an extensive genetic architecture of complex quanti... | Maize (Zea mays L.) is one of the most important food, feed and industrial crops globally. Grown extensively under different climate conditions across the world, maize shows an astonishing amount of phenotypic diversity [1]. Identifying the underlying natural allelic variations for the phenotypic diversity will have im... |
10.1371/journal.ppat.1002439 | HIV-1 Capsid-Cyclophilin Interactions Determine Nuclear Import Pathway, Integration Targeting and Replication Efficiency | Lentiviruses such as HIV-1 traverse nuclear pore complexes (NPC) and infect terminally differentiated non-dividing cells, but how they do this is unclear. The cytoplasmic NPC protein Nup358/RanBP2 was identified as an HIV-1 co-factor in previous studies. Here we report that HIV-1 capsid (CA) binds directly to the cyclo... | During infection HIV-1 enters the nucleus by crossing the nuclear membrane and incorporating itself into the host DNA by a process called integration. Here we show that the viral capsid protein gets tethered to a cyclophilin protein called Nup358, a component of the nuclear membrane gateways that allow transport betwee... | The ability to infect terminally differentiated cells of the monocyte-macrophage lineage is a conserved property of lentiviruses, including HIV-1 [1]. This process requires pre-integration complexes (PICs) to traverse the nuclear pore, though the molecular mechanism remains unclear. The HIV-1 proteins matrix, Vpr and i... |
10.1371/journal.pcbi.1000391 | How to Get the Most out of Your Curation Effort | Large-scale annotation efforts typically involve several experts who may disagree with each other. We propose an approach for modeling disagreements among experts that allows providing each annotation with a confidence value (i.e., the posterior probability that it is correct). Our approach allows computing certainty-l... | Data annotation (manual data curation) tasks are at the very heart of modern biology. Experts performing curation obviously differ in their efficiency, attitude, and precision, but directly measuring their performance is not easy. We propose an experimental design schema and associated mathematical models with which to... | Virtually every large-scale biological project today, ranging from creation of sequence repositories, collections of three-dimensional structures, annotated experiments, controlled vocabularies and ontologies, or providing evidence from the literature in organism-specific genome databases, utilizes manual curation.
A ... |
10.1371/journal.pcbi.1002201 | Changes in Dynamics upon Oligomerization Regulate Substrate Binding and Allostery in Amino Acid Kinase Family Members | Oligomerization is a functional requirement for many proteins. The interfacial interactions and the overall packing geometry of the individual monomers are viewed as important determinants of the thermodynamic stability and allosteric regulation of oligomers. The present study focuses on the role of the interfacial int... | Protein function requires a three-dimensional structure with specific dynamic features for catalytic and binding events, and, in many cases, the structure results from the assembly of more than one polypeptide chain (also called monomer or subunit) to form an oligomer or multimer. Proteins such as hemoglobin or chapero... | The biological function of proteins is usually enabled by their dynamics under native state conditions, which, in turn, is encoded by their 3-dimensional (3D) structure. Unraveling this functional code has been the aim of many experimental and theoretical studies [1]–[9]. In particular the slow conformational dynamics ... |
10.1371/journal.pntd.0003755 | Deletion of Fibrinogen-like Protein 2 (FGL-2), a Novel CD4+ CD25+ Treg Effector Molecule, Leads to Improved Control of Echinococcus multilocularis Infection in Mice | The growth potential of the tumor-like Echinococcus multilocularis metacestode (causing alveolar echinococcosis, AE) is directly linked to the nature/function of the periparasitic host immune-mediated processes. We previously showed that Fibrinogen-like-protein 2 (FGL2), a novel CD4+CD25+ Treg effector molecule, was ov... | In larval E. multilocularis infection causing alveolar echinococcosis (AE) in humans as well as mice, immune tolerance and/or down-regulation of protective immunity is a marked characteristic of this chronic disease. Our study provides a comprehensive evidence for a major involvement of the recently identified CD4+ CD2... | Alveolar echinococcosis (AE) is a very severe zoonotic helminthic disease in humans, exhibiting a fatal outcome if remaining untreated [1]. AE is characterized by chronic and progressive hepatic damage caused by the continuous proliferation of the larval stage (metacestode) of Echinococcus multilocularis [2], that beha... |
10.1371/journal.pntd.0001927 | Appraisal of a Leishmania major Strain Stably Expressing mCherry Fluorescent Protein for Both In Vitro and In Vivo Studies of Potential Drugs and Vaccine against Cutaneous Leishmaniasis | Leishmania major cutaneous leishmaniasis is an infectious zoonotic disease. It is produced by a digenetic parasite, which resides in the phagolysosomal compartment of different mammalian macrophage populations. There is an urgent need to develop new therapies (drugs) against this neglected disease that hits developing ... | Leishmaniasis is a parasitic disease that is far from eradication. The lack of an efficacious vaccine and treatment failures are major factors in its intractable worldwide prevalence. A non-invasive imaging technique using genetically engineered parasites that expressed fluorescent proteins could give to researchers a ... | Leishmania major is the main cause of cutaneous leishmaniasis (CL) in the Old World. Parasites are transmitted by Phlebotominae sandflies whilst blood feeding on infected mammalian hosts. CL is widely spread in the developing world, affecting people in 88 countries with 1.5 million new cases reported each year. CL usua... |
10.1371/journal.pntd.0001647 | Lower Richness of Small Wild Mammal Species and Chagas Disease Risk | A new epidemiological scenario involving the oral transmission of Chagas disease, mainly in the Amazon basin, requires innovative control measures. Geospatial analyses of the Trypanosoma cruzi transmission cycle in the wild mammals have been scarce. We applied interpolation and map algebra methods to evaluate mammalian... | The classical methodology of mapping works with discrete units and sharp boundaries does not consider gradient transition areas. Spatial analysis by the interpolation method, followed by map algebra, is able to model the spatial distribution of biological phenomena and their distribution and eventual association with o... | The causative agent of Chagas disease, Trypanosoma cruzi (Chagas, 1909), is a multi-host parasite capable of infecting almost all tissues of more than one hundred mammal species [1]. Dozens of species of insects from the Triatominae subfamily can act as its vector. Except for the epimastigote form, all other T. cruzi e... |
10.1371/journal.pntd.0004637 | Mapping the Distribution of Anthrax in Mainland China, 2005–2013 | Anthrax, a global re-emerging zoonotic disease in recent years is enzootic in mainland China. Despite its significance to the public health, spatiotemporal distributions of the disease in human and livestock and its potential driving factors remain poorly understood.
Using the national surveillance data of human and li... | Anthrax is a worldwide zoonosis affecting mostly grazing herbivores, with occasional spillover to humans who have contact with infected animals or contaminated animal products. We characterized the distributional patterns of both human and livestock anthrax in China from 2005 to 2013, and identified agro-ecological, en... | Anthrax is one of the ancient zoonoses caused by Bacillus anthracis [1]. It is primarily a disease in herbivores and sometimes sparks outbreaks in human with potentially serious consequences [2]. It is enzootic in most countries in Africa and Asia as well as some countries in Europe and America [3]. The disease occurs ... |
10.1371/journal.ppat.1003799 | Myeloid Dendritic Cells Induce HIV-1 Latency in Non-proliferating CD4+ T Cells | Latently infected resting CD4+ T cells are a major barrier to HIV cure. Understanding how latency is established, maintained and reversed is critical to identifying novel strategies to eliminate latently infected cells. We demonstrate here that co-culture of resting CD4+ T cells and syngeneic myeloid dendritic cells (m... | Current antiretroviral drugs significantly prolong life and reduce morbidity but are unable to cure HIV. While on treatment, the virus is able to hide in resting memory T cells in a silent or “latent” form. These latently infected cells are rare and thus are hard to study using blood from HIV-infected individuals on tr... | Antiretroviral therapy (ART) for the treatment of HIV has led to a substantial reduction in morbidity and mortality; however, ART cannot cure HIV and life-long treatment is required. This is directly due to the persistence of long-lived latently infected cellular reservoirs, that include microglia, astrocytes, macropha... |
10.1371/journal.ppat.1004908 | A Single Protein S-acyl Transferase Acts through Diverse Substrates to Determine Cryptococcal Morphology, Stress Tolerance, and Pathogenic Outcome | Cryptococcus neoformans is an opportunistic yeast that kills over 625,000 people yearly through lethal meningitis. Host phagocytes serve as the first line of defense against this pathogen, but fungal engulfment and subsequent intracellular proliferation also correlate with poor patient outcome. Defining the interaction... | Cryptococcus neoformans is a ubiquitous environmental yeast that kills over 625,000 people annually, mainly in developing countries. Healthy humans frequently inhale infectious particles without noticeable symptoms. However, in immunocompromised people, the initial lung infection can spread to other sites, particularly... | Cryptococcus neoformans is a fungal pathogen that causes over 625,000 deaths per year, mainly in severely immunocompromised individuals. Cryptococcosis is contracted by inhalation of infectious particles from the environment [1], which leads to a primary pulmonary infection. In healthy people this infection is typicall... |
10.1371/journal.pgen.1000006 | Differential Allelic Expression in the Human Genome: A Robust Approach To Identify Genetic and Epigenetic Cis-Acting Mechanisms Regulating Gene Expression | The recent development of whole genome association studies has lead to the robust identification of several loci involved in different common human diseases. Interestingly, some of the strongest signals of association observed in these studies arise from non-coding regions located in very large introns or far away from... | We describe a new methodology to identify individual differences in the expression of the two copies of one gene. This is achieved by comparing the mRNA level of the two alleles using a heterozygous polymorphism in the transcript as marker. We show that this approach allows an exhaustive survey of cis-acting regulation... | Understanding the genetic causes of phenotypic variation in humans still remains a major challenge for human genetics. In hundreds of cases, a single DNA sequence polymorphism affecting a protein coding sequence has been linked to a clear simple Mendelian phenotype (see e.g. [1]) and, for a much smaller but increasing ... |
10.1371/journal.pbio.0050035 | Chemically Diverse Toxicants Converge on Fyn and c-Cbl to Disrupt Precursor Cell Function | Identification of common mechanistic principles that shed light on the action of the many chemically diverse toxicants to which we are exposed is of central importance in understanding how toxicants disrupt normal cellular function and in developing more effective means of protecting against such effects. Of particular... | Discovering general principles underlying the effects of toxicant exposure on biological systems is one of the central challenges of toxicological research. We have discovered a previously unrecognized regulatory pathway on which chemically diverse toxicants converge, at environmentally relevant exposure levels, to dis... | Determining whether chemically diverse substances induce similar adverse effects at the cellular and molecular level is one of the central challenges of toxicological research. If the structural diversity of different toxicants, and of potential toxicants, means that each works through distinctive mechanisms then this ... |
10.1371/journal.pgen.1003115 | SLI-1 Cbl Inhibits the Engulfment of Apoptotic Cells in C. elegans through a Ligase-Independent Function | The engulfment of apoptotic cells is required for normal metazoan development and tissue remodeling. In Caenorhabditis elegans, two parallel and partially redundant conserved pathways act in cell-corpse engulfment. One pathway, which includes the small GTPase CED-10 Rac and the cytoskeletal regulator ABI-1, acts to rea... | Cell death is a normal part of organismal development. When cells die, other cells engulf them. In the roundworm C. elegans, engulfment is facilitated by one pathway that rearranges the actin cytoskeleton and another that recruits membrane. Together they cause the formation of cellular extensions that surround the dead... | The engulfment of apoptotic cells requires at least two processes to occur in the engulfing cell at the interface with the dying cell. Actin cytoskeletal elements need to be reorganized and membrane needs to be recruited. Together, these two processes result in the engulfing cell surrounding the dying cell. Two conserv... |
10.1371/journal.ppat.1003379 | Increase in Gut Microbiota after Immune Suppression in Baculovirus-infected Larvae | Spodoptera exigua microarray was used to determine genes differentially expressed in S. exigua cells challenged with the species-specific baculovirus SeMNPV as well as with a generalist baculovirus, AcMNPV. Microarray results revealed that, in contrast to the host transcriptional shut-off that is expected during baculo... | Baculoviruses are large DNA viruses that infect invertebrates, mainly insects from the order Lepidoptera. They were first discovered to cause insects' epizootics and are now used worldwide as biocontrol agents. Extensive studies on baculovirus biology led to the discovery that they can serve as expression vectors in in... | Baculoviruses are large DNA viruses that infect arthropods, mainly insects from the orders, Lepidoptera, Diptera and Hymenoptera. During their replication cycle, they produce two distinct morphological forms, the occlusion-derived virus that is responsible for transmission of the infection between insects and the budde... |
10.1371/journal.pntd.0002073 | High Content Screening of a Kinase-Focused Library Reveals Compounds Broadly-Active against Dengue Viruses | Dengue virus is a mosquito-borne flavivirus that has a large impact in global health. It is considered as one of the medically important arboviruses, and developing a preventive or therapeutic solution remains a top priority in the medical and scientific community. Drug discovery programs for potential dengue antiviral... | Dengue, a re-emergent human disease that places nearly half of the world's population at risk, threatens to further expand in geographical distribution. The lack of an available effective dengue vaccine has encouraged the search for antiviral drugs as an alternative approach. In recent years, drug discovery through hig... | Dengue virus (DENV) is an important mosquito-borne pathogen responsible for causing dengue fever (DF) and the more severe, life-threatening dengue hemorrhagic fever/shock syndrome (DHF/DSS) [1]. DENV is a small, enveloped virus belonging to the genus Flavivirus, family Flaviviridae. [2]. Dengue virions are approximatel... |
10.1371/journal.ppat.1000249 | Surviving Mousepox Infection Requires the Complement System | Poxviruses subvert the host immune response by producing immunomodulatory proteins, including a complement regulatory protein. Ectromelia virus provides a mouse model for smallpox where the virus and the host's immune response have co-evolved. Using this model, our study investigated the role of the complement system d... | As one of the most successful pathogens ever, smallpox caused death and disfigurement worldwide until its eradication in the 1970s. The complement system, an essential part of the innate immune response, protects against many pathogens; however, its role during smallpox infection is unclear. In this study, we investiga... | Poxviruses remain a threat to the human population despite the eradication decades ago of naturally circulating variola virus, the causative agent of smallpox. Smallpox, with its up to 30% mortality rate, could devastate the large unvaccinated population if released accidentally or by bioterrorists [1]. Closely related... |
10.1371/journal.pntd.0006293 | A rabies lesson improves rabies knowledge amongst primary school children in Zomba, Malawi | Rabies is an important neglected disease, which kills around 59,000 people a year. Over a third of these deaths are in children less than 15 years of age. Almost all human rabies deaths in Africa and Asia are due to bites from infected dogs. Despite the high efficacy of current rabies vaccines, awareness about rabies p... | Rabies is a fatal disease that claims the lives of approximately 59,000 people every year. Children under the age of 15 make up 40% of all human rabies deaths yet this is preventable through a combination of vaccinating dogs against rabies and education. Numerous studies have shown that people in rabies endemic areas l... | Of the estimated 59,000 people who die from rabies annually [1], the vast majority result from a bite from a rabid dog. Children are at greater risk of suffering dog bites than adults [2,3] and as a result approximately 40% of all human rabies deaths occur in children aged under 15 years old [4,5]. Elimination of the r... |
10.1371/journal.pbio.2005952 | Spatiotemporal coordination of cell division and growth during organ morphogenesis | A developing plant organ exhibits complex spatiotemporal patterns of growth, cell division, cell size, cell shape, and organ shape. Explaining these patterns presents a challenge because of their dynamics and cross-correlations, which can make it difficult to disentangle causes from effects. To address these problems, ... | Organ morphogenesis involves two coordinated processes: growth of tissue and increase in cell number through cell division. Both processes have been analysed individually in many systems and shown to exhibit complex patterns in space and time. However, it is unclear how these patterns of growth and cell division are co... | The development of an organ from a primordium typically involves two types of processes: increase in cell number through division, and change in tissue shape and size through growth. However, how these processes are coordinated in space and time is unclear. It is possible that spatiotemporal regulation operates through... |
10.1371/journal.pgen.1007443 | Convergent evolution of gene expression in two high-toothed stickleback populations | Changes in developmental gene regulatory networks enable evolved changes in morphology. These changes can be in cis regulatory elements that act in an allele-specific manner, or changes to the overall trans regulatory environment that interacts with cis regulatory sequences. Here we address several questions about the ... | Convergent evolution, where a similar trait evolves in different lineages, provides an opportunity to study the repeatability of evolution. Convergent morphological evolution has been well studied at multiple evolutionary time scales ranging from ancient, to recent, such as the gain in tooth number in freshwater stickl... | Development is controlled by a complex series of interlocking gene regulatory networks. Much of this regulation occurs at the level of transcription initiation, where trans acting factors bind to cis regulatory elements to control their target gene’s expression [1,2]. Evolved changes in an organism's morphology are the... |
10.1371/journal.pgen.1003028 | Genomic Study of RNA Polymerase II and III SNAPc-Bound Promoters Reveals a Gene Transcribed by Both Enzymes and a Broad Use of Common Activators | SNAPc is one of a few basal transcription factors used by both RNA polymerase (pol) II and pol III. To define the set of active SNAPc-dependent promoters in human cells, we have localized genome-wide four SNAPc subunits, GTF2B (TFIIB), BRF2, pol II, and pol III. Among some seventy loci occupied by SNAPc and other facto... | SNAPc-dependent promoters are unique among cellular promoters in being very similar to each other, even though some of them recruit RNA polymerase II and others RNA polymerase III. We have examined all SNAPc-bound promoters present in the human genome. We find a surprisingly small number of them, some 70 promoters. Amo... | The human pol II snRNA genes and type 3 pol III genes have the particularity of containing highly similar promoters, composed of a distal sequence element (DSE) that enhances transcription and a proximal sequence element (PSE) required for basal transcription. In pol II snRNA promoters, the PSE is the sole essential co... |
10.1371/journal.pcbi.1004245 | Geometrical and Mechanical Properties Control Actin Filament Organization | The different actin structures governing eukaryotic cell shape and movement are not only determined by the properties of the actin filaments and associated proteins, but also by geometrical constraints. We recently demonstrated that limiting nucleation to specific regions was sufficient to obtain actin networks with di... | Many cellular processes or morphological changes, for example division and migration, strongly depend on the cytoskeleton. For successful completion of these processes in higher cells, thousands of cytoskeletal filaments need to be organized into precise higher-order structures. Identifying the most important parameter... | Actin assembles to form higher order structures [1] that are essential to cell morphogenesis, adhesion and motility [2]. A single filament can either resist or generate forces according to its local environment [3,4], but most physiological processes require the assembly of a higher ordered network [5,6]. Therefore, on... |
10.1371/journal.pntd.0005345 | Exploring local knowledge and perceptions on zoonoses among pastoralists in northern and eastern Tanzania | Zoonoses account for the most commonly reported emerging and re-emerging infectious diseases in Sub-Saharan Africa. However, there is limited knowledge on how pastoral communities perceive zoonoses in relation to their livelihoods, culture and their wider ecology. This study was carried out to explore local knowledge a... | Zoonoses are diseases transmissible between animals and humans. Risk factors include animal slaughter, the handling and preparing food of animal origin and particularly the consumption of such food when raw or undercooked. Pastoralists are daily in contact with their livestock and are likely to be more frequently expos... | Zoonoses account for the most commonly reported emerging and re-emerging infectious diseases (EIDs) in Sub-Saharan Africa [1]. There is a large number of human diseases that originate from both domestic and wild animals (900 +), and a smaller number of zoonoses (250+), which are diseases transmitted between animals and... |
10.1371/journal.pcbi.1003206 | Spike Triggered Covariance in Strongly Correlated Gaussian Stimuli | Many biological systems perform computations on inputs that have very large dimensionality. Determining the relevant input combinations for a particular computation is often key to understanding its function. A common way to find the relevant input dimensions is to examine the difference in variance between the input d... | In many areas of computational biology, including the analyses of genetic mutations, protein stability and neural coding, as well as in economics, one of the most basic and important steps of data analysis is to find the relevant input dimensions for a particular task. In neural coding problems, the spike-triggered cov... | How do neurons encode sensory stimuli? One of the primary difficulties in answering this long-standing problem is the fact that sensory stimuli have high dimensionality. For example, responses of many visual neurons are affected by image patterns that require at least a pixel grid for their description as well as a te... |
10.1371/journal.pgen.1007753 | Evidence that regulation of intramembrane proteolysis is mediated by substrate gating during sporulation in Bacillus subtilis | During the morphological process of sporulation in Bacillus subtilis two adjacent daughter cells (called the mother cell and forespore) follow different programs of gene expression that are linked to each other by signal transduction pathways. At a late stage in development, a signaling pathway emanating from the fores... | Regulated Intramembrane Proteolysis is a broadly conserved mechanism for transducing information across lipid bilayers. In these signaling pathways a protease on one side of the membrane triggers the activation of a membrane-embedded protease that cleaves its substrate within or adjacent to the cytoplasmic face of the ... | Regulated Intramembrane Proteolysis (RIP) is a broadly used strategy to transduce information across lipid bilayers [1–3]. In many of these RIP pathways, proteolysis on one side of the membrane by a so-called site-1 protease leads to the activation of a membrane-embedded site-2 protease that cleaves and activates a sub... |
10.1371/journal.pcbi.1000421 | Maximum-Likelihood Model Averaging To Profile Clustering of Site Types across Discrete Linear Sequences | A major analytical challenge in computational biology is the detection and description of clusters of specified site types, such as polymorphic or substituted sites within DNA or protein sequences. Progress has been stymied by a lack of suitable methods to detect clusters and to estimate the extent of clustering in dis... | The invention and application of high-throughput technologies for DNA sequencing have resulted in an increasing abundance of biological sequence data. DNA or protein sequence data are naturally arranged as discrete linear sequences, and one of the fundamental challenges of analysis of sequence data is the description o... | Analysis of discrete linear sequences has played an increasingly important role in biology. In particular, the detection of heterogeneous regions among sequences can aid in understanding the heterogeneous processes that act upon those regions [1],[2]. Therefore, determining whether specified types or categories of site... |
10.1371/journal.pcbi.1004952 | Filopodial-Tension Model of Convergent-Extension of Tissues | In convergent-extension (CE), a planar-polarized epithelial tissue elongates (extends) in-plane in one direction while shortening (converging) in the perpendicular in-plane direction, with the cells both elongating and intercalating along the converging axis. CE occurs during the development of most multicellular organ... | The development of an embryo from a fertilized egg to an adult organism requires not only cell proliferation and differentiation, but also numerous types of tissue restructuring. The development of a relatively round initial embryo into one elongated along its rostral-caudal axis involves coordinated tissue elongation ... | Embryonic development requires numerous changes in tissue morphology. Convergent-extension (CE) is a basic tissue shape change [1–9], during which cells in an epithelial sheet rearrange to narrow (converge) the tissue along one planar axis while lengthening (extending) it along the perpendicular planar axis (Fig 1). Al... |
10.1371/journal.pbio.1002089 | ATPase-Dependent Control of the Mms21 SUMO Ligase during DNA Repair | Modification of proteins by SUMO is essential for the maintenance of genome integrity. During DNA replication, the Mms21-branch of the SUMO pathway counteracts recombination intermediates at damaged replication forks, thus facilitating sister chromatid disjunction. The Mms21 SUMO ligase docks to the arm region of the S... | The modification of target proteins by conjugation to SUMO—a small protein that acts as a regulatory tag—is essential for maintaining the integrity of genomes in most eukaryotic organisms. One critical step during the attachment of SUMO is the activation of the enzymes that catalyze this reaction—E1, E2, and the SUMO l... | During mitotic division, cells dedicate a large part of their efforts to accurately maintain and transmit genetic material to their offspring. The Structural Maintenance of Chromosomes (SMC) complexes play key structural roles in chromosome organization and dynamics and are crucial to maintain the integrity of the geno... |
10.1371/journal.pbio.3000094 | Contingency in the convergent evolution of a regulatory network: Dosage compensation in Drosophila | The repeatability or predictability of evolution is a central question in evolutionary biology and most often addressed in experimental evolution studies. Here, we infer how genetically heterogeneous natural systems acquire the same molecular changes to address how genomic background affects adaptation in natural popul... | We address how predictable evolution is at the DNA sequence level in nature by studying the parallel evolution of a phenotype that is well understood at the molecular level: the acquisition of sex chromosome dosage compensation in fruit flies. While female flies have two X chromosomes, the males have to compensate by u... | What would happen if we “replay the tape of life” [1]? The question of whether adaptation follows a deterministic route largely prescribed by the environment or whether evolution is fundamentally unpredictable and can proceed along a large number of alternative trajectories has until recently been a fascinating problem... |
10.1371/journal.ppat.1005974 | Dual microRNA Screens Reveal That the Immune-Responsive miR-181 Promotes Henipavirus Entry and Cell-Cell Fusion | Hendra and Nipah viruses (family Paramyxoviridae, genus Henipavirus) are bat-borne viruses that cause fatal disease in humans and a range of other mammalian species. Gaining a deeper understanding of host pathways exploited by henipaviruses for infection may identify targets for new anti-viral therapies. Here we have p... | The henipaviruses Hendra and Nipah are bat-borne paramyxoviruses that are highly pathogenic in humans. Until recently the constraints of working at biosafety level 4 had hindered the large scale study of host factors associated with henipavirus infection. MicroRNAs are a class of single-stranded non-coding RNAs that re... | Hendra virus (HeV) and Nipah virus (NiV) are highly pathogenic zoonotic paramyxoviruses belonging to the genus Henipavirus [1]. First isolated in Australia in 1994, HeV disease has caused seven clinically confirmed human cases with four fatalities. NiV initially appeared in Malaysia in 1998–1999, resulting in 105 human... |
10.1371/journal.pntd.0001936 | Clofazimine Modulates the Expression of Lipid Metabolism Proteins in Mycobacterium leprae-Infected Macrophages | Mycobacterium leprae (M. leprae) lives and replicates within macrophages in a foamy, lipid-laden phagosome. The lipids provide essential nutrition for the mycobacteria, and M. leprae infection modulates expression of important host proteins related to lipid metabolism. Thus, M. leprae infection increases the expression... | Leprosy, caused by Mycobacterium leprae (M. leprae), is an ancient infectious disease that remains the leading infectious cause of disability. After infection, M. leprae lives inside host macrophages that contain a large amount of lipids, which is thought to be an essential microenvironment for M. leprae to survive in ... | Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae), which is a typical intracellular pathogen that parasitizes tissue macrophages (histiocytes) and Schwann cells of the peripheral nerves of the dermis. Although its prevalence has declined over the last several decades due to the introduc... |
10.1371/journal.pgen.1003226 | TDP2–Dependent Non-Homologous End-Joining Protects against Topoisomerase II–Induced DNA Breaks and Genome Instability in Cells and In Vivo | Anticancer topoisomerase “poisons” exploit the break-and-rejoining mechanism of topoisomerase II (TOP2) to generate TOP2-linked DNA double-strand breaks (DSBs). This characteristic underlies the clinical efficacy of TOP2 poisons, but is also implicated in chromosomal translocations and genome instability associated wit... | DNA double-strand breaks (DSBs) are dangerous because they can lead to cellular death and tissue degeneration if not repaired, or to genome rearrangements, which are a common hallmark of cancer, if repaired incorrectly. Although required for all chromosomal transitions in cells, transient DNA cleavage by topoisomerase ... | The double-stranded helical structure of DNA creates topological problems in all processes that involve opening of the double helix and accessing the genetic information [1], [2]. In particular, the transcription and duplication of DNA and its condensation into chromosomes generates knots and tangles that need to be re... |
10.1371/journal.pgen.1004696 | Fast Evolution from Precast Bricks: Genomics of Young Freshwater Populations of Threespine Stickleback Gasterosteus aculeatus | Adaptation is driven by natural selection; however, many adaptations are caused by weak selection acting over large timescales, complicating its study. Therefore, it is rarely possible to study selection comprehensively in natural environments. The threespine stickleback (Gasterosteus aculeatus) is a well-studied model... | Adaptation to novel environments is a keystone of evolution. There is only a handful of natural and experimental systems in which the process of adaptation has been studied in detail, and each studied system brings its own surprises with regard to the number of loci involved, dynamics of adaptation, extent of interacti... | Studies of adaptation in nature are complicated by the typically long timescales at which evolution proceeds, and therefore are rather rare (e.g. [1]–[3]). Positive selection, the hallmark of adaptation, can be inferred from patterns of divergence and/or polymorphism in genome comparisons. While experimental evolution ... |
10.1371/journal.pgen.1005948 | Regulation of Gap Junction Dynamics by UNC-44/ankyrin and UNC-33/CRMP through VAB-8 in C. elegans Neurons | Gap junctions are present in both vertebrates and invertebrates from nematodes to mammals. Although the importance of gap junctions has been documented in many biological processes, the molecular mechanisms underlying gap junction dynamics remain unclear. Here, using the C. elegans PLM neurons as a model, we show that ... | The nervous system is made up of individual neurons connected by junction structures called synapses. There are two fundamentally different types of synapses: chemical synapses and electrical synapses (also called gap junctions). Through studies in different model organisms, we have gained rich knowledge about the deve... | Gap junctions were first discovered in the myocardium and nerves for their properties of electrical transmission between two adjacent cells [1,2], and they are clusters of channels connecting two cells to allow direct transfer of ions and small molecules [3–5]. Gap junctions play essential roles in many biological proc... |
10.1371/journal.pmed.1002512 | Prevalence of sexually transmitted infections among young people in South Africa: A nested survey in a health and demographic surveillance site | Sexually transmitted infections (STIs) and bacterial vaginosis (BV) are associated with increased transmission of HIV, and poor reproductive and sexual health. The burden of STIs/BV among young people is unknown in many high HIV prevalence settings. We conducted an acceptability, feasibility, and prevalence study of ho... | Adolescents and young adults are particularly vulnerable to sexually transmitted infections (STIs).
The first strategic direction of the WHO Global Health Sector Strategy on Sexually Transmitted Infections 2016–2021 is to collect information on STI prevalence and incidence across representative populations.
There is ev... | In 2012, 286 million people aged 12–24 years lived in Africa, accounting for 18% of the global youth population. By 2040, the number of young people in Africa is projected to increase by 60% to 466 million [1]. Health interventions targeted at this age group are important for current and future adult health and for the... |
10.1371/journal.pcbi.1003656 | Variability of Metabolite Levels Is Linked to Differential Metabolic Pathways in Arabidopsis's Responses to Abiotic Stresses | Constraint-based approaches have been used for integrating data in large-scale metabolic networks to obtain insights into metabolism of various organisms. Due to the underlying steady-state assumption, these approaches are usually not suited for making predictions about metabolite levels. Here, we ask whether we can ma... | Organisms are usually exposed to changing environments and balance these perturbations by altering their metabolic state. Gaining a deeper understanding of metabolic adjustment to varying external conditions is important for the development of advanced engineering strategies for microorganisms as well as for higher pla... | Organisms, especially plants, are exposed to almost perpetually changing environments (e.g., light intensity and quality, nutrient and water supply) to which they respond by readjusting their cellular setup to efficiently utilize available resources and to ensure viability [1]–[6]. These transitions are often systemic ... |
10.1371/journal.ppat.1002615 | An “Escape Clock” for Estimating the Turnover of SIV DNA in Resting CD4+ T Cells | Persistence of HIV DNA presents a major barrier to the complete control of HIV infection under current therapies. Most studies suggest that cells with latently integrated HIV decay very slowly under therapy. However, it is much more difficult to study the turnover and persistence of HIV DNA during active infection. We ... | New treatments for HIV have proved very successful at controlling viral replication and preventing the onset of AIDS. However, these treatments must be continued for life, because if they are stopped the virus rapidly ‘rebounds’ to its original levels. The reason for this rebound is the existence of a population of vir... | Treatment of HIV-1 infected individuals with highly active antiretroviral therapy (HAART) can suppress plasma viral RNA levels below the threshold of detection by standard diagnostic assays. However after cessation of even long-term HAART, virus replication is quickly re-established [1]–[4]. A barrier to viral eradicat... |
10.1371/journal.pbio.1002349 | Wuho Is a New Member in Maintaining Genome Stability through its Interaction with Flap Endonuclease 1 | Replication forks are vulnerable to wayward nuclease activities. We report here our discovery of a new member in guarding genome stability at replication forks. We previously isolated a Drosophila mutation, wuho (wh, no progeny), characterized by a severe fertility defect and affecting expression of a protein (WH) in a... | Accurate genome replication is essential for the transmission of genetic information, and this process is vulnerable to factors that can induce DNA damage or block replication. To avoid this and achieve genome stability, many enzymes need to coordinate their activities at the replication forks (the area where the two D... | Faithful DNA replication is important for both the proliferation of cells and transmission of genetic information. This key biological process is vulnerable to many impediments, including numerous intrinsic and extrinsic agents that can damage DNA and create blockage for the movement of enzymatic machinery at the repli... |
10.1371/journal.pntd.0005899 | Cost-effectiveness of a national enterovirus 71 vaccination program in China | Enterovirus 71 (EV71) has caused great morbidity, mortality, and use of health service in children younger than five years in China. Vaccines against EV71 have been proved effective and safe by recent phase 3 trials and are now available in China. The purpose of this study was to evaluate the health impact and cost-eff... | Enterovirus 71 (EV71) has caused great morbidity, mortality, and use of health service in children younger than five years in China. Recently, effective and safe vaccines against EV71 have been approved. Whether EV71 vaccination should be included as part of China’s routine childhood immunization schedule is unknown. I... | Enterovirus 71 (EV71) is one of the major agents that cause outbreaks of hand, foot, and mouth disease (HFMD) and herpangina worldwide[1]. Since the 1990s, the epidemic has mainly affected the Asia-Pacific region and EV71 has become a major public health issue across this region[2,3,4,5].
HFMD is characterized with fe... |
10.1371/journal.ppat.1004577 | Extreme Divergence of Wolbachia Tropism for the Stem-Cell-Niche in the Drosophila Testis | Microbial tropism, the infection of specific cells and tissues by a microorganism, is a fundamental aspect of host-microbe interactions. The intracellular bacteria Wolbachia have a peculiar tropism for the stem cell niches in the Drosophila ovary, the microenvironments that support the cells producing the eggs. The mol... | Microbes evolve to infect structures favoring their transmission in host populations. A large fraction of insects are infected with Wolbachia bacteria. Usually Wolbachia are transmitted the same way we inherit our mitochondria, via the eggs from the mother. In fruit flies, to favor maternal transmission, Wolbachia infe... | The evolutionary interests of males and females are frequently divergent. Sexual conflict arises when phenotypes that enhance the reproductive success of one sex reduces the fitness of the other sex [1]. A well-characterized example in Drosophila is sperm competition between males. Sperm competition results in rapid ev... |
10.1371/journal.pgen.1002128 | A Functional Variant in MicroRNA-146a Promoter Modulates Its Expression and Confers Disease Risk for Systemic Lupus Erythematosus | Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a strong genetic predisposition, characterized by an upregulated type I interferon pathway. MicroRNAs are important regulators of immune homeostasis, and aberrant microRNA expression has been demonstrated in patients with autoimmune diseases. We re... | Genome-wide association studies have identified quite a number of susceptibility loci associated with complex diseases such as systemic lupus erythematosus (SLE). However, for most of them, the intrinsic link between genetic variation and disease mechanism is not fully understood. SLE is characterized by a significantl... | Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a complex etiology and diverse clinical manifestations [1]. The role of genetic factors in the SLE risk has long been established, and demonstrated in familial aggregations, twin studies, and sibling recurrence rates [2]. Recently, high-throughput ... |
10.1371/journal.pcbi.1007229 | Predictions of time to HIV viral rebound following ART suspension that incorporate personal biomarkers | Antiretroviral therapy (ART) effectively controls HIV infection, suppressing HIV viral loads. Suspension of therapy is followed by rebound of viral loads to high, pre-therapy levels. However, there is significant heterogeneity in speed of rebound, with some rebounds occurring within days, weeks, or sometimes years. We ... | Antiretroviral therapy (ART) effectively controls HIV infection, holding HIV viral loads to levels undetectable by commercial assays. Therapy interruption is followed by rebound of viral loads to high, pre-therapy levels, but there is significant heterogeneity in the timing of the rebound to those high levels. Some reb... | Antiretroviral therapy (ART) for HIV infection can very effectively control the infection and hold the amount of circulating virus below the level detectable by clinical assays, improving both the quality and length of life. ART suspension generally is followed by HIV rebound to high viral loads [1], and consequently t... |
10.1371/journal.pgen.1006773 | Recurrent promoter mutations in melanoma are defined by an extended context-specific mutational signature | Sequencing of whole tumor genomes holds the promise of revealing functional somatic regulatory mutations, such as those described in the TERT promoter. Recurrent promoter mutations have been identified in many additional genes and appear to be particularly common in melanoma, but convincing functional data such as infl... | Cancer is caused by somatic mutations that alter cell behavior. While such mutations typically occur in protein-coding genes, recent studies describe individual positions in gene regulatory regions (promoters) that are recurrently mutated in many independent tumors. This suggests that positive selection could be acting... | A major challenge in cancer genomics is the separation of functional somatic driver mutations from non-functional passengers. This problem is relevant not only in coding regions, but also in the context of non-coding regulatory regions such as promoters, where putative driver mutations are now mappable with relative ea... |
10.1371/journal.pgen.1007568 | cis-regulatory architecture of a short-range EGFR organizing center in the Drosophila melanogaster leg | We characterized the establishment of an Epidermal Growth Factor Receptor (EGFR) organizing center (EOC) during leg development in Drosophila melanogaster. Initial EGFR activation occurs in the center of leg discs by expression of the EGFR ligand Vn and the EGFR ligand-processing protease Rho, each through single enhan... | The EGFR signaling pathway plays a major role in innumerable developmental processes in all animals and its deregulation leads to different types of cancer, as well as many other developmental diseases in humans. Here we explored the integration of inputs from the Wnt- and TGF-beta signaling pathways and the leg-specif... | cis-regulatory modules (CRMs) are critical for the development and evolution of all organisms. CRMs integrate the information that a single cell or group of cells receives and, in response, trigger changes in cellular and tissue fate specification [reviewed in 1]. The Drosophila melanogaster leg imaginal disc, which gi... |
10.1371/journal.pcbi.1006549 | Simulations of blood as a suspension predicts a depth dependent hematocrit in the circulation throughout the cerebral cortex | Recent advances in modeling oxygen supply to cortical brain tissue have begun to elucidate the functional mechanisms of neurovascular coupling. While the principal mechanisms of blood flow regulation after neuronal firing are generally known, mechanistic hemodynamic simulations cannot yet pinpoint the exact spatial and... | The brain’s astonishing cognitive capacity depends on the coordination between neurons and the cerebral circulation, a system known as the neurovascular unit. The spatial and temporal coupling between these two networks is the object of intense research. However, the concise anatomical description of the cerebral circu... | Metabolic activity of the brain is controlled by a complex system of neuroreceptors, small molecular regulators such as nitric oxide, hormones and proteins. The supply, clearance, and balance of metabolites, oxygen, glucose and waste are controlled by the cerebral circulation which is coupled with the cerebrospinal and... |
10.1371/journal.pgen.1007095 | A MIG-15/JNK-1 MAP kinase cascade opposes RPM-1 signaling in synapse formation and learning | The Pam/Highwire/RPM-1 (PHR) proteins are conserved intracellular signaling hubs that regulate synapse formation and axon termination. The C. elegans PHR protein, called RPM-1, acts as a ubiquitin ligase to inhibit the DLK-1 and MLK-1 MAP kinase pathways. We have identified several kinases that are likely to form a new... | We explored the molecular mechanisms that govern synapse formation in vivo using the nematode C. elegans. Our results have identified a conserved MIG-15/JNK-1 MAPK pathway that restricts formation of glutamatergic, neuron-neuron synapses in the mechanosensory neurons, but does not restrict synapse formation in motor ne... | Information is relayed throughout the nervous system via chemical synapses, and the process of synapse formation is essential for construction of neural circuitry [1, 2]. In the central nervous system, most synaptic connections are glutamatergic and often referred to as central synapses.
Different neurons in the nemat... |
10.1371/journal.pcbi.1004888 | Identifying Network Perturbation in Cancer | We present a computational framework, called DISCERN (DIfferential SparsE Regulatory Network), to identify informative topological changes in gene-regulator dependence networks inferred on the basis of mRNA expression datasets within distinct biological states. DISCERN takes two expression datasets as input: an express... | Certain genes can regulate other genes’ expression and activity levels to perform key biological processes in a cell. Understanding how genes affect expression levels among one another is a fundamental goal in molecular biology. New statistical techniques that analyze genome-wide mRNA expression data obtained from diff... | Genes do not act in isolation but instead work as part of complex networks to perform various cellular processes. Many human diseases including cancer are caused by dysregulated genes, with underlying DNA or epigenetic mutations within the gene region or its regulatory elements, leading to perturbation (topological cha... |
10.1371/journal.pntd.0004870 | Insights into an Optimization of Plasmodium vivax Sal-1 In Vitro Culture: The Aotus Primate Model | Malaria is one of the most significant tropical diseases, and of the Plasmodium species that cause human malaria, P. vivax is the most geographically widespread. However, P. vivax remains a relatively neglected human parasite since research is typically limited to laboratories with direct access to parasite isolates fr... | Plasmodium vivax has a tremendous impact on public health; accounting for 13.8 million cases of clinical illness estimated in 2015, causing a wide spectrum of symptoms including severe disease. Development of new therapies requires a better understanding of the parasite’s biology, however, understanding the fundamental... | Plasmodium vivax is the most geographically widespread human malaria parasite causing 13.8 million clinical cases every year [1]. While P. vivax was once considered the benign malaria, it can cause severe disease and death [2,3]. P. vivax presents unique challenges compared to other human malaria parasites. P. vivax fo... |
10.1371/journal.pgen.1007849 | Elevated pyrimidine dimer formation at distinct genomic bases underlies promoter mutation hotspots in UV-exposed cancers | Sequencing of whole cancer genomes has revealed an abundance of recurrent mutations in gene-regulatory promoter regions, in particular in melanoma where strong mutation hotspots are observed adjacent to ETS-family transcription factor (TF) binding sites. While sometimes interpreted as functional driver events, these mu... | Cancer is caused by somatic mutations that typically occur in protein-coding genes. However, the advent of whole genome sequencing has made it possible to venture beyond protein-coding DNA in search of non-coding mutations with putative cancer driver roles. Indeed, recent studies, in particular in skin cancers, describ... | Whole genome analysis of cancer genomes has the potential to reveal non-coding somatic mutations that drive tumor development, but it remains a major challenge to separate these events from non-functional passengers. The main principle for identifying drivers is recurrence across independent tumors, suggestive of posit... |
10.1371/journal.pgen.1002010 | A Bow-Tie Genetic Architecture for Morphogenesis Suggested by a Genome-Wide RNAi Screen in Caenorhabditis elegans | During animal development, cellular morphogenesis plays a fundamental role in determining the shape and function of tissues and organs. Identifying the components that regulate and drive morphogenesis is thus a major goal of developmental biology. The four-celled tip of the Caenorhabditis elegans male tail is a simple ... | Morphogenesis is a process in which cells change their shape and position to give rise to mature structures. Elucidation of the molecular basis of morphogenesis and its regulation would be a major step towards understanding organ formation and functionality. We focus on a powerful model for morphogenesis, the four-cell... | Morphogenesis involves the coordinated change in the shape of cells and tissues during development, eventually giving rise to functional structures in the adult animal. Such coordinated change must occur at the correct time and in the proper position. In the case of structures that differ between the sexes, this proces... |
10.1371/journal.pcbi.1005475 | Mechanisms underlying different onset patterns of focal seizures | Focal seizures are episodes of pathological brain activity that appear to arise from a localised area of the brain. The onset patterns of focal seizure activity have been studied intensively, and they have largely been distinguished into two types—low amplitude fast oscillations (LAF), or high amplitude spikes (HAS). H... | Much attention has been devoted to the mechanisms underlying epileptic seizures. However, so far, the morphology of how seizures start on electrographic recordings (i.e. the seizure onset pattern) has been neglected as a potential indicator of the underlying dynamic mechanism. In this work, we take a spatio-temporal mo... | Focal seizures are episodes of highly disruptive brain activity, which are considered to arise from local sites of pathological abnormality in the brain. Identification of the precise focal origin in a given patient is crucial for the clinical management of their epilepsy. Various clinical evidence can point to the nat... |
10.1371/journal.pbio.1002330 | ELF5 Drives Lung Metastasis in Luminal Breast Cancer through Recruitment of Gr1+ CD11b+ Myeloid-Derived Suppressor Cells | During pregnancy, the ETS transcription factor ELF5 establishes the milk-secreting alveolar cell lineage by driving a cell fate decision of the mammary luminal progenitor cell. In breast cancer, ELF5 is a key transcriptional determinant of tumor subtype and has been implicated in the development of insensitivity to ant... | The transcription factor Elf5 defines hormone-insensitive and endocrine-therapy–resistant breast cancer. In this study, we have discovered that ELF5 drives the spread of tumor cells to the lungs. We demonstrate that the underlying mechanism for this metastatic spread is via recruitment of the innate immune system. Inte... | Breast cancer is a heterogeneous disease in which subtypes predicting differential clinical outcome are recognized based on shared patterns of gene expression and mutation, indicating a shared path to cancer [1]. The most striking subtype distinction in breast cancer is provided by expression of ESR1, the estrogen rece... |
10.1371/journal.pgen.1001251 | Thymus-Associated Parathyroid Hormone Has Two Cellular Origins with Distinct Endocrine and Immunological Functions | In mammals, parathyroid hormone (PTH) is a key regulator of extracellular calcium and inorganic phosphorus homeostasis. Although the parathyroid glands were thought to be the only source of PTH, extra-parathyroid PTH production in the thymus, which shares a common origin with parathyroids during organogenesis, has been... | Due to the important role of PTH in the regulation of physiological activities, disorders in PTH production can cause many diseases in humans. Thus it is very important to understand where PTH is produced and how it is regulated. Many people have been found to have ectopic and supernumerary parathyroid glands without c... | Mammals have evolved an integrated system consisting of the parathyroid glands, bone, kidney and the intestine, to regulate ionized calcium and inorganic phosphorus homeostasis in the extracellular environment [1]. Circulating ionized Ca2+ and inorganic phosphorus are required for a wide range of physiological activiti... |
10.1371/journal.ppat.1003776 | The Neonatal Fc Receptor (FcRn) Enhances Human Immunodeficiency Virus Type 1 (HIV-1) Transcytosis across Epithelial Cells | The mechanisms by which human immunodeficiency virus type 1 (HIV-1) crosses mucosal surfaces to establish infection are unknown. Acidic genital secretions of HIV-1-infected women contain HIV-1 likely coated by antibody. We found that the combination of acidic pH and Env-specific IgG, including that from cervicovaginal ... | HIV-1 causes a sexually transmitted disease. However, the mechanisms employed by the virus to cross genital tract tissue and establish infection are uncertain. Since cervicovaginal fluid is acidic and HIV-1 in cervicovaginal fluid is likely coated with antibodies, we explored the effect of low pH and HIV-1-specific ant... | Sexual transmission of HIV-1 requires that virus establish infection across genital tract or intestinal tissue. Sexually transmitted infections, other causes of inflammation, and localized trauma may allow susceptible CD4+ target cells at skin or mucosal surfaces to become directly exposed to secretions from infected s... |
10.1371/journal.pcbi.1005310 | Customized Regulation of Diverse Stress Response Genes by the Multiple Antibiotic Resistance Activator MarA | Stress response networks frequently have a single upstream regulator that controls many downstream genes. However, the downstream targets are often diverse, therefore it remains unclear how their expression is specialized when under the command of a common regulator. To address this, we focused on a stress response net... | Bacteria can sense and respond to stress in their environment. This process is often coordinated by a master regulator that turns on or off many downstream genes, allowing the cell to survive the stress. However, individual genes encode products that are diverse and optimal expression for each gene may differ. Here, we... | Genetic networks often feature master regulators that control suites of downstream genes. This type of architecture is particularly common in stress response; examples include Msn2 and Crz1 in Saccharomyces cerevisiae, σB in Bacillus subtillis, and the multiple antibiotic resistance activator MarA in Escherichia coli [... |
10.1371/journal.ppat.1002104 | Hemoglobin Promotes Staphylococcus aureus Nasal Colonization | Staphylococcus aureus nasal colonization is an important risk factor for community and nosocomial infection. Despite the importance of S. aureus to human health, molecular mechanisms and host factors influencing nasal colonization are not well understood. To identify host factors contributing to nasal colonization, we ... | Staphylococcus aureus is a medically important human pathogen that is found in the nasal passages of approximately 1/3 of the population. The nose serves as a reservoir for spread of this pathogen and predisposes the host to potential infection. Factors contributing to S. aureus nasal colonization are only beginning to... | Staphylococcus aureus is a human commensal and the causative agent of many serious acute and chronic infections [1]. The primary reservoir for S. aureus is the nasal cavity [2], [3]. Asymptomatic colonization occurs in approximately 20% of the normal population, another 60% are transiently colonized and the remaining 2... |
10.1371/journal.ppat.1005434 | Establishment of a Wolbachia Superinfection in Aedes aegypti Mosquitoes as a Potential Approach for Future Resistance Management | Wolbachia pipientis is an endosymbiotic bacterium estimated to chronically infect between 40–75% of all arthropod species. Aedes aegypti, the principle mosquito vector of dengue virus (DENV), is not a natural host of Wolbachia. The transinfection of Wolbachia strains such as wAlbB, wMel and wMelPop-CLA into Ae. aegypti... | Dengue fever is a viral disease transmitted by Aedes aegypti mosquitoes and more than 30% of the world’s population is at risk. The control of dengue virus (DENV) transmission has been problematic as no vaccines or drugs are effective against the four serotypes. Vector control of mosquitoes during epidemics is consider... | The endosymbiotic bacterium Wolbachia pipientis was first discovered in 1924 by Marshall Hertig and Burt Wolbach in ovaries of the mosquito Culex pipiens [1]. Wolbachia is a Gram-negative, obligate endosymbiont that is maternally transmitted [2]. It is estimated that around 40–75% of all arthropod species are infected ... |
10.1371/journal.pgen.1005508 | A NIMA-Related Kinase Suppresses the Flagellar Instability Associated with the Loss of Multiple Axonemal Structures | CCDC39 and CCDC40 were first identified as causative mutations in primary ciliary dyskinesia patients; cilia from patients show disorganized microtubules, and they are missing both N-DRC and inner dynein arms proteins. In Chlamydomonas, we used immunoblots and microtubule sliding assays to show that mutants in CCDC40 (... | Cilia are specialized projections found on the surface of eukaryotic cells. They play crucial sensory functions, as well as motile functions needed for clearing airways or propelling cells. Ciliary motility is perturbed in the inherited disease, Primary Ciliary Dyskinesia (PCD). Two coiled coil domain-containing (CCDC3... | Defects in ciliary assembly and function cause a wide range of human diseases and syndromes called ciliopathies. Primary ciliary dyskinesia (PCD) is diagnosed by defects in ciliary motility, and is associated with a genetically heterogeneous group of recessive disorders [1]. Mutations causing PCD have been identified i... |
10.1371/journal.ppat.1003376 | A Unique Spumavirus Gag N-terminal Domain with Functional Properties of Orthoretroviral Matrix and Capsid | The Spumaretrovirinae, or foamyviruses (FVs) are complex retroviruses that infect many species of monkey and ape. Although FV infection is apparently benign, trans-species zoonosis is commonplace and has resulted in the isolation of the Prototypic Foamy Virus (PFV) from human sources and the potential for germ-line tra... | Foamyviruses (FVs) or spuma-retroviruses derive their name from the cytopathic effects they cause in cell culture. By contrast, infection in humans is benign and FVs have entered the human population through zoonosis from apes resulting in the emergence of Prototypic Foamyvirus (PFV). Like all retroviruses FVs contain ... | Spuma- or foamy viruses (FVs) are complex retroviruses and constitute the only members of the Spumaretrovirinae subfamily within the Retroviridae family. They have been isolated from a variety of primate hosts [1], [2], [3], [4] as well as from cats [5], [6], [7], cattle [8], horses [9] and sheep [10]. Endogenous FVs h... |
10.1371/journal.pgen.1004293 | Drosophila Embryogenesis Scales Uniformly across Temperature in Developmentally Diverse Species | Temperature affects both the timing and outcome of animal development, but the detailed effects of temperature on the progress of early development have been poorly characterized. To determine the impact of temperature on the order and timing of events during Drosophila melanogaster embryogenesis, we used time-lapse im... | Temperature profoundly impacts the rate of development of “cold-blooded” animals, which proceeds far faster when it is warm. There is, however, no universal relationship. Closely related species can develop at markedly different speeds at the same temperature. This creates a major challenge when comparing development a... | It has long been known that Drosophila, like most poikilotherms, develops faster at higher temperatures, with embryonic [1], larval [1], [2], and pupal stages [3], [4], as well as total lifespan [5], [6] showing similar logarithmic trends. While genetics, ecology, and evolution of this trait have been investigated for ... |
10.1371/journal.pgen.1008326 | Methyl-CpG-binding domain 9 (MBD9) is required for H2A.Z incorporation into chromatin at a subset of H2A.Z-enriched regions in the Arabidopsis genome | The SWR1 chromatin remodeling complex, which deposits the histone variant H2A.Z into nucleosomes, has been well characterized in yeast and animals, but its composition in plants has remained uncertain. We used the conserved SWR1 subunit ACTIN RELATED PROTEIN 6 (ARP6) as bait in tandem affinity purification experiments ... | The histone H2A variant, H2A.Z, is found in all known eukaryotes and plays important roles in transcriptional regulation. H2A.Z is selectively incorporated into nucleosomes within many genes by the activity of a conserved ATP-dependent chromatin remodeling complex in yeast, insects, and mammals. Whether this complex ex... | Nucleosomes, the fundamental units of chromatin that consist of ~147 bp of DNA wrapped around a histone octamer, efficiently condense large eukaryotic DNA molecules inside the nucleus. At the same time, nucleosomes present a physical barrier that restricts the access of DNA-binding proteins to regulatory sequences. Thi... |
10.1371/journal.pntd.0004810 | Relationship between Community Drug Administration Strategy and Changes in Trachoma Prevalence, 2007 to 2013 | Australia is the only high income country with persisting endemic trachoma. A national control program involving mass drug administration with oral azithromycin, in place since 2006, has some characteristics which differ from programs in low income settings, particularly in regard to the use of a wider range of treatme... | Australia is the only high income country with persisting endemic trachoma and a national control program has been in place since 2006. The program involves annual screening of children for trachoma in communities designated to be at high risk of disease and treatment of those affected with the antibiotic azithromycin.... | Trachoma, caused by serotypes of Chlamydia trachomatis is a major cause of blindness globally.[1] In 1997 The Alliance for the Global Elimination of Blinding Trachoma by 2020 (GET 2020) initiative was launched. Supported by the World Health Organization (WHO), the alliance promotes its goal of elimination through the S... |
10.1371/journal.pntd.0002578 | Knockdown of Asparagine Synthetase A Renders Trypanosoma brucei Auxotrophic to Asparagine | Asparagine synthetase (AS) catalyzes the ATP-dependent conversion of aspartate into asparagine using ammonia or glutamine as nitrogen source. There are two distinct types of AS, asparagine synthetase A (AS-A), known as strictly ammonia-dependent, and asparagine synthetase B (AS-B), which can use either ammonia or gluta... | The amino acid asparagine is important not only for protein biosynthesis, but also for nitrogen homeostasis. Asparagine synthetase catalyzes the synthesis of this amino acid. There are two forms of asparagine synthetase, A and B. The presence of type A in trypanosomes, and its absence in humans, makes this protein a po... | Asparagine is a naturally occurring non-essential amino acid found in many proteins. Due to its high nitrogen/carbon ratio, asparagine is likely to be linked to nitrogen homeostasis and protein biosynthesis [1]. AS is the protein involved in asparagine biosynthesis. There are two distinct types of AS, AS-A and AS-B, en... |
10.1371/journal.ppat.1006538 | A SIV molecular clone that targets the CNS and induces neuroAIDS in rhesus macaques | Despite effective control of plasma viremia with the use of combination antiretroviral therapies (cART), minor cognitive and motor disorders (MCMD) persist as a significant clinical problem in HIV-infected patients. Non-human primate models are therefore required to study mechanisms of disease progression in the centra... | Despite effective control of plasma viremia with the use of combination antiretroviral therapies, neurologic disease resulting from HIV-infection of the central nervous system (CNS) persists as a significant clinical problem. Non-human primate models are therefore required to study mechanisms of disease progression in ... | Entry of HIV to the CNS occurs early in the course of infection and can progress to HIV-associated dementia (HAD) or HIV encephalitis (HIVE) [1]. HAD is a neurological syndrome that affects 20–30% of infected individuals in the later stages of HIV-infection and includes a range of cognitive and motor disorders, such as... |
10.1371/journal.pntd.0006151 | In vitro studies of Rickettsia-host cell interactions: Confocal laser scanning microscopy of Rickettsia helvetica-infected eukaryotic cell lines | Rickettsia (R.) helvetica is the most prevalent rickettsia found in Ixodes ricinus ticks in Germany. Several studies reported antibodies against R. helvetica up to 12.5% in humans investigated, however, fulminant clinical cases are rare indicating a rather low pathogenicity compared to other rickettsiae. We investigate... | The pathogenicity of Rickettsia helvetica has not been investigated in depth to date. In humans, seroprevalences up to 12.5% against R. helvetica have been demonstrated with forest workers being predisposed to infection. However, fulminant clinical cases are rare indicating a rather low pathogenicity compared to other ... | Rickettsia (R.) helvetica is the most prevalent rickettsia found in Ixodes (I.) ricinus ticks in Germany with varying prevalence up to 17% [1–4]. The organism has mainly been considered non-pathogenic and affected patients usually show a mild disease, manifesting in non-specific fever without erythema (so-called unerup... |
10.1371/journal.pgen.1007157 | The Arabidopsis SUMO E3 ligase SIZ1 mediates the temperature dependent trade-off between plant immunity and growth | Increased ambient temperature is inhibitory to plant immunity including auto-immunity. SNC1-dependent auto-immunity is, for example, fully suppressed at 28°C. We found that the Arabidopsis sumoylation mutant siz1 displays SNC1-dependent auto-immunity at 22°C but also at 28°C, which was EDS1 dependent at both temperatur... | Ambient temperature is a major actor in plant immunity and in growth regulation. Foremost, high temperature (>27°C) is known to block plant defence responses. High temperature also alters the plant morphology by inducing elongation growth, which facilitates plant ‘cooling’. This process is called thermomorphogenesis. I... | Ambient temperature is a major factor that affects plant growth and development, but also plant immunity [1,2]. In particular, the temperature range of 16-32ºC modulates the output of many plant immune receptors. For example, the tobacco N (Necrosis) gene fails to trigger resistance against Tobacco mosaic virus (TMV) a... |
10.1371/journal.ppat.1003697 | MicroRNA-155 Promotes Autophagy to Eliminate Intracellular Mycobacteria by Targeting Rheb | Mycobacterium tuberculosis is a hard-to-eradicate intracellular pathogen that infects one-third of the global population. It can live within macrophages owning to its ability to arrest phagolysosome biogenesis. Autophagy has recently been identified as an effective way to control the intracellular mycobacteria by enhan... | microRNA-155 (miR-155) plays an essential role in regulating the host immune response by post-transcriptionally repressing the expression of target genes. However, little is known regarding its activity in modulating autophagy, an important host defense mechanism against intracellular bacterial infection. Mycobacterium... | Mycobacterium tuberculosis (M. tuberculosis) is a hard-to-eradicate intracellular pathogen [1] that infects approximately one-third of the global population, and causes 1.5 million deaths annually [2]. However, only 10% of latent infections lead to active tuberculosis, indicating the importance of host immune defense a... |
10.1371/journal.pgen.1006837 | A conserved role for the ESCRT membrane budding complex in LINE retrotransposition | Long interspersed nuclear element-1s (LINE-1s, or L1s) are an active family of retrotransposable elements that continue to mutate mammalian genomes. Despite the large contribution of L1 to mammalian genome evolution, we do not know where active L1 particles (particles in the process of retrotransposition) are located i... | Long interspersed nuclear elements (LINEs) are a class of retrotransposable elements that mutate mammalian genomes. LINEs have been highly successful in the human genome, multiplying to over 800,000 copies. The LINE-encoded replication machinery is also used by other retrotransposons, and in total, has been responsible... | Long Interspersed Nuclear Elements (LINEs) are an ancient class of non-long terminal repeat (non-LTR) retrotransposable elements widely dispersed among eukaryotes. These elements can be categorized into distinct clades based on homology of conserved domains [1]. The L1 clade is of particular interest because its namesa... |
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