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10.1371/journal.pgen.1007730 | The telomere bouquet is a hub where meiotic double-strand breaks, synapsis, and stable homolog juxtaposition are coordinated in the zebrafish, Danio rerio | Meiosis is a cellular program that generates haploid gametes for sexual reproduction. While chromosome events that contribute to reducing ploidy (homologous chromosome pairing, synapsis, and recombination) are well conserved, their execution varies across species and even between sexes of the same species. The telomere... | Inherent to reproduction is the transmission of genetic information from one generation to the next. In sexually reproducing organisms, each parent contributes an equal amount of genetic information, packaged in chromosomes, to the offspring. Diploid organisms, like humans, have two copies of every chromosome, while th... | Meiosis is a process that generates haploid gametes via one round of DNA replication and two rounds of chromosome segregation. Typically, homologous chromosomes (homologs) separate during meiosis I, and sister chromatids separate at meiosis II. Errors at either stage can lead to the production of aneuploid gametes, whi... |
10.1371/journal.pcbi.1006424 | Mechanisms of hysteresis in human brain networks during transitions of consciousness and unconsciousness: Theoretical principles and empirical evidence | Hysteresis, the discrepancy in forward and reverse pathways of state transitions, is observed during changing levels of consciousness. Identifying the underlying mechanism of hysteresis phenomena in the brain will enhance the ability to understand, monitor, and control state transitions related to consciousness. We hyp... | Hysteresis, characterized by distinct forward and reverse phase transitions, is ubiquitous in nature. For example, there are distinct temperatures for water freezing and ice melting. Similarly, it has been found that state transitions related to consciousness exhibit hysteresis. In particular, the concentration of gene... | Hysteresis, the differential pathway of forward and reverse state transitions, is a universal phenomenon observed in nature and has been investigated in various fields such as physics, engineering, biology, and economics[1–12]. Hysteresis has also been observed during state transitions in the brain, such as sleep[6,7] ... |
10.1371/journal.pntd.0006278 | Multiplex serology for impact evaluation of bed net distribution on burden of lymphatic filariasis and four species of human malaria in northern Mozambique | Universal coverage with long-lasting insecticidal nets (LLINs) is a primary control strategy against Plasmodium falciparum malaria. However, its impact on the three other main species of human malaria and lymphatic filariasis (LF), which share the same vectors in many co-endemic areas, is not as well characterized. The... | Plasmodium falciparum malaria is the principal cause of illness and death in Mozambique. However, the same mosquitoes that transmit P. falciparum parasites also transmit three other species of malaria (P. malariae, P. ovale, and P. vivax) and the worm that causes lymphatic filariasis. To date, we do not know how much t... | Northern Mozambique has one of the highest rates of Plasmodium falciparum transmission and disease burden in the world [1]. As in the rest of Mozambique, infection with P. falciparum malaria parasites is among the principal causes of outpatient visits, hospitalizations, and deaths. Malaria transmission occurs year-roun... |
10.1371/journal.pgen.1005802 | Functional Investigation of a Non-coding Variant Associated with Adolescent Idiopathic Scoliosis in Zebrafish: Elevated Expression of the Ladybird Homeobox Gene Causes Body Axis Deformation | Previously, we identified an adolescent idiopathic scoliosis susceptibility locus near human ladybird homeobox 1 (LBX1) and FLJ41350 by a genome-wide association study. Here, we characterized the associated non-coding variant and investigated the function of these genes. A chromosome conformation capture assay revealed... | Scoliosis is the most common type of spinal deformity with a lateral spinal curvature of at least 10 degrees, affecting 2–4% of the population. Scoliosis caused by a primary problem related to the spine itself is classified into congenital scoliosis (CS) and idiopathic scoliosis (IS). Among these, adolescent idiopathic... | Scoliosis is defined as lateral curvature of the spine with a Cobb angle greater than 10 degrees [1]. It is categorized into congenital, idiopathic, and secondary scoliosis [2]. Congenital scoliosis (CS) is caused by embryonic vertebral malformation that results in deviation of the normal spinal alignment [3]. Idiopath... |
10.1371/journal.ppat.1006367 | Mycobacterium tuberculosis subverts negative regulatory pathways in human macrophages to drive immunopathology | Tuberculosis remains a global pandemic and drives lung matrix destruction to transmit. Whilst pathways driving inflammatory responses in macrophages have been relatively well described, negative regulatory pathways are less well defined. We hypothesised that Mycobacterium tuberculosis (Mtb) specifically targets negativ... | The mechanisms whereby Mycobacterium tuberculosis (Mtb) evades host immunity are well described, but Mtb must also engage the host immune response to drive tissue destruction, cavitation and transmission as part of its life cycle. We identify negative regulatory pathways that suppress pathogenic matrix metalloproteinas... | Tuberculosis (TB) is a global pandemic, killing more than any other infectious disease [1], and ongoing transmission in high incidence settings impedes control measures [2]. Mycobacterium tuberculosis (Mtb), the causative organism, must cause lung destruction to create highly infectious individuals with pulmonary cavit... |
10.1371/journal.pgen.1007689 | A metabolic checkpoint protein GlmR is important for diverting carbon into peptidoglycan biosynthesis in Bacillus subtilis | The Bacillus subtilis GlmR (formerly YvcK) protein is essential for growth on gluconeogenic carbon sources. Mutants lacking GlmR display a variety of phenotypes suggestive of impaired cell wall synthesis including antibiotic sensitivity, aberrant cell morphology and lysis. To define the role of GlmR, we selected suppre... | Bacterial cells are surrounded by a peptidoglycan cell wall that is, under most conditions, required for viability. Synthesis of the cell wall requires a considerable diversion of resources from central carbon metabolism into a lipid-linked precursor (lipid II) that is exported from the cell for wall assembly. Here, we... | Bacillus subtilis provides a powerful model system for understanding cell wall homeostasis in Gram positive bacteria. Disruption of pathways for the synthesis of peptidoglycan (PG) and other cell envelope components elicits complex adaptive responses often controlled by alternative σ factors or two-component systems [1... |
10.1371/journal.pntd.0000568 | Human Probing Behavior of Aedes aegypti when Infected with a Life-Shortening Strain of Wolbachia | Mosquitoes are vectors of many serious pathogens in tropical and sub-tropical countries. Current control strategies almost entirely rely upon insecticides, which increasingly face the problems of high cost, increasing mosquito resistance and negative effects on non-target organisms. Alternative strategies include the p... | Mosquitoes transmit diseases when they are actively searching for a source of blood. This so called probing behavior comprises the “searching” time, the beginning of the feeding process until the first sign of blood can be seen within the insect body. The manipulation of this behavior can have important consequences fo... | Insect transmitted diseases such as malaria and dengue occur in more than 100 countries worldwide, placing at risk around half the world's population. The disease burden is high with more than 500 million cases each year. Despite various vector control measures, there continues to be emergence and resurgence of these d... |
10.1371/journal.pgen.1003091 | MicroRNA–Mediated Repression of the Seed Maturation Program during Vegetative Development in Arabidopsis | The seed maturation program only occurs during late embryogenesis, and repression of the program is pivotal for seedling development. However, the mechanism through which this repression is achieved in vegetative tissues is poorly understood. Here we report a microRNA (miRNA)–mediated repression mechanism operating in ... | Seed development can be conceptually divided into two phases: namely the morphogenesis phase, in which cell division is active and all the major organs are formed, and the maturation phase, in which cells enlarge and storage reserves are synthesized and accumulated. Expression of the seed maturation program is tightly ... | Seed maturation is a highly coordinated developmental phase in which storage reserves, including seed storage proteins (SSPs), are synthesized and accumulated to high levels. The maturation genes need to be repressed, however, in order to allow seedling development to occur. Indeed, these genes are not expressed in veg... |
10.1371/journal.pcbi.1005470 | Quantifying the roles of host movement and vector dispersal in the transmission of vector-borne diseases of livestock | The role of host movement in the spread of vector-borne diseases of livestock has been little studied. Here we develop a mathematical framework that allows us to disentangle and quantify the roles of vector dispersal and livestock movement in transmission between farms. We apply this framework to outbreaks of bluetongu... | Diseases which are transmitted by the bites of insects can be spread to new locations through the movement of both infected insects and infected hosts. The importance of these routes has implications for disease control, because we can often restrict host movement, and so potentially reduce spread, but cannot easily re... | The role of host movements in the transmission of vector-borne diseases has largely been ignored [1,2]. Recently, however, several studies have quantified the importance of human movements for the spread of vector-borne diseases. Mobile phone data were used to infer mobility patterns and, hence, the impact of large-sca... |
10.1371/journal.pmed.1002673 | Patient-centered primary care and self-rated health in 6 Latin American and Caribbean countries: Analysis of a public opinion cross-sectional survey | Despite the substantial attention to primary care (PC), few studies have addressed the relationship between patients’ experience with PC and their health status in low-and middle-income countries. This study aimed to (1) test the association between overall patient-centered PC experience (OPCE) and self-rated health (S... | In the 40 years since the Declaration of Alma-Ata, empirical studies using ecological data have shown positive effects of access to primary care on population health outcomes, such as child mortality, adult overall mortality, and adult avoidable hospitalizations, both in high-income countries and in low- and middle-inc... | Primary care (PC) has been described as being uniquely positioned to promote health and well-being at the population level [1–3]. Its central role in providing adequate, efficient, and equitable access to preventive and curative healthcare was strongly emphasized by the Declaration of Alma-Ata 40 years ago [2]. However... |
10.1371/journal.ppat.1000922 | The Early Stage of Bacterial Genome-Reductive Evolution in the Host | The equine-associated obligate pathogen Burkholderia mallei was developed by reductive evolution involving a substantial portion of the genome from Burkholderia pseudomallei, a free-living opportunistic pathogen. With its short history of divergence (∼3.5 myr), B. mallei provides an excellent resource to study the earl... | It has been known for some time that bacteria undergo genome-reduction when they transition from a free-living state to a constantly host-restricted state. High levels of IS element expansion were also found in these bacteria, and the IS elements were suggested to play a role in genome reductive evolution. Here we prov... | The genomes of host-adapted bacteria, including endosymbionts and obligatory intracellular pathogens, go through reductive evolution [1], [2], [3]. Such changes are partly due to a reduced pressure to maintain genes that are not essential for survival in the host. Similarly, decreased efficiency of purifying selection,... |
10.1371/journal.pcbi.1004909 | A MAPK-Driven Feedback Loop Suppresses Rac Activity to Promote RhoA-Driven Cancer Cell Invasion | Cell migration in 3D microenvironments is fundamental to development, homeostasis and the pathobiology of diseases such as cancer. Rab-coupling protein (RCP) dependent co-trafficking of α5β1 and EGFR1 promotes cancer cell invasion into fibronectin (FN) containing extracellular matrix (ECM), by potentiating EGFR1 signal... | The majority of cancer-related fatalities are caused by the movement of cancer cells away from the primary site to form metastases, making understanding the signalling mechanisms which underpin cell migration and invasion through their local environment of paramount importance. Much has been discovered about key events... | An estimated 90% of cancer deaths are caused by metastatic secondary tumours [1], a process instigated as certain cells escape the primary tumour to migrate in, and invade through, the local micro-environment. Cancer cells can adopt a range of different migratory mechanisms to achieve such invasion [2]: some migrate in... |
10.1371/journal.ppat.1004291 | Plasmacytoid Dendritic Cells Suppress HIV-1 Replication but Contribute to HIV-1 Induced Immunopathogenesis in Humanized Mice | The role of plasmacytoid dendritic cells (pDC) in human immunodeficiency virus type 1 (HIV-1) infection and pathogenesis remains unclear. HIV-1 infection in the humanized mouse model leads to persistent HIV-1 infection and immunopathogenesis, including type I interferons (IFN-I) induction, immune-activation and depleti... | Persistent expression of IFN-I is correlated with disease progression in HIV-1 infected humans or SIV-infected monkeys. Thus, persistent pDC activation has been implicated in contributing to AIDS pathogenesis. To define the role of pDC in HIV-1 infection and immunopathogenesis in vivo, we developed a monoclonal antibod... | Chronic immune activation induced by HIV-1 infection is highly correlated with CD4 T cell depletion and immunodeficiency [1], [2], [3]. The level of T cell activation (HLA-DR+CD38+CD8+ T cells) is correlated with disease progression independent of HIV-1 viral load and CD4+ T cell count [4]. It is also proposed that imm... |
10.1371/journal.pgen.1007616 | Artificial selection on storage protein 1 possibly contributes to increase of hatchability during silkworm domestication | Like other domesticates, the efficient utilization of nitrogen resources is also important for the only fully domesticated insect, the silkworm. Deciphering the way in which artificial selection acts on the silkworm genome to improve the utilization of nitrogen resources and to advance human-favored domestication trait... | Like other domesticates, nitrogen resources are also important for the only fully domesticated insect, the silkworm. Deciphering the way in which artificial selection acts on the silkworm genome to improve the utilization of nitrogen resources, thereby advancing human-favored domestication traits, will provide clues fr... | The silkworm, Bombyx mori, is the only fully domesticated insect species, originating from its wild ancestor, B. mandarina, approximately 5000 years ago. During the domestication process, the domestic silkworm evolved rapidly under human-preferred selection. Deciphering the way in which artificial selection acts on the... |
10.1371/journal.pbio.2001492 | Dramatic and concerted conformational changes enable rhodocetin to block α2β1 integrin selectively | The collagen binding integrin α2β1 plays a crucial role in hemostasis, fibrosis, and cancer progression amongst others. It is specifically inhibited by rhodocetin (RC), a C-type lectin-related protein (CLRP) found in Malayan pit viper (Calloselasma rhodostoma) venom. The structure of RC alone reveals a heterotetramer a... | In animals, collagen-mediated platelet aggregation is an essential component of the blood’s clotting response following vascular injury. A small group of snake venom toxins belonging to the C-type lectin protein family exert their harmful effects by directly targeting this pathway. Rhodocetin (RC) is a heterotetrameric... | Most cellular processes depend on the formation of interactions between cells and the extracellular matrix (ECM). Key facilitators of these interactions are the integrins. They consist of 2 subunits, α and β, each of which has multiple isoforms [1,2]. The different subunit composition between integrins determines their... |
10.1371/journal.ppat.1004295 | Cytolethal Distending Toxins Require Components of the ER-Associated Degradation Pathway for Host Cell Entry | Intracellular acting protein exotoxins produced by bacteria and plants are important molecular determinants that drive numerous human diseases. A subset of these toxins, the cytolethal distending toxins (CDTs), are encoded by several Gram-negative pathogens and have been proposed to enhance virulence by allowing evasio... | Cytolethal distending toxins (CDTs) are produced by several bacterial pathogens and increase the ability of these bacteria to cause disease. After being taken up by host cells, CDTs are trafficked to the endoplasmic reticulum (ER) where they must translocate across the ER membrane to gain access to their intracellular ... | Cytolethal distending toxins (CDTs) are produced by a variety of Gram-negative pathogens including the oral pathogen Aggregatibacter actinomycetemcomitans, the sexually transmitted pathogen Haemophilus ducreyi, and the gastrointestinal pathogens, Escherichia coli and Campylobacter jejuni. These toxins belong to a large... |
10.1371/journal.pntd.0003457 | Effectiveness of Routine BCG Vaccination on Buruli Ulcer Disease: A Case-Control Study in the Democratic Republic of Congo, Ghana and Togo | The only available vaccine that could be potentially beneficial against mycobacterial diseases contains live attenuated bovine tuberculosis bacillus (Mycobacterium bovis) also called Bacillus Calmette-Guérin (BCG). Even though the BCG vaccine is still widely used, results on its effectiveness in preventing mycobacteria... | After tuberculosis and leprosy, Buruli Ulcer Disease (BUD) is the third most common human mycobacterial disease. The only available vaccine that could be potentially beneficial against these diseases is BCG. Even though BCG vaccine is widely used, the results on its effectiveness are partially contradictory, probably s... | Buruli Ulcer Disease (BUD), caused by Mycobacterium ulcerans, is an infectious disease affecting skin, subcutanous adipose tissue, and in rare cases, bones. It is one of the 17 neglected tropical diseases as defined by the World Health Organization (WHO). BUD has been reported in 33 countries, with a major endemic focu... |
10.1371/journal.pntd.0006723 | Comparison of individual and pooled diagnostic examination strategies during the national mapping of soil-transmitted helminths and Schistosoma mansoni in Ethiopia | Laboratory-based studies have highlighted that pooling stool and urine samples can reduce costs and diagnostic burden without a negative impact on the ability to estimate the intensity of soil-transmitted helminth (STH, Ascaris lumbricoides, Trichuris trichiura and hookworms) and schistosome infections (Schistosoma man... | Infections with intestinal (roundworms, whipworm and hookworms) and blood-dwelling (schistosomes) worms pose a significant public health burden in developing tropical countries. To optimize control programs against these worms, large-scale surveys are required to determine the worm distribution to initiate control and ... | Neglected tropical diseases (NTDs) are a group of parasitic, bacterial and viral infections that pose an important burden on public health, particularly in tropical and sub-tropical countries [1]. In 2015, this group of 17 diseases resulted in approximately 26 million disability-adjusted life years (DALYs) and are cons... |
10.1371/journal.pntd.0002178 | Viperin Is Induced following Dengue Virus Type-2 (DENV-2) Infection and Has Anti-viral Actions Requiring the C-terminal End of Viperin | The host protein viperin is an interferon stimulated gene (ISG) that is up-regulated during a number of viral infections. In this study we have shown that dengue virus type-2 (DENV-2) infection significantly induced viperin, co-incident with production of viral RNA and via a mechanism requiring retinoic acid-inducible ... | Viperin is a virally induced host protein that has been previously shown to have antiviral activity against a variety of viruses. Here we have demonstrated that viperin is also anti-viral against the medically significant arbovirus, dengue virus. Viperin was able to inhibit dengue virus at the level of viral replicatio... | The interferon (IFN) response is triggered in cells infected by RNA viruses, including members of the Flaviviridae family via a number of RNA recognition pathways that ultimately act to limit viral replication [1], [2]. Production of type I interferons (IFNs; IFN-α and IFN-β) by virus infected cells results in up-regul... |
10.1371/journal.pgen.1002557 | DNA Damage in Nijmegen Breakage Syndrome Cells Leads to PARP Hyperactivation and Increased Oxidative Stress | Nijmegen Breakage Syndrome (NBS), an autosomal recessive genetic instability syndrome, is caused by hypomorphic mutation of the NBN gene, which codes for the protein nibrin. Nibrin is an integral member of the MRE11/RAD50/NBN (MRN) complex essential for processing DNA double-strand breaks. Cardinal features of NBS are ... | Damage to DNA is extremely dangerous because it can lead to mutations in genes that initiate or accelerate the development of a tumor. Evolution has led to highly complex networks of DNA repair enzymes, which for the majority of individuals are extremely effective in keeping our DNA intact. The devastating consequences... | Genetic cancer susceptibility disorders, such as Xeroderma pigmentosum and Fanconi anemia, generally have deficiencies in DNA repair and cell cycle regulation leading to tumour initiation. The specific mutagen sensitivities underlying these disorders define a set of enzymes and pathways involved in the DNA damage respo... |
10.1371/journal.pcbi.1004964 | Phylogenetic Analysis Reveals That ERVs "Die Young" but HERV-H Is Unusually Conserved | About 8% of the human genome is made up of endogenous retroviruses (ERVs). Though most human endogenous retroviruses (HERVs) are thought to be irrelevant to our biology notable exceptions include members of the HERV-H family that are necessary for the correct functioning of stem cells. ERVs are commonly found in two fo... | Animal genomes contain ancient pathogens known as endogenous retroviruses (ERVs). Though the widespread abundance of ERVs is due to their ability to self replicate, some ERVs are known to have become important to host processes including placentation, and in the case of HERV-H, the functioning of human stem cells. In o... | By definition, endogenous retroviruses (ERVs) are the result of the Mendelian (vertical germ line) transmission of retroviruses from parent to progeny. Over many generations it is possible for an ERV to fix in a host population so that in humans, for example, as much as 8% of the genome is thought to be retrovirally de... |
10.1371/journal.pgen.1001295 | Phosphoinositide Regulation of Integrin Trafficking Required for Muscle Attachment and Maintenance | Muscles must maintain cell compartmentalization when remodeled during development and use. How spatially restricted adhesions are regulated with muscle remodeling is largely unexplored. We show that the myotubularin (mtm) phosphoinositide phosphatase is required for integrin-mediated myofiber attachments in Drosophila ... | Muscles require strong extracellular attachments to preserve cellular integrity during force-generating contractions. Integrin transmembrane receptors mediate muscle attachments at highly localized sites, but how this pattern of attachments is continuously maintained with muscle use is not understood. Human X-linked my... | Myofibers are large, highly differentiated contractile cells that rely on strong extracellular attachments to preserve their integrity during force-generating muscle contractions. Myofiber attachments are mediated by integrin adhesion complexes (IACs) composed of α- and β- transmembrane heterodimers that associate with... |
10.1371/journal.pntd.0005613 | Transmission dynamics and control of Rickettsia rickettsii in populations of Hydrochoerus hydrochaeris and Amblyomma sculptum | Brazilian Spotted Fever (BSF), caused by the bacterium Rickettsia rickettsii, is the tick-borne disease that generates the largest number of human deaths in the world. In Brazil, the current increase of BSF human cases has been associated with the presence and expansion of capybaras Hydrochoerus hydrochaeris, which act... | A stochastic model for the spread of R. rickettsii among the Amblyomma sculptum tick vector and the Hydrochoerus hydrochaeris, amplifier host, was formulated. We found that the introduction of a single infected capybara, with at least one infected attached tick, is enough to trigger the disease in a non-endemic area. T... | Rickettsia rickettsii is the etiological agent of the Brazilian spotted fever (BSF), the deadliest spotted fever in the world. This infection is partially pathogenic to Amblyomma sculptum ticks, main vectors of the R. rickettsii in South America [1, 2], generating a drop in the infection rate with each tick generation ... |
10.1371/journal.pcbi.1002066 | A New View of the Bacterial Cytosol Environment | The cytosol is the major environment in all bacterial cells. The true physical and dynamical nature of the cytosol solution is not fully understood and here a modeling approach is applied. Using recent and detailed data on metabolite concentrations, we have created a molecular mechanical model of the prokaryotic cytoso... | The cytosol is the major cellular environment housing the majority of cellular activity. Although the cytosol is an aqueous environment, it contains high concentrations of ions, metabolites, and proteins, making it very different from dilute aqueous solution, which is frequently used for in vitro biochemistry. Recent a... | The composition of metabolites, ions and proteins, and processes such as metabolism and signalling which take place in the E.coli cytosol are largely well defined [1], [2]. However, the structure and dynamical nature of the cytosol solution is less well understood whether on the local or cytosol-wide levels. Current pe... |
10.1371/journal.pntd.0003726 | Insensitivity to the Spatial Repellent Action of Transfluthrin in Aedes aegypti: A Heritable Trait Associated with Decreased Insecticide Susceptibility | New vector control paradigms expanding the use of spatial repellents are promising, but there are many gaps in our knowledge about how repellents work and how their long-term use might affect vector populations over time. Reported here are findings from a series of in vitro studies that investigated the plasticity and ... | There is growing evidence to support the expanded use of spatial repellents for vector control, but there are still many uncertainties about how repellents work and how their long term use may impact vector populations over time. Here, we conducted a series of in vitro experiments that investigated spatial repellent (S... | New vector control tools and paradigms are desperately needed to complement existing approaches [1–3], and there is growing evidence to support the expanded use of spatial repellents to help address this need [4–9]. The ultimate goal of public health interventions utilizing repellents is to exploit the behavior modifyi... |
10.1371/journal.pcbi.1004040 | Rational Design and Adaptive Management of Combination Therapies for Hepatitis C Virus Infection | Recent discoveries of direct acting antivirals against Hepatitis C virus (HCV) have raised hopes of effective treatment via combination therapies. Yet rapid evolution and high diversity of HCV populations, combined with the reality of suboptimal treatment adherence, make drug resistance a clinical and public health con... | Hepatitis C virus (HCV) affects approximately 170 million people world-wide and chronic infections can lead to cirrhosis and liver cancer. New combination therapies of direct acting antivirals have achieved remarkably high cure rates in clinical trials. However, high mutation rates and high diversity of HCV populations... | Hepatitis C virus (HCV) affects approximately 170 million people and chronic infections can lead to cirrhosis and hepatocellular carcinoma [1,2]. Recently, development of direct acting antivirals (DAAs) against HCV infection has revolutionized the field of HCV treatment, because of their high potency, broad applicabili... |
10.1371/journal.pcbi.1002096 | Interrogation of the Protein-Protein Interactions between Human BRCA2 BRC Repeats and RAD51 Reveals Atomistic Determinants of Affinity | The breast cancer suppressor BRCA2 controls the recombinase RAD51 in the reactions that mediate homologous DNA recombination, an essential cellular process required for the error-free repair of DNA double-stranded breaks. The primary mode of interaction between BRCA2 and RAD51 is through the BRC repeats, which are ∼35 ... | The atomic scale interactions that occur at the interfaces between proteins are fundamental to all biological processes. One such critical interface is formed between the proteins, human BRCA2 and RAD51. BRCA2 binds to and delivers RAD51 to sites of DNA damage, where RAD51 mediates the error-free repair of double-stran... | The human breast cancer suppressor protein BRCA2 controls the functions of the RAD51 recombinase, an enzyme conserved in all kingdoms of life, which carries out the strand exchange reaction central to homologous DNA recombination (HDR) [1]. This essential cellular pathway is responsible for the error-free repair of DNA... |
10.1371/journal.pgen.1000816 | Genetic Dissection of Differential Signaling Threshold Requirements for the Wnt/β-Catenin Pathway In Vivo | Contributions of null and hypomorphic alleles of Apc in mice produce both developmental and pathophysiological phenotypes. To ascribe the resulting genotype-to-phenotype relationship unambiguously to the Wnt/β-catenin pathway, we challenged the allele combinations by genetically restricting intracellular β-catenin expr... | Germline or somatic mutations in genes are the underlying cause of many human diseases, most notably cancer. Interestingly though, even in situations where every cell of every tissue of an organism carries the same mutation (as is the case for germline mutations), some tissues are more susceptible to the development of... | The evolutionarily conserved Wnt/β-catenin pathway is a critical regulator of proliferation and differentiation and plays a pivotal role during embryonic development and in the maintenance of tissue homeostasis in the adult. A multitude of studies have documented that impaired or excessive activation of the Wnt/β-caten... |
10.1371/journal.pgen.1000223 | Variations in Stress Sensitivity and Genomic Expression in Diverse
S. cerevisiae Isolates | Interactions between an organism and its environment can significantly influence
phenotypic evolution. A first step toward understanding this process is to
characterize phenotypic diversity within and between populations. We explored
the phenotypic variation i... | Much attention has been given to the ways in which organisms evolve new
phenotypes and the influence of the environment on this process. A major focus
of study is defining the genetic basis for phenotypes important for organismal
fitness. As a first step towar... | A major focus of genetic study is to elucidate the effects of genetic variation on
phenotypic diversity. The evolution of phenotypes is often driven by environmental
factors and the interactions between each organism and its environment. Recently,
there has been a renewed... |
10.1371/journal.pbio.1000550 | Co-Evolution of Transcriptional Silencing Proteins and the DNA Elements Specifying Their Assembly | Co-evolution of transcriptional regulatory proteins and their sites of action has been often hypothesized but rarely demonstrated. Here we provide experimental evidence of such co-evolution in yeast silent chromatin, a finding that emerged from studies of hybrids formed between two closely related Saccharomyces species... | As eukaryotic species evolve, transcriptionally silent portions of their genomes—termed “heterochromatin”—mutate rapidly. To maintain the “off” state of certain genes in silenced regions, regulatory DNA sequences called silencers, which reside within a rapidly mutating region, must co-evolve with the regulatory protein... | Among all specialized chromatin structures, the difference between heterochromatin and euchromatin is perhaps the most fundamental, motivating intense study of the differences between these two structures. DNA sequences within heterochromatic regions evolve rapidly in animals [1],[2], plants [3],[4], and fungi [5], pre... |
10.1371/journal.pgen.0030186 | αADα Hybrids of Cryptococcus neoformans: Evidence of Same-Sex Mating in Nature and Hybrid Fitness | Cryptococcus neoformans is a ubiquitous human fungal pathogen that causes meningoencephalitis in predominantly immunocompromised hosts. The fungus is typically haploid, and sexual reproduction involves two individuals with opposite mating types/sexes, α and a. However, the overwhelming predominance of mating type (MAT)... | Cryptococcus neoformans is a major cause of fungal meningitis, predominantly in immunocompromised individuals. This fungus has two mating types/sexes, a and α, and mating typically requires two individuals with opposite mating types. It is mysterious why the α mating type is overwhelmingly predominant in nature and how... | The level of genetic variation within a species is correlated with evolutionary potential [1]. Hybridization can provide genetic variation within and between populations by yielding progeny more fit in novel or changing environments, and both intra- and interspecies hybridization are a driving force for evolution [2,3]... |
10.1371/journal.ppat.1002499 | Temporal Expression of Bacterial Proteins Instructs Host CD4 T Cell Expansion and Th17 Development | Pathogens can substantially alter gene expression within an infected host depending on metabolic or virulence requirements in different tissues, however, the effect of these alterations on host immunity are unclear. Here we visualized multiple CD4 T cell responses to temporally expressed proteins in Salmonella-infected... | Pathogens alter protein expression in an infected host, depending on metabolic or virulence requirements, but the effect of these changes on the immune response is unclear. We identified new class-II epitopes within Salmonella type-III secretion system effector proteins and generated a methodology to visualize endogeno... | Generating vaccines for current and emerging infectious diseases remains an important goal of immunological research [1], [2]. An ideal vaccine will induce the expansion and maturation of naïve pathogen-specific lymphocyte clones that exist at low frequency in uninfected or unimmunized individuals [3]. During infection... |
10.1371/journal.pgen.1006657 | Novel genes involved in severe early-onset obesity revealed by rare copy number and sequence variants | Obesity is a multifactorial disorder with high heritability (50–75%), which is probably higher in early-onset and severe cases. Although rare monogenic forms and several genes and regions of susceptibility, including copy number variants (CNVs), have been described, the genetic causes underlying the disease still remai... | Although there is strong evidence for a high genetic component of obesity, the underlying genetic causes are largely unknown, mostly due to the highly heterogeneous nature of the disorder. In this work, we have focused on the most severe end of the spectrum, severe obesity with early-onset in childhood, which is more l... | Early-onset overweight (body mass index [BMI] ≥ 85th percentile for age and sex) and obesity (BMI ≥ 95th percentile for age and sex) currently affects 27.8% of children in Spain (Spanish National Health Survey, 2011–2012), being the most prevalent chronic disorder in childhood and adolescence. In the United States, 17.... |
10.1371/journal.pntd.0005609 | Rabies surveillance in dogs in Lao PDR from 2010-2016 | Rabies is a fatal viral disease that continues to threaten both human and animal health in endemic countries. The Lao People’s Democratic Republic (Lao PDR) is a rabies-endemic country in which dogs are the main reservoir and continue to present health risks for both human and animals throughout the country.
Passive, l... | Rabies is a viral disease that continues to threaten both human and animal health in endemic countries and almost always results in death of the infected individual. In most areas of Southeast Asia, rabies continues to be a major zoonosis with the main source of human cases being dog bites. In this study, we examined t... | Rabies is an acute viral encephalomyelitis caused by the rabies virus (genus Lyssavirus; family Rhabdoviridae) which can affect all warm-blooded animals including humans. Humans and animals may be infected with rabies virus via saliva through a bite or scratch [1] or butchering [2] of a rabid animal, and if left untrea... |
10.1371/journal.pbio.1001013 | Development of Axon-Target Specificity of Ponto-Cerebellar Afferents | The function of neuronal networks relies on selective assembly of synaptic connections during development. We examined how synaptic specificity emerges in the pontocerebellar projection. Analysis of axon-target interactions with correlated light-electron microscopy revealed that developing pontine mossy fibers elaborat... | Brain functions rely on highly selective neuronal networks which are assembled during development. Network assembly involves targeted neuronal growth followed by recognition of the appropriate target cells and selective synapse formation. How neuronal processes select their appropriate target cells from an array of int... | The specificity of synaptic connectivity in the central nervous system is a prerequisite for brain function. The neuronal circuits in the vertebrate cerebellum represent a remarkable example of wiring specificity. This was first recognized by Santiago Ramón y Cajal when he chose cerebellar circuits as revealed by the G... |
10.1371/journal.ppat.1000605 | Human Papillomaviruses Activate the ATM DNA Damage Pathway for Viral Genome Amplification upon Differentiation | Human papillomaviruses (HPV) are the causative agents of cervical cancers. The infectious HPV life cycle is closely linked to the differentiation state of the host epithelia, with viral genome amplification, late gene expression and virion production restricted to suprabasal cells. The E6 and E7 proteins provide an env... | Over 100 types of human papillomavirus (HPV) have been identified, and approximately one-third of these infect epithelial cells of the genital mucosa. A subset of these HPV types are the causative agents of cervical and other anogenital cancers. The infectious life cycle of HPV is dependent on differentiation of the ho... | Human papillomaviruses (HPV) are the etiological agents of most anogenital cancers and their productive life cycle is dependent upon epithelial differentiation [1],[2]. HPVs infect cells in the basal layer of stratified epithelia, but restrict the productive phase of the life cycle to highly differentiated suprabasal c... |
10.1371/journal.pcbi.1003291 | On the Role of Aggregation Prone Regions in Protein Evolution, Stability, and Enzymatic Catalysis: Insights from Diverse Analyses | The various roles that aggregation prone regions (APRs) are capable of playing in proteins are investigated here via comprehensive analyses of multiple non-redundant datasets containing randomly generated amino acid sequences, monomeric proteins, intrinsically disordered proteins (IDPs) and catalytic residues. Results ... | Biotechnology requires the large-scale expression, yield, and storage of recombinant proteins. Each step in protein production has the potential to cause aggregation as proteins, not evolved to exist outside the cell, endure the various steps involved in commercial manufacturing processes. Mechanistic studies into prot... | Irreversible β-strand driven protein aggregation and amyloidogenesis is a tremendous burden to biological organisms. Protein loss-of function due to aggregation causes stress to the cell and metabolic energy is lost on the expression, synthesis, and degradation of proteins which aggregate. To overcome these challenges ... |
10.1371/journal.ppat.1000836 | T Cell-Dependence of Lassa Fever Pathogenesis | Lassa virus (LASV), the causative agent of Lassa fever (LF), is endemic in West Africa, accounting for substantial morbidity and mortality. In spite of ongoing research efforts, LF pathogenesis and mechanisms of LASV immune control remain poorly understood. While normal laboratory mice are resistant to LASV, we report ... | Lassa virus (LASV) is the causative agent of Lassa fever (LF), accounting for substantial morbidity and mortality in West Africa. Yet the mechanisms leading to disease remain poorly understood. Here we propose a concept whereby the body's immune defense either defeats LASV rapidly or, if unsuccessful, becomes an essent... | Lassa virus (LASV) is the causative agent of Lassa fever (LF) [1]. It accounts for an estimated number of 300′000 infections and several thousand deaths in endemic areas each year [2], while imported cases have been reported from around the globe [3]. The virus is listed category A by the Center for Disease Control and... |
10.1371/journal.pcbi.1002087 | Stimulus-Dependent State Transition between Synchronized Oscillation and Randomly Repetitive Burst in a Model Cerebellar Granular Layer | Information processing of the cerebellar granular layer composed of granule and Golgi cells is regarded as an important first step toward the cerebellar computation. Our previous theoretical studies have shown that granule cells can exhibit random alternation between burst and silent modes, which provides a basis of po... | Intensive studies of Pavlovian delay eyelid conditioning suggest that the cerebellum can memorize a passage-of-time (POT) from the onset of an external stimulus. To account for possible mechanisms of such POT representation, some network models have been proposed to show that granule cells (grcs) in the cerebellar gran... | The cerebellar granular layer is one of the stations receiving external stimuli for information processing of the cerebellar cortex. The granular layer is thought to transform spatial patterns of mossy fibers (MFs) input signals into a population of active granule cells (grcs) [1], [2]. Recently, Yamazaki and Tanaka [3... |
10.1371/journal.pntd.0006915 | Molecular analysis of clinical Burkholderia pseudomallei isolates from southwestern coastal region of India, using multi-locus sequence typing | The Gram-negative soil dwelling bacterium Burkholderia pseudomallei is the etiological agent of melioidosis. The disease is endemic in most parts of Southeast Asia and northern Australia. Over last few years, there has been an increase in number of melioidosis cases from India; however the disease epidemiology is less ... | Burkholderia pseudomallei, a gram negative bacterium, is the causative agent of melioidosis. B. pseudomallei is a soil saprophyte and causes infections in humans by percutaneous inoculation, inhalation or ingestion. Melioidosis is a life threatening disease, which requires prolonged antibiotic treatment and is classica... | Melioidosis, caused by soil saprophyte Gram-negative bacterium Burkholderia pseudomallei, is classically characterized by pneumonia, septicemia and multiple abscesses. There are various predisposing factors for melioidosis with diabetes mellitus as one of the most important factors. Until recently, the disease was cons... |
10.1371/journal.ppat.1006973 | Limited immune surveillance in lymphoid tissue by cytolytic CD4+ T cells during health and HIV disease | CD4+ T cells subsets have a wide range of important helper and regulatory functions in the immune system. Several studies have specifically suggested that circulating effector CD4+ T cells may play a direct role in control of HIV replication through cytolytic activity or autocrine β-chemokine production. However, it re... | CD4+ T cells have classically been divided into different subsets based on their different abilities to help and regulate specific parts of the immune system. Recent work in the HIV field has demonstrated that HIV-specific CD4+ T cells with unique effector functions, such as cytolytic activity and β-chemokine productio... | CD4+ T cells are classically known to orchestrate immunity by providing helper functions to other arms of the immune system. However, CD4+ T cells can also exercise direct cell-to-cell mediated effector functions to control pathogens and tumors. Effector CD4+ T cells with cytolytic activity are generated during many ac... |
10.1371/journal.pcbi.1003500 | MRFalign: Protein Homology Detection through Alignment of Markov Random Fields | Sequence-based protein homology detection has been extensively studied and so far the most sensitive method is based upon comparison of protein sequence profiles, which are derived from multiple sequence alignment (MSA) of sequence homologs in a protein family. A sequence profile is usually represented as a position-sp... | Sequence-based protein homology detection has been extensively studied, but it remains very challenging for remote homologs with divergent sequences. So far the most sensitive methods employ HMM-HMM comparison, which models a protein family using HMM (Hidden Markov Model) and then detects homologs using HMM-HMM alignme... | Sequence-based protein alignment and homology detection has been extensively studied and widely applied to many biological problems such as homology modeling [1]–[4], phylogeny inference [5]–[7] and protein function prediction [8]–[10]. Although extensively studied, remote homology detection still remains very challeng... |
10.1371/journal.ppat.1004303 | Distinct APC Subtypes Drive Spatially Segregated CD4+ and CD8+ T-Cell Effector Activity during Skin Infection with HSV-1 | Efficient infection control requires potent T-cell responses at sites of pathogen replication. However, the regulation of T-cell effector function in situ remains poorly understood. Here, we show key differences in the regulation of effector activity between CD4+ and CD8+ T-cells during skin infection with HSV-1. IFN-γ... | HSV-1 is a widely distributed pathogen causing a life-long latent infection associated with periodic bouts of reactivation and severe clinical complications. Adaptive immune responses encompassing CD4+ and CD8+ T-cell activities are key to both the clearance of infectious virus and the control of latent infection. Howe... | Infection results in the priming of pathogen-specific T-cell responses in LNs draining the site of infection. Depending on the nature of the pathogen, this critical step in generating adaptive immunity involves the interaction of naive T cells with various types of migrating and LN-resident DCs [1], [2]. During skin in... |
10.1371/journal.ppat.1000075 | Intraspecies Transmission of BASE Induces Clinical Dullness and Amyotrophic Changes | The disease phenotype of bovine spongiform encephalopathy (BSE) and the molecular/ biological properties of its prion strain, including the host range and the characteristics of BSE-related disorders, have been extensively studied since its discovery in 1986. In recent years, systematic testing of the brains of cattle ... | For approximately two decades, bovine spongiform encephalopathy (BSE), now termed classical BSE (BSE-C), has been regarded as the only and exclusive prion disorder affecting cattle. However, over the last 4 years, two additional bovine prion strains, bovine amyloidotic spongiform encephalopathy (BASE, also named BSE-L)... | Prion diseases, or transmissible spongiform encephalopathies (TSEs), are mammalian neurodegenerative disorders of sporadic, genetic, or infectious origin characterized by accumulation and deposition of an abnormal isoform (PrPTSE) of the cellular prion protein (PrPC) in the brain [1]. TSEs include a wide range of anima... |
10.1371/journal.ppat.1003157 | Therapeutic Efficacy of Antibodies Lacking FcγR against Lethal Dengue Virus Infection Is Due to Neutralizing Potency and Blocking of Enhancing Antibodies | Dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS) are life-threatening complications following infection with one of the four serotypes of dengue virus (DENV). At present, no vaccine or antiviral therapies are available against dengue. Here, we characterized a panel of eight human or mouse-human chimeric mon... | The four dengue virus serotypes (DENV1-4) cause the most prevalent mosquito-transmitted viral disease globally, infecting 50–100 million people annually in tropical and sub-tropical regions worldwide, yet no vaccine or therapy has been licensed to prevent or treat dengue. The greatest risk factor for severe dengue dise... | The four serotypes of dengue virus (DENV) are transmitted by Aedes aegypti and Ae. albopictus mosquitoes and are endemic predominantly in tropical and sub-tropical regions of the world [1], [2]. Syndromes associated with DENV infection range from inapparent infection to classic dengue fever (DF), a debilitating self-li... |
10.1371/journal.pgen.1004446 | DNA Topoisomerase 1α Promotes Transcriptional Silencing of Transposable Elements through DNA Methylation and Histone Lysine 9 Dimethylation in Arabidopsis | RNA-directed DNA methylation (RdDM) and histone H3 lysine 9 dimethylation (H3K9me2) are related transcriptional silencing mechanisms that target transposable elements (TEs) and repeats to maintain genome stability in plants. RdDM is mediated by small and long noncoding RNAs produced by the plant-specific RNA polymerase... | DNA topoisomerase is an enzyme that releases the torsional stress in DNA generated during DNA replication or transcription. Here, we uncovered an unexpected role of DNA topoisomerase 1α (TOP1α) in the maintenance of genome stability. Eukaryotic genomes are usually littered with transposable elements (TEs) and repeats, ... | DNA methylation and histone H3 lysine 9 (H3K9) methylation are two chromatin modifications widely employed by eukaryotes to maintain genome stability [1], [2]. H3K9 methylation and DNA methylation are targeted via small interfering RNAs (siRNAs) to repeats and transposable elements (TEs) and are required for their tran... |
10.1371/journal.pbio.1000151 | Inherent Dynamics of the Acid-Sensing Ion Channel 1 Correlates with the Gating Mechanism | The acid-sensing ion channel 1 (ASIC1) is a key receptor for extracellular protons. Although numerous structural and functional studies have been performed on this channel, the structural dynamics underlying the gating mechanism remains unknown. We used normal mode analysis, mutagenesis, and electrophysiological method... | The acid-sensing ion channels (ASICs) are key receptors for extracellular protons and are becoming increasingly important drug targets. However, their gating mechanism is still not fully understood. The crystallographic structure of the ASIC1 protein provides a clue, but the dynamics of the channel remains to be elucid... | Extracellular acidosis has profound effects on neuronal function, and acid-sensing ion channels (ASICs) are the key receptors for extracellular protons [1],[2]. ASICs are members of the degenerin/epithelial channel family, which transport Na+ through the cell membrane [1],[3], and serve as a paradigm for all proton-gat... |
10.1371/journal.pgen.1002470 | USF-1 Is Critical for Maintaining Genome Integrity in Response to UV-Induced DNA Photolesions | An important function of all organisms is to ensure that their genetic material remains intact and unaltered through generations. This is an extremely challenging task since the cell's DNA is constantly under assault by endogenous and environmental agents. To protect against this, cells have evolved effective mechanism... | UV is responsible for DNA damage and genetic alterations of key players of the Nucleotide Excision Repair (NER) machinery promote the development of UV-induced skin cancers. The NER is the major DNA–repair process involved in the recognition and removal of UV-mediated DNA damage. Different factors participating in this... | Maintaining the integrity of the genome through cell generations is critical to ensure accurate cell function and to avoid tumor formation. Cells are continuously challenged by environmental insults and they are equipped with specific and efficient defense machinery to remove any DNA alterations. The importance of thes... |
10.1371/journal.pbio.1002053 | FAX1, a Novel Membrane Protein Mediating Plastid Fatty Acid Export | Fatty acid synthesis in plants occurs in plastids, and thus, export for subsequent acyl editing and lipid assembly in the cytosol and endoplasmatic reticulum is required. Yet, the transport mechanism for plastid fatty acids still remains enigmatic. We isolated FAX1 (fatty acid export 1), a novel protein, which inserts ... | Fatty acid synthesis in plants occurs in chloroplasts—the organelle more commonly known for conducting photosynthesis. For subsequent lipid assembly to be possible in the endoplasmatic reticulum (ER), export of these fatty acids across the chloroplast envelope membranes is required. The mechanism of this transport unti... | Fatty acids (FAs) are building blocks for the majority of cellular lipids, which are essential throughout life of organisms. Besides their role as constituents of biological membranes, plant acyl-lipids are used for diverse functions at different destinations and tissues (reviewed in [1]). For example, triacylglycerols... |
10.1371/journal.pgen.1000313 | Sexually Antagonistic “Zygotic Drive” of the Sex Chromosomes | Genomic conflict is perplexing because it causes the fitness of a species to decline rather than improve. Many diverse forms of genomic conflict have been identified, but this extant tally may be incomplete. Here, we show that the unusual characteristics of the sex chromosomes can, in principle, lead to a previously un... | Our study describes a new form of sexual genomic conflict that operates through the process of antagonistic green-beard effects. Although past theoretical and empirical work indicated that green-beard effects rarely operate in nature, our new theory shows why this conclusion may have to be reevaluated. We integrate mod... | Sex chromosomes are unusual compared to the autosomes for three reasons. First, when present in the heterogametic sex, the two types of sex chromosome are transmitted to opposite sex offspring. Second, it is common for recombination to be suppressed over a part or all of their length. Third, non-recombining sex chromos... |
10.1371/journal.pgen.1000461 | Genetic Evidence That the Non-Homologous End-Joining Repair Pathway Is Involved in LINE Retrotransposition | Long interspersed elements (LINEs) are transposable elements that proliferate within eukaryotic genomes, having a large impact on eukaryotic genome evolution. LINEs mobilize via a process called retrotransposition. Although the role of the LINE-encoded protein(s) in retrotransposition has been extensively investigated,... | Long interspersed elements (LINEs) are transposable elements that mobilize and amplify their own copies within eukaryotic genomes. Although LINEs had been considered as “junk” DNA, recent studies have suggested that the LINE-induced alterations of host chromosomes are a major driving force for eukaryotic genome evoluti... | Long interspersed elements (LINEs) and short interspersed elements (SINEs) are transposable elements widely distributed in eukaryotic genomes [1],[2]; as such, they substantially affect genome complexity and evolution [3],[4]. These elements mobilize and amplify their own sequences by a mechanism called retrotransposit... |
10.1371/journal.pgen.1006761 | Identification of breast cancer associated variants that modulate transcription factor binding | Genome-wide association studies (GWAS) have discovered thousands loci associated with disease risk and quantitative traits, yet most of the variants responsible for risk remain uncharacterized. The majority of GWAS-identified loci are enriched for non-coding single-nucleotide polymorphisms (SNPs) and defining the molec... | The promise of effective personalized medicine is dependent upon the ability to identify genetic variants in the population that influence disease risk and then use this information to accurately predict the likelihood of disease incidence for individual patients. High-risk individuals may be entered into clinical trai... | Genome-wide association studies (GWAS) have identified more than 90 genomic loci and common genetic variants associated with breast cancer [1–5]. The single nucleotide polymorphisms (SNPs) associated with breast cancer have been shown to be enriched in DNA regulatory regions [6, 7], with few residing in coding regions ... |
10.1371/journal.pgen.1001365 | An Evolutionary Genomic Approach to Identify Genes Involved in Human Birth Timing | Coordination of fetal maturation with birth timing is essential for mammalian reproduction. In humans, preterm birth is a disorder of profound global health significance. The signals initiating parturition in humans have remained elusive, due to divergence in physiological mechanisms between humans and model organisms ... | The control of birth timing in humans is the greatest unresolved question in reproductive biology, and preterm birth is the most important medical issue in maternal and child health. To begin to address this critical problem, we test the hypothesis that genes accelerated in their rate of evolution in humans, as compare... | Despite the important public health consequences of preterm birth [1], [2], determinants of human parturition remain largely uncharacterized. While some important physiological antecedents of labor have been identified in model organisms, such as progesterone withdrawal in rodents, such signals do not seem to precede h... |
10.1371/journal.ppat.1006157 | The Rice Dynamin-Related Protein OsDRP1E Negatively Regulates Programmed Cell Death by Controlling the Release of Cytochrome c from Mitochondria | Programmed cell death (PCD) mediated by mitochondrial processes has emerged as an important mechanism for plant development and responses to abiotic and biotic stresses. However, the role of translocation of cytochrome c from the mitochondria to the cytosol during PCD remains unclear. Here, we demonstrate that the rice... | Plants have developed a hypersensitive response (HR) that shows rapid programed cell death (PCD) around the infection site, which in turn limits pathogen invasion and restricts the spread of pathogens. Although many studies reported the characterization of PCD in different pathosystems in the last decade, the molecular... | Programmed cell death (PCD) occurs in animals and plants, and the primary forms of PCD in mammals include apoptosis, autophagy, and necrosis [1]. In plants, PCD occurs during normal growth, development, and responses to biotic and abiotic stresses [2]. In plant disease resistance, PCD in the hypersensitive reaction (HR... |
10.1371/journal.ppat.1003207 | Cooperativity Between CD8+ T Cells, Non-Neutralizing Antibodies, and Alveolar Macrophages Is Important for Heterosubtypic Influenza Virus Immunity | Seasonal epidemics of influenza virus result in ∼36,000 deaths annually in the United States. Current vaccines against influenza virus elicit an antibody response specific for the envelope glycoproteins. However, high mutation rates result in the emergence of new viral serotypes, which elude neutralization by preexisti... | Influenza virus continues to pose a significant risk to global health and is responsible for thousands of deaths each year in the United States. This threat is largely due to the ability of the influenza virus to undergo rapid changes, allowing it to escape from immune responses elicited by previous infections or vacci... | Influenza virus remains a significant threat to global health, and results in 200,000 hospitalizations and 3,000–49,000 deaths each year in the United States [1]–[3]. The ability of influenza virus to rapidly mutate and/or undergo reassortment, allows the virus to evade protective immunity obtained from previous infect... |
10.1371/journal.ppat.1003491 | Irf8-Regulated Genomic Responses Drive Pathological Inflammation during Cerebral Malaria | Interferon Regulatory Factor 8 (IRF8) is required for development, maturation and expression of anti-microbial defenses of myeloid cells. BXH2 mice harbor a severely hypomorphic allele at Irf8 (Irf8R294C) that causes susceptibility to infection with intracellular pathogens including Mycobacterium tuberculosis. We repor... | Cerebral malaria is a severe and often lethal complication from infection with Plasmodium falciparum which is driven in part by pathological host inflammatory response to parasitized red cells′ adherence in the brain microvasculature. However, the pathways that initiate and amplify this pathological neuroinflammation a... | IRF8 is a member of the Interferon Regulatory Factor (IRF) family of transcription factors that plays a central role in interferon signaling, response to infection and maturation of dendritic cells (DCs) and other myeloid lineages [1], [2]. IRF8 regulates elements of constitutive gene expression in both myeloid and lym... |
10.1371/journal.pgen.1004273 | Folliculin Regulates Ampk-Dependent Autophagy and Metabolic Stress Survival | Dysregulation of AMPK signaling has been implicated in many human diseases, which emphasizes the importance of characterizing AMPK regulators. The tumor suppressor FLCN, responsible for the Birt-Hogg Dubé renal neoplasia syndrome (BHD), is an AMPK-binding partner but the genetic and functional links between FLCN and AM... | The FLCN gene is responsible for the hereditary human tumor disease called Birt-Hogg-Dube syndrome (BHD). Patients that inherit an inactivating mutation in the FLCN gene develop lung collapse as well as tumors in the kidney, colon, and skin. It is not clear yet what the exact function of this protein is in the cell or ... | Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant neoplasia disorder that was originally described by Hornstein and Knickenberg in 1975 and by Birt, Hogg, and Dubé in 1977 as a disorder associated with colon polyps and fibrofolliculomas of the skin [1], [2]. Toro et al. recognized in 1999 that BHD patients were al... |
10.1371/journal.ppat.1002414 | The Enteropathogenic E. coli (EPEC) Tir Effector Inhibits NF-κB Activity by Targeting TNFα Receptor-Associated Factors | Enteropathogenic Escherichia coli (EPEC) disease depends on the transfer of effector proteins into epithelia lining the human small intestine. EPEC E2348/69 has at least 20 effector genes of which six are located with the effector-delivery system genes on the Locus of Enterocyte Effacement (LEE) Pathogenicity Island. O... | Enteropathogenic Escherichia coli (EPEC) remain an important cause of infant diarrhoea and death in developing countries. Undoubtedly, a key pathogenic event relates to the bacteria's ability to inhibit the expression of anti-microbial and inflammation-inducing molecules regulated by the NF-κB transcription factor. Thi... | The EPEC disease process depends on a protein delivery system, encoded by the Locus of Enterocyte Effacement (LEE) Pathogenicity Island, that transfers effector proteins directly into the cytoplasm of infected epithelia [1]–[3]. This delivery apparatus is composed of a Type Three Secretion System (T3SS) and a filamento... |
10.1371/journal.pgen.1006601 | Excess of genomic defects in a woolly mammoth on Wrangel island | Woolly mammoths (Mammuthus primigenius) populated Siberia, Beringia, and North America during the Pleistocene and early Holocene. Recent breakthroughs in ancient DNA sequencing have allowed for complete genome sequencing for two specimens of woolly mammoths (Palkopoulou et al. 2015). One mammoth specimen is from a main... | We observe an excess of detrimental mutations, consistent with genomic meltdown in woolly mammoths on Wrangel Island just prior to extinction. We observe an excess of deletions, an increase in the proportion of deletions affecting gene sequences, and an excess of premature stop codons in response to evolution under low... | Woolly mammoths (Mammuthus primigenius) were among the most populous large herbivores in North America, Siberia, and Beringia during the Pleistocene and early Holocene [1]. However warming climates and human predation led to extinction on the mainland roughly 10,000 years ago [2]. Lone isolated island populations persi... |
10.1371/journal.ppat.1003038 | HCMV-Infected Cells Maintain Efficient Nucleotide Excision Repair of the Viral Genome while Abrogating Repair of the Host Genome | Many viruses subvert the host cell's ability to mount and complete various DNA damage responses (DDRs) after infection. HCMV infection of permissive fibroblasts activates host DDRs at the time of viral deposition and during replication, but the DDRs remain uncompleted without arrest or apoptosis. We believe this was in... | Human cytomegalovirus (HCMV) is a leading cause of birth defects. This may be due in part to this virus' ability to inflict specific damage to its host's DNA, combined with the disruption of an infected cell's ability to repair damage. Earlier studies found that components of the cell's repair machinery were differenti... | Human Cytomegalovirus (HCMV) is among the leading causes of birth defects in the United States, affecting an estimated 8000 children per year [1]. Each year ∼1% of all newborns are congenitally infected with HCMV. Of these infants, 5–10% manifest signs of serious neurological defects at birth [2]–[5], with an additiona... |
10.1371/journal.pgen.1002348 | Foxn1 Regulates Lineage Progression in Cortical and Medullary Thymic Epithelial Cells But Is Dispensable for Medullary Sublineage Divergence | The forkhead transcription factor Foxn1 is indispensable for thymus development, but the mechanisms by which it mediates thymic epithelial cell (TEC) development are poorly understood. To examine the cellular and molecular basis of Foxn1 function, we generated a novel and revertible hypomorphic allele of Foxn1. By vary... | The thymus is the specialized organ responsible for generating T cells, which are required to regulate and effect immune responses. The unique functions of the thymus are mediated by a diverse array of specialized epithelial cells found only within this organ. These specialized, functionally mature thymic epithelial ce... | T cell development occurs in the thymus and depends on progressive interactions with the thymic stroma. Critical to this function is the thymic epithelium (TE), which comprises a diverse array of phenotypically and functionally distinct cell types broadly organized into cortical and medullary regions [1].
During... |
10.1371/journal.pntd.0006373 | Diet and hygiene practices influence morbidity in schoolchildren living in Schistosomiasis endemic areas along Lake Victoria in Kenya and Tanzania—A cross-sectional study | Since 2011, cohorts of schoolchildren in regions bordering Lake Victoria in Kenya and Tanzania have been investigated for morbidity caused by Schistosoma mansoni infection. Despite being neighbouring countries with similar lifestyles and ecological environments, Tanzanian schoolchildren had lower S. mansoni prevalence ... | Millions of school-age children in Kenya and Tanzania are at risk for infection with Schistosoma mansoni, which has an impact on their physical health. A total of 490 schoolchildren (163 from Kenya and 327 from Tanzania) aged 9–11 years living along the shores of Lake Victoria in Kenya and Tanzania provided data on S. ... | Schistosomiasis, also known as bilharzia, is an infectious disease caused by parasitic flatworms of the genus Schistosoma. Schistosomiasis is considered as one of the Neglected Tropical Diseases (NTDs) and is estimated to affect at least 230 million people annually [1] with a majority in sub-Saharan Africa [2]. In term... |
10.1371/journal.ppat.1002759 | Polyfunctional Type-1, -2, and -17 CD8+ T Cell Responses to Apoptotic Self-Antigens Correlate with the Chronic Evolution of Hepatitis C Virus Infection | Caspase-dependent cleavage of antigens associated with apoptotic cells plays a prominent role in the generation of CD8+ T cell responses in various infectious diseases. We found that the emergence of a large population of autoreactive CD8+ T effector cells specific for apoptotic T cell-associated self-epitopes exceeds ... | The emergence of a large population of mixed polyfunctional (type-1, -2, -17) CD8+ T cell effector responses specific for apoptotic T cell-associated self-epitopes rather than the dysfunction or altered quality of virus-specific CD8+ T cells is associated with the progression toward chronic disease in the human model o... | The fate of the enormous number of apoptotic cells that derive from effector Tcells undergoing apoptosis after performing their functions during acute or chronic infections remain to be determined [1], [2]. Phagocytosis of apoptotic cells by dendritic cells (DCs) leads to the processing of apoptotic cell-associated ant... |
10.1371/journal.pgen.1001063 | Transcriptional Regulation by CHIP/LDB Complexes | It is increasingly clear that transcription factors play versatile roles in turning genes “on” or “off” depending on cellular context via the various transcription complexes they form. This poses a major challenge in unraveling combinatorial transcription complex codes. Here we use the powerful genetics of Drosophila c... | Different cell types in multi-cellular organisms are determined by the repertoire of genes active in each cell. This repertoire, or transcriptome, is established by the coordinated activity of transcription factors and cofactors that form modular transcription complexes. The modular nature of transcription complexes co... | The intricate regulation of gene expression in multi-cellular organisms involves an elaborate collaboration between repertoires of cis-regulatory sequences and modular, multi-protein transcription complexes that bind them (reviewed in [1]). Transcription complexes are now viewed as being composed of relatively ubiquito... |
10.1371/journal.pgen.1007410 | Evolution via recombination: Cell-to-cell contact facilitates larger recombination events in Streptococcus pneumoniae | Homologous recombination in the genetic transformation model organism Streptococcus pneumoniae is thought to be important in the adaptation and evolution of this pathogen. While competent pneumococci are able to scavenge DNA added to laboratory cultures, large-scale transfers of multiple kb are rare under these conditi... | Bacteria shuffle their genes far less often than humans do and genes or traits are more directly linked with the singular bacterial parent cell rather than the two parents that are involved in sexual reproduction. However, bacteria do occasionally have sex in the form of homologous recombination by taking up external D... | Streptococcus pneumoniae (the pneumococcus) is a paradigm for genetic transformation, in which cells become ‘competent’ for uptake of DNA through binding of a cognate competence stimulating peptide. The single stranded DNA that is taken up is then incorporated into the genome of the competent cell and can be detected a... |
10.1371/journal.ppat.1004583 | A Wild C. Elegans Strain Has Enhanced Epithelial Immunity to a Natural Microsporidian Parasite | Microbial pathogens impose selective pressures on their hosts, and combatting these pathogens is fundamental to the propagation of a species. Innate immunity is an ancient system that provides the foundation for pathogen resistance, with epithelial cells in humans increasingly appreciated to play key roles in innate de... | Infectious diseases caused by microbes create some of the strongest forces in evolution, by killing their hosts, and impairing their ability to produce progeny. Microsporidia are very common microbes that cause disease in all animals, including roundworms, insects, fish and people. We investigated microsporidia infecti... | Infectious disease is one of the strongest drivers of evolution, generating diversification in hosts and pathogens through a dynamic co-evolutionary process of adaptation and counter-adaptation. The dynamism of these relationships is apparent in emerging infectious diseases, whereby an interaction between organisms cha... |
10.1371/journal.pgen.1005534 | Insect Resistance to Bacillus thuringiensis Toxin Cry2Ab Is Conferred by Mutations in an ABC Transporter Subfamily A Protein | The use of conventional chemical insecticides and bacterial toxins to control lepidopteran pests of global agriculture has imposed significant selection pressure leading to the rapid evolution of insecticide resistance. Transgenic crops (e.g., cotton) expressing the Bt Cry toxins are now used world wide to control thes... | Transgenic crops expressing the insecticidal protein Cry2Ab from Bacillus thuringiensis (Bt) are used worldwide to suppress damage by lepidopteran pests, often used in combination with Cry1Ac toxin to delay resistance evolution. Until now, the Cry2Ab mode of action and the mechanism of resistance were unknown, with fie... | In recent decades, agriculture has increasingly come to rely on toxins encoded by the Gram-positive bacterium Bacillus thuringiensis (Bt) for the production of insect–resistant transgenic crops. Narrow spectrum insecticides such as the protoxin crystals produced by Bt during sporulation are highly specific for certain ... |
10.1371/journal.ppat.1004600 | Reprogramming of Yersinia from Virulent to Persistent Mode Revealed by Complex In Vivo RNA-seq Analysis | We recently found that Yersinia pseudotuberculosis can be used as a model of persistent bacterial infections. We performed in vivo RNA-seq of bacteria in small cecal tissue biopsies at early and persistent stages of infection to determine strategies associated with persistence. Comprehensive analysis of mixed RNA popul... | To establish infection and colonize within a host, infecting pathogens have to cope with a variety of destructive surroundings. The food-borne pathogen Y. pseudotuberculosis can cause persistent infection in mice. Upon infection, Y. pseudotuberculosis passes the anti-microbial gastrointestinal milieu and finally remain... | Yersinia pseudotuberculosis is a food borne pathogen that can penetrate the intestinal epithelium and cause gastroenteritis. This enteropathogen invades lymphoid follicles of Peyer’s patches and cecum, where it survives extracellularly before breaking the barrier and becoming systemic [1,2]. All pathogenic Yersinia spe... |
10.1371/journal.pntd.0005568 | Detecting the impact of temperature on transmission of Zika, dengue, and chikungunya using mechanistic models | Recent epidemics of Zika, dengue, and chikungunya have heightened the need to understand the seasonal and geographic range of transmission by Aedes aegypti and Ae. albopictus mosquitoes. We use mechanistic transmission models to derive predictions for how the probability and magnitude of transmission for Zika, chikungu... | Understanding the drivers of recent Zika, dengue, and chikungunya epidemics is a major public health priority. Temperature may play an important role because it affects virus transmission by mosquitoes, through its effects on mosquito development, survival, reproduction, and biting rates as well as the rate at which mo... | Epidemics of dengue, chikungunya, and Zika are sweeping through the Americas, and are part of a global public health crisis that places an estimated 3.9 billion people in 120 countries at risk [1]. Dengue virus (DENV) distribution and intensity in the Americas has increased over the last three decades, infecting an est... |
10.1371/journal.ppat.1007397 | The RNA helicase DDX3X is an essential mediator of innate antimicrobial immunity | DExD/H box RNA helicases, such as the RIG-I-like receptors (RLR), are important components of the innate immune system. Here we demonstrate a pivotal and sex-specific role for the heterosomal isoforms of the DEAD box RNA helicase DDX3 in the immune system. Mice lacking DDX3X during hematopoiesis showed an altered leuko... | The establishment of innate immunity to pathogens requires cells to sense microbial molecules and to initiate a de novo transcription-based antimicrobial response. With the identification of Rig I and Mda5, two RNA helicases were shown to serve as pivotal receptors of viral RNA. Subsequently, a considerable number of R... | Upon infection, germline-encoded pattern recognition receptors (PRRs) located on the surface of cells, in endosomal compartments and throughout the cytosol initiate an array of signaling cascades that culminate in the production of type I interferons (IFN-I), pro-inflammatory cytokines and chemokines. These cytokines e... |
10.1371/journal.pntd.0002752 | Trichuris suis and Oesophagostomum dentatum Show Different Sensitivity and Accumulation of Fenbendazole, Albendazole and Levamisole In Vitro | The single-dose benzimidazoles used against Trichuris trichiura infections in humans are not satisfactory. Likewise, the benzimidazole, fenbendazole, has varied efficacy against Trichuris suis whereas Oesophagostomum dentatum is highly sensitive to the drug. The reasons for low treatment efficacy of Trichuris spp. infe... | The human whipworm Trichuris trichiura is together with the roundworm Ascaris lumbricoides and the hookworms Ancylostoma duodenale and Necator Americanus the most common intestinal worms worldwide. Together they place more than 5 billion people at risk of infection. The current global control strategy against these wor... | The whipworm Trichuris trichiura has been estimated to infect 600 million people worldwide resulting in an estimated 1.6–6.4 million disability adjusted life-years lost globally [1]. The current control strategy against T. trichiura and other soil-transmitted helminths (STHs) is administration of single-dose anthelmint... |
10.1371/journal.pntd.0000129 | Interspecific Hybridization Yields Strategy for South Pacific Filariasis Vector Elimination | Lymphatic filariasis (LF) is a leading cause of disability in South Pacific regions, where >96% of the 1.7 million population are at risk of LF infection. As part of current global campaign, mass drug administration (MDA) has effectively reduced lymphatic filiariasis prevalence, but mosquito vector biology can complica... | Lymphatic filariasis (LF) is a global health problem, with over 120 million people affected annually. The current LF elimination program is focused on administering anti-filarial drugs to the entire at-risk population via annual mass drug administration (MDA). While the MDA program is proving effective in many areas, o... | Lymphatic filariasis (LF) is a global health problem, with over 120 million infected individuals and an estimated one billion people at risk of infection [1]. The current LF elimination campaign is premised upon the lack of a non-human reservoir for Wuchereria bancrofti and is enabled by recent advances in diagnostic t... |
10.1371/journal.pcbi.1004025 | Evolution and Phenotypic Selection of Cancer Stem Cells | Cells of different organs at different ages have an intrinsic set of kinetics that dictates their behavior. Transformation into cancer cells will inherit these kinetics that determine initial cell and tumor population progression dynamics. Subject to genetic mutation and epigenetic alterations, cancer cell kinetics can... | We present an in silico computational model of tumor growth and evolution according to the cancer stem cell hypothesis. Inheritable traits of cells may be genetically or epigenetically altered, and traits that confer increased fitness to the cell will be selected for on the population level. Phenotypic evolution yields... | Human organs and tissues are comprised of cells that have evolved to maintain functionality and integrity. Cells of different organs and ages have different traits, such as migration rate, turnover time, proliferation potential and lifespan until senescence. While fetal diploid cell strains in culture demonstrate a lar... |
10.1371/journal.pcbi.1003032 | Steered Molecular Dynamics Simulations of a Type IV Pilus Probe Initial Stages of a Force-Induced Conformational Transition | Type IV pili are long, protein filaments built from a repeating subunit that protrudes from the surface of a wide variety of infectious bacteria. They are implicated in a vast array of functions, ranging from bacterial motility to microcolony formation to infection. One of the most well-studied type IV filaments is the... | There are a large number of infectious bacteria that can be harmful to humans. Some bacterial infections are facilitated by long, tether-like filaments called type IV pili which extend from the surface of bacterial cells and attach to the surface of host cells. Type IV pilus filaments can grow to be many micrometers in... | Type IV pili (T4P), long (lengths at the micron scale) filamentous proteins composed of pilin subunits, are associated with a variety of bacteria, and emanate from the surface of the bacterial cell [1], [2]. T4P have been known as virulence factors for a long time as they are borne by many pathogens [1], [3]. They are ... |
10.1371/journal.pgen.1005457 | Runx1 Transcription Factor Is Required for Myoblasts Proliferation during Muscle Regeneration | Following myonecrosis, muscle satellite cells proliferate, differentiate and fuse, creating new myofibers. The Runx1 transcription factor is not expressed in naïve developing muscle or in adult muscle tissue. However, it is highly expressed in muscles exposed to myopathic damage yet, the role of Runx1 in muscle regener... | In response to muscle injury, the muscle initiates a repair process that calls for the proliferation of muscle stem cells, which differentiate and fuse to create the myofibers that regenerate the tissue. Maintaining the balance between myoblast proliferation and differentiation is crucial for proper regeneration, with ... | Striated muscles are highly organized structure composed of bundles of multinucleated myofibers. Each myofiber harbors peripheral nuclei and highly-organized myofibrils, granting the muscle its contractile force [1]. Muscle satellite cells (SC) comprise 2–5% of adult muscle cells [2]. Located at the myofiber periphery,... |
10.1371/journal.ppat.1005653 | Inhibition of Nuclear Transport of NF-ĸB p65 by the Salmonella Type III Secretion System Effector SpvD | Salmonella enterica replicates in macrophages through the action of effector proteins translocated across the vacuolar membrane by a type III secretion system (T3SS). Here we show that the SPI-2 T3SS effector SpvD suppresses proinflammatory immune responses. SpvD prevented activation of an NF-ĸB-dependent promoter and ... | Salmonella Typhimurium replicates in macrophages through the action of effector proteins translocated into host cells by a type III secretion system (T3SS). We show that the T3SS effector SpvD targets the NF-ĸB pathway by interfering with nuclear translocation of p65. SpvD interacts with the exportin Xpo2. Perturbation... | The NF-ĸB signalling pathway has a central role in the host response to infection by microbial pathogens, by stimulating innate and acquired host immune responses. Under normal physiological conditions, transcription factors of the NF-ĸB family such as p65 remain inactive in the cytoplasm through their interaction with... |
10.1371/journal.pgen.1003646 | Genome-Wide Association Mapping in Dogs Enables Identification of the Homeobox Gene, NKX2-8, as a Genetic Component of Neural Tube Defects in Humans | Neural tube defects (NTDs) is a general term for central nervous system malformations secondary to a failure of closure or development of the neural tube. The resulting pathologies may involve the brain, spinal cord and/or vertebral column, in addition to associated structures such as soft tissue or skin. The condition... | Neural tube defects (NTDs) are birth defects resulting from errors in the closure of the neural tube, an embryonic structure which develops into tissues of the central nervous system during pregnancy. NTDs commonly lead to costly lifelong disabilities. They are considered to be caused by a combination of nutritional, i... | Neural tube defects (NTDs) is a general term used to describe developmental defects resulting from abnormal closure or development of the neural tube during embryogenesis. The resulting pathologies may involve the brain, spinal cord, and associated structures such as vertebrae, soft tissue or skin [1]. The condition is... |
10.1371/journal.pntd.0004290 | Systematic Review and Meta-analysis of the Impact of Chemical-Based Mollusciciding for Control of Schistosoma mansoni and S. haematobium Transmission | Programs for schistosomiasis control are advancing worldwide, with many benefits noted in terms of disease reduction. Yet risk of reinfection and recurrent disease remain, even in areas with high treatment coverage. In the search for means to better prevent new Schistosoma infections, attention has returned to an older... | Infection with Schistosoma blood flukes is a leading cause of chronic parasitic disease in at-risk areas of Africa, South America, Asia, and the Philippines. Over past decades, many national programs have implemented regular drug treatment to control or prevent the advanced complications of Schistosoma infection. Howev... | Schistosomiasis, the chronic human disease caused by Schistosoma spp. parasite infections, is a preventable illness that, if left untreated, is associated with long-term undernutrition, anemia, organ scarring and fibrosis, resulting in disabling patient symptoms [1, 2]. Current anti-schistosomiasis chemotherapy program... |
10.1371/journal.pntd.0002777 | Challenges in Dengue Fever in the Elderly: Atypical Presentation and Risk of Severe Dengue and Hospita-Acquired Infection | To better understand dengue fever in the elderly, we compared clinical features, World Health Organization (WHO) dengue classification and outcomes between adult (<60) and elderly (≥60) dengue patients. We explored the impact of co-morbidity and hospital-acquired infection (HAI) on clinical outcomes in the elderly. All... | Dengue is a neglected tropical disease that is increasingly affecting elderly patients; however, there is a paucity of data on clinical presentation and outcomes in this group. The limited data suggests that elderly dengue patients have the highest case-fatality rate but the pathogenesis of mortality in elderly dengue ... | Dengue is the most significant mosquito-borne virus in humans [1] and is endemic to Singapore. In Asia dengue classically affects children with the majority of cases of dengue hemorrhagic fever (DHF), dengue shock syndrome (DSS), and dengue related mortality observed in this group [2]. However, in Singapore dengue pred... |
10.1371/journal.pgen.1003412 | Drosophila DJ-1 Decreases Neural Sensitivity to Stress by Negatively Regulating Daxx-Like Protein through dFOXO | DJ-1, a Parkinson's disease (PD)–associated gene, has been shown to protect against oxidative stress in Drosophila. However, the molecular mechanism underlying oxidative stress-induced phenotypes, including apoptosis, locomotive defects, and lethality, in DJ-1-deficient flies is not fully understood. Here we showed tha... | DJ-1 is an antioxidant protein that has been implicated in autosomal recessive Parkinson's disease (PD), although the mechanism by which DJ-1 deficiency causes PD remains elusive. Drosophila DJ-1 mutants are highly sensitive to oxidative stress and UV irradiation, and oxidative stress-induced cell death is significantl... | Oxidative stress, a state of imbalance between the generation and elimination of reactive oxygen and nitrogen species, has been implicated in a variety of neurodegenerative diseases [1]–[3]. The central nervous system is presumed to be particularly vulnerable to oxidative stress, as it consumes abundant quantities of o... |
10.1371/journal.pcbi.1004413 | Bulk Genotyping of Biopsies Can Create Spurious Evidence for Hetereogeneity in Mutation Content | When multiple samples are taken from the neoplastic tissues of a single patient, it is natural to compare their mutation content. This is often done by bulk genotyping of whole biopsies, but the chance that a mutation will be detected in bulk genotyping depends on its local frequency in the sample. When the underlying ... | Researchers who take multiple samples from a cancer or pre-cancer tissue and find that some samples show far more mutations than others are likely to conclude that the high-mutation samples reflect cells with an abnormal mutation or growth rate. We considered the common practice of testing a bulk sample for mutations, ... | The somatic genotypes of cancerous and pre-cancerous tissues are frequently assayed by taking biopsies containing a substantial number of cells and genotyping each biopsy as a whole (via SNP chip, exome or genome sequencing, or other techniques). For example, in a study of Barrett’s esophagus genotypes were derived fro... |
10.1371/journal.ppat.1004418 | A Critical Role for IL-17RB Signaling in HTLV-1 Tax-Induced NF-κB Activation and T-Cell Transformation | Human T-cell leukemia virus type 1 (HTLV-1) infection is linked to the development of adult T-cell leukemia (ATL) and the neuroinflammatory disease HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax protein functions as a potent viral oncogene that constitutively activates the NF-κB tra... | The retrovirus HTLV-1 is the causative agent of an aggressive lymphoproliferative disorder known as adult T-cell leukemia (ATL). The HTLV-1 Tax regulatory protein constitutively activates the host NF-κB transcription factor to promote T-cell proliferation, survival and cell transformation. However, it remains unknown p... | The retrovirus human T-cell leukemia virus type 1 (HTLV-1) infects between 10–20 million people worldwide [1]. HTLV-1 is the etiological agent of the neuroinflammatory disease HTLV-1-associated myelopathy (HAM/TSP) and adult T-cell leukemia (ATL), a CD4+CD25+ T-cell malignancy [2], [3]. ATL develops in about 5% of HTLV... |
10.1371/journal.pntd.0004255 | Cissampelos pareira Linn: Natural Source of Potent Antiviral Activity against All Four Dengue Virus Serotypes | Dengue, a mosquito-borne viral disease, poses a significant global public health risk. In tropical countries such as India where periodic dengue outbreaks can be correlated to the high prevalence of the mosquito vector, circulation of all four dengue viruses (DENVs) and the high population density, a drug for dengue is... | India represents ~50% of the global population estimated to be at risk of dengue. Severe dengue, which is potentially fatal, correlates with very high virus load, reduction in platelet counts and haemorrhage. Antiviral therapy to reduce high virus load may be beneficial in attenuating disease severity. We have explored... | Dengue disease is a major public health concern around the world. It is spread to humans through the bite of Aedes mosquitoes which serve as carriers of the disease-causing viruses. There are four serotypes of dengue viruses (DENV-1, -2, -3 and -4), belonging to the family Flaviviridae [1], which are prevalent in more ... |
10.1371/journal.pcbi.1004779 | Evolution of Cooperation in Social Dilemmas on Complex Networks | Cooperation in social dilemmas is essential for the functioning of systems at multiple levels of complexity, from the simplest biological organisms to the most sophisticated human societies. Cooperation, although widespread, is fundamentally challenging to explain evolutionarily, since natural selection typically favor... | Social dilemmas embody the tension between individual self-interest on the one hand and the public good on the other that underlie many of the greatest challenges facing human and animal societies, such as the maintenance of altruism and the responsible use of common resources. Understanding the mechanisms through whic... | The evolution and maintenance of cooperation in social dilemmas is essential for the formation of systems at all levels of complexity, from replicating molecules to multi-cellular organisms to human societies. A small selection of examples of cooperative behavior in social dilemmas from the bewilderingly large number o... |
10.1371/journal.ppat.1000023 | Cationic Amino Acid Transporter-2 Regulates Immunity by Modulating Arginase Activity | Cationic amino acid transporters (CAT) are important regulators of NOS2 and ARG1 activity because they regulate L-arginine availability. However, their role in the development of Th1/Th2 effector functions following infection has not been investigated. Here we dissect the function of CAT2 by studying two infectious dis... | Recent studies conducted with amino transporter Slc7a2-deficient mice (CAT2) demonstrated that NOS2 activity in macrophages is regulated by CAT2. NOS2, which synthesizes nitric oxide, regulates numerous important activities, including resistance to infectious organisms, tumor development, and autoimmune diseases. It al... | Tissue macrophages comprise a heterogeneous population of cells, recently separated into three major categories based on their unique functional capabilities. The TH2 cytokines IL-4 and IL-13 trigger a characteristic ‘alternative’ state of activation in macrophages that is distinct from the ‘classical’ TH1-type activat... |
10.1371/journal.pntd.0004808 | Antibody-Mediated Neutralization of the Exotoxin Mycolactone, the Main Virulence Factor Produced by Mycobacterium ulcerans | Mycolactone, the macrolide exotoxin produced by Mycobacterium ulcerans, causes extensive tissue destruction by inducing apoptosis of host cells. In this study, we aimed at the production of antibodies that could neutralize the cytotoxic activities of mycolactone.
Using the B cell hybridoma technology, we generated a se... | Mycolactones A/B (also simply referred to as mycolactone) are macrolide exotoxins produced by Mycobacterium ulcerans, the causative agent of the neglected tropical skin disease Buruli ulcer (BU). The potent cytotoxic and anti-inflammatory activities of mycolactones lead to severe destruction of the subcutaneous fat tis... | Mycobacterium ulcerans, the causative agent of the neglected tropical skin disease Buruli ulcer (BU), produces the exotoxin mycolactone, which is responsible for the formation of chronic necrotizing skin lesions [1, 2]. Early diagnosis followed by rapid initiation of the currently recommended treatment with rifampicin ... |
10.1371/journal.pcbi.1007319 | From Escherichia coli mutant 13C labeling data to a core kinetic model: A kinetic model parameterization pipeline | Kinetic models of metabolic networks offer the promise of quantitative phenotype prediction. The mechanistic characterization of enzyme catalyzed reactions allows for tracing the effect of perturbations in metabolite concentrations and reaction fluxes in response to genetic and environmental perturbation that are beyon... | Microbial production hosts are used for production of a wide range of commodity chemicals. Improving the conversion efficiency of microbial strains is critical to the economic viability and the continued push towards the use of environmentally neutral bioprocesses as a means for producing the chemicals society depends ... | The standardization and automation of genome characterization and editing techniques has been accompanied by a rapid increase in the number of prokaryotic and eukaryotic microbial organisms available for engineering for overproduction of target commodity metabolites. With annotated genomes and CRISPR-Cas toolboxes cons... |
10.1371/journal.pntd.0003637 | Validation of Serological Tests for the Detection of Antibodies Against Treponema pallidum in Nonhuman Primates | There is evidence to suggest that the yaws bacterium (Treponema pallidum ssp. pertenue) may exist in non-human primate populations residing in regions where yaws is endemic in humans. Especially in light of the fact that the World Health Organizaiton (WHO) recently launched its second yaws eradication campaign, there i... | The success of any disease eradication campaign depends on considering possible non-human reservoirs of the disease. Although the first report of T. pallidum infection in baboons was published in the 1970’s and the zoonotic potential was demonstrated by inoculation of a West African simian strain into humans, nonhuman ... | Treponema pallidum is the bacterium that causes venereal syphilis (ssp. pallidum) and the non-venereal diseases yaws (ssp. pertenue) and endemic syphilis (ssp. endemicum) in humans [1]. The spirochete is able to cause a life-long chronic infection in untreated individuals [2] and elicits a strong adaptive immune respon... |
10.1371/journal.ppat.1007323 | Independent amplification of co-infected long incubation period low conversion efficiency prion strains | Prion diseases are caused by a misfolded isoform of the prion protein, PrPSc. Prion strains are hypothesized to be encoded by strain-specific conformations of PrPSc and prions can interfere with each other when a long-incubation period strain (i.e. blocking strain) inhibits the conversion of a short-incubation period s... | This is the first example of prion strains that replicate independently in vitro and in vivo. This observation changes the paradigm of the interactions of prion strains and provides further evidence that strains are a dynamic mixture of substrains. Strain interference is influenced by the abundance of PrPC that is conv... | Prion diseases are a group of transmissible neurodegenerative diseases that affect animals, including humans. Animal prion diseases include scrapie in sheep and goats, transmissible mink encephalopathy (TME) in ranch-raised mink, chronic wasting disease (CWD) in cervids, and bovine spongiform encephalopathy [1–10]. The... |
10.1371/journal.pntd.0007144 | Assessment of the new World Health Organization's dengue classification for predicting severity of illness and level of healthcare required | The objective of this study was to assess the validity of the new dengue classification proposed by the World Health Organization (WHO) in 2009 and to develop pragmatic guidelines for case triage and management. This retrospective study involved 357 laboratory-confirmed cases of dengue infection diagnosed at King Abdul... | Dengue fever, the most prevalent arthropod-borne viral disease in humans, has been conventionally classified into four main categories: non-classical, classical, dengue hemorrhagic fever, and dengue shock syndrome. Several studies reported lack of correlation between the categories of the conventional classification an... | Dengue fever (DF) is the most prevalent arthropod-borne viral disease in humans and one of the major re-emerging communicable diseases. The World Health Organization (WHO) estimates that around 50 million dengue infections occur annually and approximately 2.5 billion of the world's population live in dengue-endemic are... |
10.1371/journal.pntd.0000904 | Metabolomics to Unveil and Understand Phenotypic Diversity between Pathogen Populations | Leishmaniasis is a debilitating disease caused by the parasite Leishmania. There is extensive clinical polymorphism, including variable responsiveness to treatment. We study Leishmania donovani parasites isolated from visceral leishmaniasis patients in Nepal that responded differently to antimonial treatment due to dif... | Visceral leishmaniasis is caused by a parasite called Leishmania donovani, which every year infects about half a million people and claims several thousand lives. Existing treatments are now becoming less effective due to the emergence of drug resistance. Improving our understanding of the mechanisms used by the parasi... | Health professionals are constantly challenged with the clinical polymorphism of infectious diseases. Pathogen diversity is known to play a major role in this clinically observed variability in disease manifestation, severity and drug response. However, to obtain a greater understanding of this relationship there is a ... |
10.1371/journal.pcbi.1003743 | No, There Is No 150 ms Lead of Visual Speech on Auditory Speech, but a Range of Audiovisual Asynchronies Varying from Small Audio Lead to Large Audio Lag | An increasing number of neuroscience papers capitalize on the assumption published in this journal that visual speech would be typically 150 ms ahead of auditory speech. It happens that the estimation of audiovisual asynchrony in the reference paper is valid only in very specific cases, for isolated consonant-vowel syl... | Since a paper was published in this journal, an increasing number of neuroscience papers capitalize on the assumption that visual speech would be typically 150 ms ahead of auditory speech. It happens that the estimation of audiovisual asynchrony in the mentioned paper is valid only in very specific cases, for isolated ... | Sensory processing has long been conceived as modular and hierarchic, beginning by monosensory cue extraction in the primary sensory cortices before higher level multisensory interactions took place in associative areas, preparing the route for final decision and adequate behavioral answer. However, it is now firmly es... |
10.1371/journal.pgen.1000595 | The CUGBP2 Splicing Factor Regulates an Ensemble of Branchpoints from Perimeter Binding Sites with Implications for Autoregulation | Alternative pre-mRNA splicing adjusts the transcriptional output of the genome by generating related mRNAs from a single primary transcript, thereby expanding protein diversity. A fundamental unanswered question is how splicing factors achieve specificity in the selection of target substrates despite the recognition of... | Alternative splicing is a precisely controlled process that determines whether an exon will be included or skipped in the mature mRNA transcript. Factors that control alternative splicing bind to RNA sequence motifs in the exon or flanking introns and guide tissue and developmental specific splicing events. CUGBP2 is a... | Alternative pre-mRNA splicing is prevalent throughout vertebrate genomes where an individual gene can be diversified into hundreds or even thousands of related mRNA isoforms [1],[2]. Functional consequences of alternative splicing can involve changes to a subset of the protein's biochemical properties or subcellular lo... |
10.1371/journal.ppat.1006162 | HTLV-1 Tax Induces Formation of the Active Macromolecular IKK Complex by Generating Lys63- and Met1-Linked Hybrid Polyubiquitin Chains | The Tax protein of human T-cell leukemia virus type 1 (HTLV-1) is crucial for the development of adult T-cell leukemia (ATL), a highly malignant CD4+ T cell neoplasm. Among the multiple aberrant Tax-induced effects on cellular processes, persistent activation of transcription factor NF-κB, which is activated only trans... | NF-κB is a key transcription factor that regulates many physiologically important cellular processes. However, persistent activation of NF-κB leads to chronic inflammation, autoimmunity and malignancy. Infection with the human retrovirus HTLV-1 causes adult T-cell leukemia, and HTLV-1 Tax-mediated persistent NF-κB acti... | Human T-cell leukemia virus type 1 (HTLV-1) is etiologically associated with adult T-cell leukemia (ATL), an aggressive and lethal malignancy of CD4+ T cells, and with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) [1, 2]. The HTLV-1 provirus genome encodes a transactivator protein (Tax), which is ... |
10.1371/journal.pntd.0003341 | Natural and Vaccine-Mediated Immunity to Salmonella Typhimurium is Impaired by the Helminth Nippostrongylus brasiliensis | The impact of exposure to multiple pathogens concurrently or consecutively on immune function is unclear. Here, immune responses induced by combinations of the bacterium Salmonella Typhimurium (STm) and the helminth Nippostrongylus brasiliensis (Nb), which causes a murine hookworm infection and an experimental porin pr... | Vaccination studies in animal models have focused on understanding responses in young, previously naïve mice. In reality, humans are vaccinated or respond to infection in the context of a life-time of accumulated exposure to multiple, systemic infections and other vaccines, some of which are themselves attenuated live ... | Models examining immunity to experimental infections primarily focus on responses to a single pathogen or vaccine in an immunologically naïve host. Such studies have shaped our understanding of how infections develop and are controlled. However, in reality individuals are exposed to multiple pathogens, often concurrent... |
10.1371/journal.pgen.1005335 | Separable Crossover-Promoting and Crossover-Constraining Aspects of Zip1 Activity during Budding Yeast Meiosis | Accurate chromosome segregation during meiosis relies on the presence of crossover events distributed among all chromosomes. MutSγ and MutLγ homologs (Msh4/5 and Mlh1/3) facilitate the formation of a prominent group of meiotic crossovers that mature within the context of an elaborate chromosomal structure called the sy... | At the heart of reproductive cell formation is a nuclear division process (meiosis) whereby homologous chromosomes segregate from one another. Meiotic partner chromosomes establish exclusive associations via a patterned distribution of crossover recombination events. During the maturation of recombination intermediates... | The segregation of homologous chromosomes at meiosis I is essential for the formation of haploid reproductive cells. Accurate segregation is dependent on the establishment of one or more associations between homologous chromosomes [1,2]. For most organisms, crossover recombination events in conjunction with sister chro... |
10.1371/journal.ppat.1004781 | Macrocyclic Lactones Differ in Interaction with Recombinant P-Glycoprotein 9 of the Parasitic Nematode Cylicocylus elongatus and Ketoconazole in a Yeast Growth Assay | Macrocyclic lactones (MLs) are widely used parasiticides against nematodes and arthropods, but resistance is frequently observed in parasitic nematodes of horses and livestock. Reports claiming resistance or decreased susceptibility in human nematodes are increasing. Since no target site directed ML resistance mechanis... | Macrocyclic lactones (MLs) are widely used drugs against parasitic nematodes, but drug resistance is rapidly increasing in prevalence and spatial distribution in parasites of ruminants and horses, and is suspected in human nematodes after mass drug applications. Changes in expression levels or the amino acid sequences ... | Due to their broad-spectrum antiparasitic activity with effects against both, nematodes and arthropods (endectocides), macrocyclic lactones (MLs) are among the most important antiparasitic drugs in veterinary and human medicine [1]. However, resistance to MLs is widespread in nematodes of small ruminants and currently ... |
10.1371/journal.pntd.0004836 | Strong-LAMP: A LAMP Assay for Strongyloides spp. Detection in Stool and Urine Samples. Towards the Diagnosis of Human Strongyloidiasis Starting from a Rodent Model | Strongyloides stercoralis, the chief causative agent of human strongyloidiasis, is a nematode globally distributed but mainly endemic in tropical and subtropical regions. Chronic infection is often clinically asymptomatic but it can result in severe hyperinfection syndrome or disseminated strongyloidiasis in immunocomp... | Human strongyloidiasis, a soil-transmitted infection mainly caused by Strongyloides stercoralis, is one of the most neglected among the so-called neglected tropical diseases (NTDs). The difficult diagnosis lead to an underreporting of infection rates. Strongyloidiasis can easily be misdiagnosed because many infections ... | Strongyloidiasis, a soil-transmitted helminth human infection, is considered by World Health Organization (WHO) as a neglected condition affecting an estimated 30–100 million people worldwide [1]. The accuracy of these estimates remains actually uncertain due to lack of efficient guidelines for screening the population... |
10.1371/journal.ppat.1003708 | Regulation of Innate Responses during Pre-patent Schistosome Infection Provides an Immune Environment Permissive for Parasite Development | Blood flukes of the genus Schistosoma infect over 200 million people, causing granulomatous pathology with accompanying morbidity and mortality. As a consequence of extensive host-parasite co-evolution, schistosomes exhibit a complex relationship with their hosts, in which immunological factors are intimately linked wi... | Schistosomiasis is a devastating disease caused by Schistosoma blood flukes and is a leading parasitic cause of morbidity and mortality in the Developing World. The regulation of inflammatory responses to schistosome eggs trapped in tissues is critical for host survival and is established before egg deposition begins, ... | As a result of extensive host-parasite co-evolution, helminths exploit resources within their hosts to complete their development and ensure transmission to new hosts. Indeed, most helminths are obligate parasites, requiring the intra-host environment for successful life cycle completion. However, for the most part, th... |
10.1371/journal.pntd.0003477 | Identification of the Mycobacterium ulcerans Protein MUL_3720 as a Promising Target for the Development of a Diagnostic Test for Buruli Ulcer | Buruli ulcer (BU) caused by Mycobacterium ulcerans is a devastating skin disease, occurring mainly in remote West African communities with poor access to health care. Early case detection and subsequent antibiotic treatment are essential to counteract the progression of the characteristic chronic ulcerative lesions. Si... | According to the recommendations of the World Health Organization, the clinical diagnosis of BU should be reconfirmed by at least two laboratory techniques. However, out of the four currently available tests, three (PCR, histopathology and cultivation of M. ulcerans) can only be performed at centralized reference labor... | Buruli ulcer (BU) is a neglected mycobacterial skin disease, reported from tropical and subtropical countries world-wide with highest incidence rates in Western Africa [1]. Populations in rural areas with limited access to health facilities are most affected and often seek medical advice at late disease stages [2]. Adv... |
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