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10.1371/journal.pmed.1002509 | The potential impact of case-area targeted interventions in response to cholera outbreaks: A modeling study | Cholera prevention and control interventions targeted to neighbors of cholera cases (case-area targeted interventions [CATIs]), including improved water, sanitation, and hygiene, oral cholera vaccine (OCV), and prophylactic antibiotics, may be able to efficiently avert cholera cases and deaths while saving scarce resou... | The risk of cholera around households of cholera cases is higher than in the general population in the days after cholera symptoms start.
Rapid targeting of cholera interventions to neighbors of cholera cases may provide an effective and resource-efficient way to avert cholera cases and deaths and reduce the duration o... | With over 130,000 cases and 2,400 deaths reported globally in 2016, cholera continues to be a major public health threat, particularly in sub-Saharan Africa [1]. These numbers likely represent an underestimate of the true burden due to poor access to health care, insensitive surveillance systems, and political sensitiv... |
10.1371/journal.ppat.1003579 | Functional Specialization of the Small Interfering RNA Pathway in Response to Virus Infection | In Drosophila, post-transcriptional gene silencing occurs when exogenous or endogenous double stranded RNA (dsRNA) is processed into small interfering RNAs (siRNAs) by Dicer-2 (Dcr-2) in association with a dsRNA-binding protein (dsRBP) cofactor called Loquacious (Loqs-PD). siRNAs are then loaded onto Argonaute-2 (Ago2)... | The RNA interference (RNAi) pathway utilizes small non-coding RNAs to silence gene expression. In insects, RNAi regulates endogenous genes and functions as an RNA-based immune system against viral infection. Here we have uncovered details of how RNAi is triggered by RNA viruses. Double-stranded RNA (dsRNA) generated as... | RNA interference (RNAi) utilizes small non-coding RNAs in association with an Argonaute (Ago) protein to regulate gene expression in virtually all eukaryotes [1], [2], [3]. In animals, there are three major classes of small non-coding RNAs: microRNAs (miRNAs), piwi-interacting RNAs (piRNAs), and small interfering RNAs ... |
10.1371/journal.pgen.1007088 | Loss of the Caenorhabditis elegans pocket protein LIN-35 reveals MuvB's innate function as the repressor of DREAM target genes | The DREAM (Dp/Retinoblastoma(Rb)-like/E2F/MuvB) transcriptional repressor complex acts as a gatekeeper of the mammalian cell cycle by establishing and maintaining cellular quiescence. How DREAM’s three functional components, the E2F-DP heterodimer, the Rb-like pocket protein, and the MuvB subcomplex, form and function ... | The 8-subunit DREAM transcriptional repressor complex contains 3 functional components that together control expression of cell cycle and developmental genes. How the E2F-DP transcription factor heterodimer, the pocket protein, and the highly conserved MuvB complex coalesce on chromatin and repress DREAM target genes h... | As embryonic cells develop and differentiate, a conserved transcriptional program establishes their ordered exit from the cell cycle into a resting phase, also called G0 or quiescence. The highly conserved DREAM (for Dp, Retinoblastoma (Rb)-like, E2F, and MuvB) transcriptional repressor complex mediates this cell cycle... |
10.1371/journal.pcbi.1002656 | Weighted Frequent Gene Co-expression Network Mining to Identify Genes Involved in Genome Stability | Gene co-expression network analysis is an effective method for predicting gene functions and disease biomarkers. However, few studies have systematically identified co-expressed genes involved in the molecular origin and development of various types of tumors. In this study, we used a network mining algorithm to identi... | Proteins interact with each other in a network manner to precisely regulate complicated physiological functions of life. Diseases such as cancer may occur if the network regulations go wrong. In cancer research, network mining has been utilized to identify biomarkers, predict therapeutic targets, and discover new mecha... | Distinct types of human cancer share similar traits, including rapid cell proliferation, loss of cell identity, and the ability to migrate and seed malignant tumors in distal locations. Understanding these common traits and identifying the underlying genes/networks are key to gaining insight into cancer physiology, and... |
10.1371/journal.pntd.0002011 | Implementation of a National Reference Laboratory for Buruli Ulcer Disease in Togo | In a previous study PCR analysis of clinical samples from suspected cases of Buruli ulcer disease (BUD) from Togo and external quality assurance (EQA) for local microscopy were conducted at an external reference laboratory in Germany. The relatively poor performance of local microscopy as well as effort and time associ... | Buruli ulcer disease (BUD), the third most common mycobacterial disease worldwide, is treated with standardized antimycobacterial therapy. According to WHO recommendations at least 50% of cases should be laboratory confirmed by polymerase chain reaction (PCR). In a previous study PCR analysis of clinical samples from s... | Buruli ulcer disease (BUD), caused by Mycobacterium ulcerans, is an infectious disease affecting skin, soft tissue and bones. If left untreated, extensive destruction of tissue followed by fibrous scarring and contractures may lead to severe functional limitations [1]–[6]. BUD is treated with rifampicin and streptomyci... |
10.1371/journal.pntd.0006587 | Mapping dengue risk in Singapore using Random Forest | Singapore experiences endemic dengue, with 2013 being the largest outbreak year known to date, culminating in 22,170 cases. Given the limited resources available, and that vector control is the key approach for prevention in Singapore, it is important that public health professionals know where resources should be inve... | Dengue fever, the most prevalent mosquito-borne viral disease today, is caused by Dengue virus (DENV) and transmitted to human by Aedes mosquitoes, primarily the Ae. aegypti and Ae. albopictus. The key approach to mitigating dengue transmission is to control the Aedes population, and this often involve vector control s... | Dengue is a viral infection caused by one of the four closely related yet antigenically distinct virus serotypes (DENV-1, DENV-2, DENV-3 and DENV-4), and transmitted by Aedes mosquitoes, primarily the Ae. aegypti and Ae. albopictus [1,2]. Infection confers lifelong immunity to the infecting serotype [3]. However, it in... |
10.1371/journal.pntd.0004434 | Population Genetics of Plasmodium vivax in Four Rural Communities in Central Vietnam | The burden of malaria in Vietnam has drastically reduced, prompting the National Malaria Control Program to officially engage in elimination efforts. Plasmodium vivax is becoming increasingly prevalent, remaining a major problem in the country's central and southern provinces. A better understanding of P. vivax genetic... | In Vietnam, Plasmodium vivax (P. vivax) is the second most frequent human malaria parasite and a major obstacle to countrywide malaria elimination. Knowing the local parasite structure is useful for elimination efforts. Therefore, we analyzed, with a panel of 14 microsatellite markers, 234 P. vivax mono infections in b... | Vietnam has been extremely successful in decreasing the country’s malaria burden, thanks to the large scale implementation of control interventions such as insecticide-treated bed nets, indoor residual spraying, and prompt, free-of-charge diagnosis and treatment; the number of cases fell from 130,000 in 2004 to 27,868 ... |
10.1371/journal.pntd.0006647 | Sphingosine-1-phosphate signaling in Leishmania donovani infection in macrophages | Sphingosine-1-phosphate (S1P) is a crucial regulator of a wide array of cellular processes, such as apoptosis, cell proliferation, migration, and differentiation, but its role in Leishmania donovani infection is unknown.
In the present study, we observed that L. donovani infection in THP-1 derived macrophages (TDM) lea... | Leishmania donovani is an intracellular parasite which is internalized by host macrophages by subverting several intracellular signaling events. During infection suppression of p38 MAPK and activation of ERK1/2 MAPK have been acclaimed for survival and proliferation of these protozoan parasites. In this study, we show ... | Leishmaniasis is a neglected tropical disease that affects about 12 million people worldwide [1] It is caused by intracellular protozoa parasite Leishmania that invades macrophages and selectively impairs host’s critical signaling pathways for its successful intracellular growth and proliferation [2]. In particular, al... |
10.1371/journal.pcbi.1005651 | Possible roles of mechanical cell elimination intrinsic to growing tissues from the perspective of tissue growth efficiency and homeostasis | Cell competition is a phenomenon originally described as the competition between cell populations with different genetic backgrounds; losing cells with lower fitness are eliminated. With the progress in identification of related molecules, some reports described the relevance of cell mechanics during elimination. Furth... | When genetically different cell populations are mixed, there is competition between cells such that losing cells are eliminated from a tissue. Such cell elimination is also observed during normal development in genetically-homogeneous tissues. In addition to the identification of key genes and molecular mechanisms rela... | In 1975, Morata and Ripoll analyzed the mosaic system of the Drosophila imaginal disc composed of wild type cells and mutant cells of ribosomal protein, and found that mutant cells underwent apoptosis and were eliminated from the tissue [1]. This was the first report of cell competition resulting from local cell-cell i... |
10.1371/journal.ppat.1005605 | The SH3BGR/STAT3 Pathway Regulates Cell Migration and Angiogenesis Induced by a Gammaherpesvirus MicroRNA | Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV) is a gammaherpesvirus etiologically associated with KS, a highly disseminated angiogenic tumor of hyperproliferative spindle endothelial cells. KSHV encodes 25 mature microRNAs but their roles in KSHV-induced tumor dissemination and angiogenesis remain unknown. Here, ... | Kaposi’s Sarcoma (KS), caused by infection of Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV), is a tumor of endothelial cells characterized by angiogenesis and invasiveness. In vitro, KSHV-infected endothelial cells display an increased invasiveness and angiogenicity. KSHV encodes twelve precursor miRNAs (pre-miRN... | Kaposi’s sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus associated with AIDS-associated Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman’s disease (MCD) [1]. KS is an angiogenic vascular tumor of endothelial spindle cells [2]. KS is characterized by vast aberrant prolifera... |
10.1371/journal.pcbi.1002473 | Ligand-Dependent Conformations and Dynamics of the Serotonin 5-HT2A Receptor Determine Its Activation and Membrane-Driven Oligomerization Properties | From computational simulations of a serotonin 2A receptor (5-HT2AR) model complexed with pharmacologically and structurally diverse ligands we identify different conformational states and dynamics adopted by the receptor bound to the full agonist 5-HT, the partial agonist LSD, and the inverse agonist Ketanserin. The re... | The 5-HT2A receptor for the neurotransmitter serotonin (5-HT) belongs to family A (rhodopsin-like) G-protein coupled receptors (GPCRs), one of the most important classes of membrane proteins that are targeted by an extensive and diverse collection of external stimuli. Recently we learned that different ligands targetin... | Serotonin 2A receptors (5-HT2AR) are a very well characterized family of G-protein coupled receptors (GPCRs) in the amine sub-class of rhodopsin-like class A GPCRs [1], [2]. The 5-HT2ARs are targeted by chemically and pharmacologically distinct classes of ligands which include antidepressants, anxiolytics, antiemetics,... |
10.1371/journal.ppat.1004031 | First Experimental In Vivo Model of Enhanced Dengue Disease Severity through Maternally Acquired Heterotypic Dengue Antibodies | Dengue (DEN) represents the most serious arthropod-borne viral disease. DEN clinical manifestations range from mild febrile illness to life-threatening hemorrhage and vascular leakage. Early epidemiological observations reported that infants born to DEN-immune mothers were at greater risk to develop the severe forms of... | Dengue (DEN) is an arthropod-transmitted viral disease which affects approximately 390 million individuals in the tropical and subtropical world annually. DEN clinical manifestations range from mild febrile illness (dengue fever) to life-threatening dengue hemorrhagic/dengue shock syndrome (DHF/DSS). Epidemiological ob... | Dengue (DEN) is the most prevalent arthropod-borne viral infection in the world [1]. Approximately 3 billion people who are living in the tropical and subtropical regions from Southeast Asia, the Pacific and the Americas are at risk of infection [1]–[3]. A recent meta-analysis using cartographic approaches estimates 39... |
10.1371/journal.pgen.1005450 | Regulation of Gene Expression Patterns in Mosquito Reproduction | In multicellular organisms, development, growth and reproduction require coordinated expression of numerous functional and regulatory genes. Insects, in addition to being the most speciose animal group with enormous biological and economical significance, represent outstanding model organisms for studying regulation of... | In addition to being vectors of devastating human diseases, mosquitoes represent outstanding model organisms for studying regulatory mechanisms of differential gene expression due to their rapid reproductive cycles. About 7500 transcripts are differentially expressed in four sequential waves during the 72-h reproductiv... | Numerous studies in model organisms have identified patterns of gene expression correlated with embryogenesis and development [1–9]. These studies have eloquently demonstrated the existence of a tight coordination between large gene cohorts and various stages of a developing organism on a spatiotemporal scale. In contr... |
10.1371/journal.pgen.0030226 | Chromosome Structuring Limits Genome Plasticity in Escherichia coli | Chromosome organizations of related bacterial genera are well conserved despite a very long divergence period. We have assessed the forces limiting bacterial genome plasticity in Escherichia coli by measuring the respective effect of altering different parameters, including DNA replication, compositional skew of replic... | Genomic analyses have revealed that bacterial genomes are dynamic entities that evolve through various processes including intrachromosome genetic rearrangements, gene duplication, and gene loss or acquisition by gene transfer. Nevertheless, comparison of bacterial chromosomes from related genera revealed a conservatio... | Genomic analyses have revealed that bacterial genomes are dynamic entities that evolve through various processes, including intrachromosome genetic rearrangements, gene duplication, and gene loss or acquisition by lateral gene transfer [1]. Nevertheless, comparison of bacterial chromosomes from related genera revealed ... |
10.1371/journal.pcbi.1004824 | Inferring Strain Mixture within Clinical Plasmodium falciparum Isolates from Genomic Sequence Data | We present a rigorous statistical model that infers the structure of P. falciparum mixtures—including the number of strains present, their proportion within the samples, and the amount of unexplained mixture—using whole genome sequence (WGS) data. Applied to simulation data, artificial laboratory mixtures, and field sa... | Since the 1960’s researchers have observed that Plasmodium falciparum infections, the cause of most severe malaria, are frequently composed of several different strains of the parasite. In this work, the authors use Bayesian methods on whole genome sequence data to model the structure of these mixtures. Results from th... | The protozoan parasite Plasmodium falciparum (Pf) is the cause of the vast majority of fatal malaria cases, killing at least half a million people a year [1–3]. The parasite’s ability to develop resistance to drugs and the rapid spread of that resistance across geographically-separated populations presents a constant t... |
10.1371/journal.pntd.0007536 | Elucidating diversity in the class composition of the minicircle hypervariable region of Trypanosoma cruzi: New perspectives on typing and kDNA inheritance | Trypanosoma cruzi, the protozoan causative of Chagas disease, is classified into six main Discrete Typing Units (DTUs): TcI-TcVI. This parasite has around 105 copies of the minicircle hypervariable region (mHVR) in their kinetoplastic DNA (kDNA). The genetic diversity of the mHVR is virtually unknown. However, cross-hy... | Chagas disease is an important public health problem in Latin America showing a wide diversity of clinical manifestations and epidemiological patterns. It is caused by the parasite Trypanosoma cruzi. This parasite is genetically diverse and classified into six main lineages. However, the relationship between intra-spec... | The protozoan parasite Trypanosoma cruzi (Kinetoplastea: Trypanosomatidae) is the causative agent of Chagas disease. This parasite infects millions of people throughout its distribution in Latin America. Chagas disease can display a broad pathological spectrum, including potentially fatal cardiological and gastrointest... |
10.1371/journal.ppat.1005141 | Serine Phosphorylation of HIV-1 Vpu and Its Binding to Tetherin Regulates Interaction with Clathrin Adaptors | HIV-1 Vpu prevents incorporation of tetherin (BST2/ CD317) into budding virions and targets it for ESCRT-dependent endosomal degradation via a clathrin-dependent process. This requires a variant acidic dileucine-sorting motif (ExxxLV) in Vpu. Structural studies demonstrate that recombinant Vpu/tetherin fusions can form... | Counteraction of tetherin, a host antiviral protein that blocks viral release from infected cells, is an essential attribute of HIV-1 and its related viruses. The HIV-1 accessory protein Vpu binds to tetherin, preventing its incorporation into viral particles, and targets it for ubiquitin-dependent degradation. This in... | Counteraction of the antiviral membrane protein tetherin (BST2/ CD317) is an essential attribute of primate lentiviruses, and is mediated by either the Vpu or Nef accessory proteins, or occasionally the viral envelope glycoprotein (reviewed in [1]). In their absence, tetherin restricts the release of virions assembling... |
10.1371/journal.pbio.2006128 | Highly diverged novel subunit composition of apicomplexan F-type ATP synthase identified from Toxoplasma gondii | The mitochondrial F-type ATP synthase, a multisubunit nanomotor, is critical for maintaining cellular ATP levels. In T. gondii and other apicomplexan parasites, many subunit components necessary for proper assembly and functioning of this enzyme appear to be missing. Here, we report the identification of 20 novel subun... | The mitochondrial F-type ATP synthase, which is a major source of ATP in eukaryotic cells, is a unique nanomotor. The enzyme consists of two subcomplexes called the F1 and FO sectors. The F1 sector is the site of ATP synthesis, while the FO sector couples proton translocation to the rotary motion of the enzyme. FO sect... | The F-type ATP synthase is a ubiquitous nanomotor present on the inner membrane of mitochondria, chloroplast, and bacterial plasma membrane that catalyzes ATP formation from ADP and Pi [1,2]. In mitochondria, the energy required to drive the nanomotor is harnessed from the proton motive force and associated membrane po... |
10.1371/journal.pbio.2006613 | MEKK3 coordinates with FBW7 to regulate WDR62 stability and neurogenesis | Mutations of WD repeat domain 62 (WDR62) lead to autosomal recessive primary microcephaly (MCPH), and down-regulation of WDR62 expression causes the loss of neural progenitor cells (NPCs). However, how WDR62 is regulated and hence controls neurogenesis and brain size remains elusive. Here, we demonstrate that mitogen-a... | Microcephaly is a neural developmental disorder characterized by significantly reduced brain size and variable intellectual disability. WD repeat domain 62 (WDR62) was identified as the second most common gene for autosomal recessive primary microcephaly (MCPH) in human. Here, we studied the underlying regulatory mecha... | Establishment of the mammalian neocortex requires precise control of proliferation and self-renewal of neural progenitor cells (NPCs), as well as the differentiation of NPCs and neuronal migration [1–4]. Defects in these processes lead to brain disorders, including autosomal recessive primary microcephaly (MCPH) [5–8].... |
10.1371/journal.pcbi.1003592 | Determining Effects of Non-synonymous SNPs on Protein-Protein Interactions using Supervised and Semi-supervised Learning | Single nucleotide polymorphisms (SNPs) are among the most common types of genetic variation in complex genetic disorders. A growing number of studies link the functional role of SNPs with the networks and pathways mediated by the disease-associated genes. For example, many non-synonymous missense SNPs (nsSNPs) have bee... | Many genetic diseases in humans and animals are caused by combinations of single-letter mutations, or SNPs. When these mutations occur in a protein-coding region of a genome, they can have a profound effect on the protein's function and ultimately on a health-related phenotype. Recently, a growing number of evidence su... | Being one of the most prevalent types of genetic variation in humans, single nucleotide polymorphisms (SNPs) occur in both coding and non-coding regions of the genome and have been associated with a number of Mendelian diseases and complex genetic disorders [1], [2]. With the rapid advancement of DNA sequencing and gen... |
10.1371/journal.pntd.0004364 | A Rapid Screening Assay Identifies Monotherapy with Interferon-ß and Combination Therapies with Nucleoside Analogs as Effective Inhibitors of Ebola Virus | To date there are no approved antiviral drugs for the treatment of Ebola virus disease (EVD). While a number of candidate drugs have shown limited efficacy in vitro and/or in non-human primate studies, differences in experimental methodologies make it difficult to compare their therapeutic effectiveness. Using an in vi... | Studies to evaluate the effectiveness of candidate antiviral drugs to inhibit Ebola virus infection have been hampered by the availability and access to level 4 containment facilities. Using a mini-genome model system that generates Ebola virus-like particles that infect cells, we have been able to screen a panel of ca... | As of December 13, 2015, the current outbreak of Ebola virus disease (EVD) in West Africa has resulted in 28,633 cumulative cases and 11,314 deaths [1]. Two potential vaccine candidates, rVSVΔG-ZEBOV and ChAd3-EBO Z, have shown durable protection from lethal Ebola challenge in mice [2] and macaques [3] respectively, an... |
10.1371/journal.pntd.0000854 | Viral Etiology of Encephalitis in Children in Southern Vietnam: Results of a One-Year Prospective Descriptive Study | Acute encephalitis is an important and severe disease in children in Vietnam. However, little is known about the etiology while such knowledge is essential for optimal prevention and treatment. To identify viral causes of encephalitis, in 2004 we conducted a one-year descriptive study at Children's Hospital Number One,... | Viral encephalitis is associated with high morbidity and mortality in Vietnam. However little is known about the causes of the disease due to a lack of diagnostic facilities in this relatively resource-poor setting. Knowledge about the etiologies and clinical outcome of viral encephalitis is necessary for future design... | Acute encephalitis is associated with high morbidity and mortality and affects both children and adults. There have been few population-based studies, reporting incidences ranging between 3.5 and 7.4 cases per 100.000 patient-years [1]. Viruses are regarded as the most important etiological agents of encephalitis world... |
10.1371/journal.pntd.0004213 | siRNA-Mediated Silencing of doublesex during Female Development of the Dengue Vector Mosquito Aedes aegypti | The development of sex-specific traits, including the female-specific ability to bite humans and vector disease, is critical for vector mosquito reproduction and pathogen transmission. Doublesex (Dsx), a terminal transcription factor in the sex determination pathway, is known to regulate sex-specific gene expression du... | Only adult female mosquitoes, which require blood meals for reproduction, bite humans and spread diseases. The genes that regulate development of sex-specific traits may therefore represent novel targets for mosquito control. Here, we examine the effects of silencing the sex-determination gene doublesex (dsx) during de... | Most animal species display sexually dimorphic behaviors, the majority of which are linked to sexual reproduction [1]. Disease vector mosquitoes are excellent subjects for studies that explore the biological basis of sexual dimorphism. Only adult female mosquitoes, which require blood meals for reproduction, bite human... |
10.1371/journal.pcbi.1002948 | Localized Lipid Packing of Transmembrane Domains Impedes Integrin Clustering | Integrin clustering plays a pivotal role in a host of cell functions. Hetero-dimeric integrin adhesion receptors regulate cell migration, survival, and differentiation by communicating signals bidirectionally across the plasma membrane. Thus far, crystallographic structures of integrin components are solved only separa... | Focal adhesions are complex, dynamic structures of multiple proteins that act as the cell's mechanical anchorage to its surrounding. Integrins are proteins linking the cell inner and outer environments, which act as a bridge that crosses the cell membrane. Integrins respond to mechanical loads exerted to them by changi... | Focal adhesions are complex, dynamic structures composed of several proteins that act as the cell mechanical anchorage to the extracellular matrix (ECM). Integrins are the first signal receptors encountered in the cell mechanical micro-environment [1], [2], [3]. Integrin-mediated adhesion often occurs under forces such... |
10.1371/journal.pntd.0005980 | Reappraisal of Leishmanin Skin Test (LST) in the management of American Cutaneous Leishmaniasis: A retrospective analysis from a reference center in Argentina | Leishmania (Viannia) braziliensis is the species most frequently implicated with cutaneous and mucosal leishmaniasis in the Americas; its diagnosis is based on the identification of amastigotes in lesions, which is limited by low parasite burden. Leishmanin Skin Test (LST) is a support tool for diagnosis, based on dela... | American Cutaneous Leishmaniasis (ACL) is a vector borne Neglected Tropical Disease with skin ulcers as the main clinical manifestation. Diagnosis is suspected when characteristic lesions occur in patients in areas known to be endemic and confirmed with microscopic identification of amastigotes in samples obtained from... | The leishmaniases are a group of vector borne neglected tropical diseases affecting a significant number of people in the tropical and subtropical regions of the world; this population is estimated in over 398 and 556 million people at risk of cutaneous leishmaniasis and visceral leishmaniasis respectively, in high bur... |
10.1371/journal.ppat.1005808 | Jagged1 Instructs Macrophage Differentiation in Leprosy | As circulating monocytes enter the site of disease, the local microenvironment instructs their differentiation into tissue macrophages (MΦ). To identify mechanisms that regulate MΦ differentiation, we studied human leprosy as a model, since M1-type antimicrobial MΦ predominate in lesions in the self-limited form, where... | Mycobacterial diseases, such as leprosy, continue to be serious causes of mortality and morbidity worldwide. They pose a unique treatment challenge due to their ability to modify the immune response in infected individuals. For example, in leprosy there are two distinct manifestations of the disease, each characterized... | When circulating monocytes enter the site of disease, local cues from the tissue microenvironment direct their differentiation into specialized MΦ equipped for diverse tasks [1–3]. While classically activated M1 MΦ with antimicrobial activity promote host defense against intracellular pathogens, alternatively activated... |
10.1371/journal.pcbi.1003578 | Finding Novel Molecular Connections between Developmental Processes and Disease | Identifying molecular connections between developmental processes and disease can lead to new hypotheses about health risks at all stages of life. Here we introduce a new approach to identifying significant connections between gene sets and disease genes, and apply it to several gene sets related to human development. ... | Understanding the roles that genes involved in normal human development can play in disease processes is an important part of predicting disease risk and designing novel treatment approaches. In this study, we have identified classes of disease that are associated with a surprisingly large number of genes involved in a... | The study of the health implications of developmental processes has now entered the genomic era. The recent sequencing of an entire fetal genome [1] has demonstrated the possibility of applying molecular methods to design novel prenatal diagnostics. The development of therapeutic approaches for personalized fetal treat... |
10.1371/journal.pcbi.0030063 | Integration of Genome and Chromatin Structure with Gene Expression Profiles To Predict c-MYC Recognition Site Binding and Function | The MYC genes encode nuclear sequence specific–binding DNA-binding proteins that are pleiotropic regulators of cellular function, and the c-MYC proto-oncogene is deregulated and/or mutated in most human cancers. Experimental studies of MYC binding to the genome are not fully consistent. While many c-MYC recognition sit... | c-MYC is an important proto-oncogene that controls the expression of many other genes, and MYC regulation is deranged in many cancers. Identifying c-MYC target genes is one of the key steps to understand both the biological role and molecular mechanism of c-MYC action. Defining the complete list of c-MYC target genes a... | MYC plays a critical role in regulating cell proliferation, growth, apoptosis, and differentiation. Human malignancies are often associated with aberration of the c-MYC gene [1–3]. The diversity of its functions has been attributed to c-MYC's ability to activate or repress the transcription of an extensive array of tar... |
10.1371/journal.pcbi.1006434 | A k-mer-based method for the identification of phenotype-associated genomic biomarkers and predicting phenotypes of sequenced bacteria | We have developed an easy-to-use and memory-efficient method called PhenotypeSeeker that (a) identifies phenotype-specific k-mers, (b) generates a k-mer-based statistical model for predicting a given phenotype and (c) predicts the phenotype from the sequencing data of a given bacterial isolate. The method was validated... | Predicting phenotypic properties of bacterial isolates from their genomic sequences has numerous potential applications. A good example would be prediction of antimicrobial resistance and virulence phenotypes for use in medical diagnostics. We have developed a method that is able to predict phenotypes of interest from ... | The falling cost of sequencing has made genome sequencing affordable to a large number of labs, and therefore, there has been a dramatic increase in the number of genome sequences available for comparison in the public domain [1]. These developments have facilitated the genomic analysis of bacterial isolates. An increa... |
10.1371/journal.pntd.0001280 | Necator americanus and Helminth Co-Infections: Further Down-Modulation of Hookworm-Specific Type 1 Immune Responses | Helminth co-infection in humans is common in tropical regions of the world where transmission of soil-transmitted helminths such as Ascaris lumbricoides, Trichuris trichiura, and the hookworms Necator americanus and Ancylostoma duodenale as well as other helminths such as Schistosoma mansoni often occur simultaneously.... | Parasitic infections in humans are common in tropical regions and under bad housing and sanitation conditions multiple parasitic infections are the rule rather than the exception. For helminth infections, which are thought to affect almost a quarter of the world's population, most common combinations include soil-trans... | Helminth co-infection in humans is common in tropical regions [1], [2], where transmission of Ascaris lumbricoides, Trichuris trichiura, the hookworms (N. americanus or A. duodenale), and schistosomes often occur concurrently [3], [4]. Although co-infection is often the rule rather than the exception in endemic areas, ... |
10.1371/journal.pgen.1005975 | Gifsy-1 Prophage IsrK with Dual Function as Small and Messenger RNA Modulates Vital Bacterial Machineries | While an increasing number of conserved small regulatory RNAs (sRNAs) are known to function in general bacterial physiology, the roles and modes of action of sRNAs from horizontally acquired genomic regions remain little understood. The IsrK sRNA of Gifsy-1 prophage of Salmonella belongs to the latter class. This regul... | As the function of conserved core-genome-encoded small RNAs (sRNA) reflects the basic lifestyle of bacteria, the function of non-conserved island-encoded sRNAs remains enigmatic. The island-encoded sRNA IsrK belongs to Gifsy-1 prophage of Salmonella. Here, we report a complex mechanism in which the IsrK RNA functions a... | The first systematic searches for bacterial sRNA were based on bio-computational identification of conserved genes in intergenic regions [1]. The subsequent characterization of these conserved sRNAs identified them as important players in many adaptive and physiological responses. These conserved core-genome encoded re... |
10.1371/journal.ppat.1006337 | Mapping of the Lassa virus LAMP1 binding site reveals unique determinants not shared by other old world arenaviruses | Cell entry of many enveloped viruses occurs by engagement with cellular receptors, followed by internalization into endocytic compartments and pH-induced membrane fusion. A previously unnoticed step of receptor switching was found to be critical during cell entry of two devastating human pathogens: Ebola and Lassa viru... | To infect, enveloped viruses need to fuse their membrane with the host membrane. Fusion is mediated by special glycoprotein machineries that must be triggered only at the right time and at the right place. A major cue that viruses utilize for triggering is acidic pH. Until recently, such pH-induced triggering was assum... | Receptor switching is a newly discovered event in the cell entry process of Lassa virus (LASV) [1], a zoonotic, enveloped, negative-strand RNA virus that belongs to the Arenaviridae family [2]. LASV is a devastating pathogen that causes severe hemorrhagic fevers with significant mortality in West Africa [3]. LASV locat... |
10.1371/journal.pcbi.1000038 | A Coarse-Grained Biophysical Model of E. coli and Its Application to Perturbation of the rRNA Operon Copy Number | We propose a biophysical model of Escherichia coli that predicts growth rate and an effective cellular composition from an effective, coarse-grained representation of its genome. We assume that E. coli is in a state of balanced exponential steady-state growth, growing in a temporally and spatially constant environment,... | A bacterium like E. coli can be thought of as a self-replicating factory, where inventory synthesis, degradation, and management is concerted according to a well-defined set of rules encoded in the organism's genome. Since the organism's survival depends on this set of rules, these rules were most likely optimized by e... | The rRNA (rrn) operons of E. coli have the important role of determining ribosome synthesis in the cell (c.f. [1]–[6] for reviews). These operons are unique in the sense that a wild-type (WT) E. coli cell carries seven copies of this operon per chromosome [7] (other bacteria have copy numbers ranging between 1 and 15 [... |
10.1371/journal.pntd.0000861 | Trachoma Prevalence and Associated Risk Factors in The Gambia and Tanzania: Baseline Results of a Cluster Randomised Controlled Trial | Blinding trachoma, caused by ocular infection with Chlamydia trachomatis, is targeted for global elimination by 2020. Knowledge of risk factors can help target control interventions.
As part of a cluster randomised controlled trial, we assessed the baseline prevalence of, and risk factors for, active trachoma and ocula... | Trachoma is caused by Chlamydia trachomatis and is the leading infectious cause of blindness. The World Health Organization's (WHO) control strategy includes antibiotic treatment of all community members, facial cleanliness, and environmental improvements. By determining how prevalent trachoma is, decisions can be made... | Trachoma is caused by ocular infection with serovars A, B, Ba or C of the bacterium Chlamydia trachomatis. It is the leading infectious cause of blindness worldwide [1] with an estimated 40.6 million people suffering from active trachoma (trachomatous inflammation, follicular (TF) and/or intense (TI)) and 8.2 million h... |
10.1371/journal.ppat.1003282 | Mycobacterium tuberculosis Responds to Chloride and pH as Synergistic Cues to the Immune Status of its Host Cell | The ability of Mycobacterium tuberculosis (Mtb) to thrive in its phagosomal niche is critical for its establishment of a chronic infection. This requires that Mtb senses and responds to intraphagosomal signals such as pH. We hypothesized that Mtb would respond to additional intraphagosomal factors that correlate with m... | Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis, a disease that remains a major global health problem. To ensure its long-term survival in the host, Mtb must be able to sense and respond to changes in its immediate environment, such as the pH differences that occur in the phagosome in which it l... | Mycobacterium tuberculosis (Mtb) causes a chronic infection in approximately one third of the human population and remains an important public health problem [1]. The macrophage (MØ) is the major host cell for much of Mtb's life cycle, and a defining feature of Mtb's pathogenesis is its ability to arrest full maturatio... |
10.1371/journal.pgen.1005817 | The Zinc-Finger Protein SOP1 Is Required for a Subset of the Nuclear Exosome Functions in Arabidopsis | Correct gene expression requires tight RNA quality control both at transcriptional and post-transcriptional levels. Using a splicing-defective allele of PASTICCINO2 (PAS2), a gene essential for plant development, we isolated suppressor mutations modifying pas2-1 mRNA profiles and restoring wild-type growth. Three suppr... | Cells use various RNA quality control mechanisms to monitore the correct expression of their genome. Indeed, gene transcription can often generate faulty transcripts that are rapidly degraded to avoid possible deleterious effects to the cell. RNA degradation by the exosome is the main pathway for the removal of unwante... | The synthesis of mRNA in eukaryotes is a complex multistep process, involving the transcription of DNA into RNA, capping, splicing of intronic sequences and maturation of the 3’ end of the messenger prior to export to the cytoplasm for translation into protein. Production of functional RNA can be impaired by either gen... |
10.1371/journal.pcbi.1005270 | Novel non-invasive algorithm to identify the origins of re-entry and ectopic foci in the atria from 64-lead ECGs: A computational study | Atrial tachy-arrhytmias, such as atrial fibrillation (AF), are characterised by irregular electrical activity in the atria, generally associated with erratic excitation underlain by re-entrant scroll waves, fibrillatory conduction of multiple wavelets or rapid focal activity. Epidemiological studies have shown an incre... | Atrial tachy-arrhythmias are associated with irregular excitation waves arising from re-entrant excitation, multiple wavelets or rapid focal activity. Identifying the origin of the irregular activity may be vital for diagnosis and treatment of the disorder. Where invasive and non-invasive methods provide approaches for... | Atrial tachy-arrhythmias, including atrial fibrillation (AF), atrial tachycardia (AT) and flutter (AFL), are the most common cardiac arrhythmias, predisposing to heart attack, stroke and even possible cardiac death [1,2]. All three are characterised by rapid and irregular electrical activation of the atria, with AF pre... |
10.1371/journal.pmed.1002038 | Geographical Inequalities and Social and Environmental Risk Factors for Under-Five Mortality in Ghana in 2000 and 2010: Bayesian Spatial Analysis of Census Data | Under-five mortality is declining in Ghana and many other countries. Very few studies have measured under-five mortality—and its social and environmental risk factors—at fine spatial resolutions, which is relevant for policy purposes. Our aim was to estimate under-five mortality and its social and environmental risk fa... | Deaths among children younger than five years old have been declining worldwide for the past few decades. Children’s death rates in sub-Saharan Africa, although also declining, remain higher than in other regions.
Ghana has performed better than most other sub-Saharan African countries in terms of reducing child deaths... | Mortality in children under 5 y of age has declined in most countries, with the decline accelerating since 2000 [1,2]. The pace of under-five mortality decline has been slower in sub-Saharan Africa (SSA) than in other regions, and SSA accounts for nearly one-half of global under-five deaths [1,3]. Poverty-related risk ... |
10.1371/journal.pntd.0007011 | A high throughput neutralization test based on GFP expression by recombinant rabies virus | The effectiveness of rabies vaccination in both humans and animals is determined by the presence of virus neutralizing antibodies (VNAs). The Rapid Fluorescent Focus Inhibition Test (RFFIT) is the method traditionally used for detection and quantification of VNAs. It is a functional in vitro test for assessing the abil... | The potency of rabies vaccine is demonstrated by the presence of virus neutralizing antibodies (VNAs) in serum. It is critical to evaluate immunologic status of individuals who work directly with rabies virus (RABV) (laboratorians) or at high risk of infection due to interaction with animals (veterinarians and animal c... | Human rabies is a zoonotic disease transmitted predominantly through bites from infected animals [1]. Although, rabies is nearly 100% fatal after onset of symptoms, it is preventable by post exposure prophylaxis (PEP) when administered immediately and appropriately after a suspect exposure. The surrogate for protection... |
10.1371/journal.pgen.1000561 | Defects in tRNA Modification Associated with Neurological and Developmental Dysfunctions in Caenorhabditis elegans Elongator Mutants | Elongator is a six subunit protein complex, conserved from yeast to humans. Mutations in the human Elongator homologue, hELP1, are associated with the neurological disease familial dysautonomia. However, how Elongator functions in metazoans, and how the human mutations affect neural functions is incompletely understood... | The efficiency of protein synthesis can be modulated by alterations of various components of the translation machinery. In translation, transfer RNAs act as adapter molecules that decode mRNA into protein and thereby play a central role in gene expression. In the tRNA maturation process, a subset of the normal nucleosi... | Regulation at the level of translation is one important way in which gene activity is controlled in metazoans. Several different mechanisms have previously been identified by which translation can be regulated during development or memory formation [reviewed in 1]. During anterior-posterior patterning of the Drosophila... |
10.1371/journal.pcbi.1004466 | Structural Bridges through Fold Space | Several protein structure classification schemes exist that partition the protein universe into structural units called folds. Yet these schemes do not discuss how these units sit relative to each other in a global structure space. In this paper we construct networks that describe such global relationships between fold... | Folds are considered to be the structural units which make up the protein universe. Structural classification schemes focus on the assignment and organisation of protein domains into folds. However, they do not suggest how different folds might relate to one another in a global way. We introduce the concept of bridges ... | The vast repertoire of proteins which exist in nature are testament to billions of years of evolutionary change. The nature of their relationships and how these have evolved are questions which continue to fascinate the scientific community [1–4]. Protein structure classification schemes such as SCOP [5] and CATH [6] p... |
10.1371/journal.ppat.1006347 | ERRα negatively regulates type I interferon induction by inhibiting TBK1-IRF3 interaction | Estrogen-related receptor α (ERRα) is a member of the nuclear receptor superfamily controlling energy homeostasis; however, its precise role in regulating antiviral innate immunity remains to be clarified. Here, we showed that ERRα deficiency conferred resistance to viral infection both in vivo and in vitro. Mechanisti... | As a member of the nuclear receptor superfamily involved in metabolism signaling, the precise role of ERRα in antiviral innate immunity remains to be clarified. Here, we showed that ERRα deficiency led to increased interferon production, resulting in enhanced resistance to viral infection both in vivo and in vitro. Mec... | The innate immune system plays important roles in the detection and elimination of invading pathogens. The host senses viral and bacterial pathogen invasion via the recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs), including membrane-bound Toll-like receptors (TLRs) ... |
10.1371/journal.ppat.1004605 | The Molecular Basis for Control of ETEC Enterotoxin Expression in Response to Environment and Host | Enterotoxigenic Escherichia coli (ETEC) cause severe diarrhoea in humans and neonatal farm animals. Annually, 380,000 human deaths, and multi-million dollar losses in the farming industry, can be attributed to ETEC infections. Illness results from the action of enterotoxins, which disrupt signalling pathways that manag... | Diarrheagenic illness remains a major disease burden in the developing world. Enterotoxigenic Escherichia coli (ETEC) are the leading bacterial cause of such disease; hundreds of millions of cases occur every year. The severe watery diarrhoea associated with ETEC infections results from the action of enterotoxins. The ... | ETEC are Gram negative bacteria that cause severe diarrhoea, known as non-vibrio cholera, in humans [1], [2]. First isolated in 1971, ETEC are responsible for 210 million infections annually, mostly in developing countries, leading to 380,000 deaths [3]. Disease results primarily from the action of two enterotoxins. Th... |
10.1371/journal.pgen.1002174 | Caenorhabditis briggsae Recombinant Inbred Line Genotypes Reveal Inter-Strain Incompatibility and the Evolution of Recombination | The nematode Caenorhabditis briggsae is an emerging model organism that allows evolutionary comparisons with C. elegans and exploration of its own unique biological attributes. To produce a high-resolution C. briggsae recombination map, recombinant inbred lines were generated from reciprocal crosses between two strains... | The nematode Caenorhabditis briggsae is increasingly used for comparisons with its more famous relative, C. elegans. To improve genomic resources for C. briggsae, we created two sets of inbred lines derived from crosses between diverged C. briggsae strains. High-throughput genotyping of these has improved the resolutio... | Caenorhabditis nematodes, first described over one hundred years ago [1], are easily cultured and have been employed since the 1960s as model organisms in a number of fields. C. briggsae exhibits many features desirable of a genetic model organism: a self-fertilizing hermaphrodite, presence of rare males for genetic cr... |
10.1371/journal.ppat.1005237 | Modeling the Effects of Vorinostat In Vivo Reveals both Transient and Delayed HIV Transcriptional Activation and Minimal Killing of Latently Infected Cells | Recent efforts to cure human immunodeficiency virus type-1 (HIV-1) infection have focused on developing latency reversing agents as a first step to eradicate the latent reservoir. The histone deacetylase inhibitor, vorinostat, has been shown to activate HIV RNA transcription in CD4+ T-cells and alter host cell gene tra... | Combination antiretroviral therapy (cART) for HIV infection must be taken for life due to the existence of long lived latently infected cells. Recent efforts have focused on developing latency reversing agents to eliminate latently infected cells by activating HIV production. In this work, we assess the impact of a lat... | Treatment of HIV-infected individuals with combination antiretroviral therapy (cART) effectively suppresses HIV to levels below the limit of detection of conventional assays and substantially reduces morbidity and mortality of HIV infected patients [1]. However, it does not eradicate the virus and treatment is lifelong... |
10.1371/journal.pcbi.1000564 | Identifying Changes in Selective Constraints: Host Shifts in Influenza | The natural reservoir of Influenza A is waterfowl. Normally, waterfowl viruses are not adapted to infect and spread in the human population. Sometimes, through reassortment or through whole host shift events, genetic material from waterfowl viruses is introduced into the human population causing worldwide pandemics. Id... | Influenza A's natural reservoir is waterfowl. Sometimes avian virus genomic segments are able to shift to a human host, either in toto or by combining with those that underwent a previous host shift event. Such host shift events can cause worldwide pandemics in their immunologically naive hosts. In order for these host... | Influenza A has the distinction of being an old disease, a recurring disease, and an ‘emerging’ disease. Influenza A viruses are found in humans as well as in other animals including swine, horses, sea mammals, and birds, of which waterfowl are considered the natural reservoir [1]. Subtypes of influenza A are distingui... |
10.1371/journal.pcbi.1007269 | Non-trophic interactions strengthen the diversity—functioning relationship in an ecological bioenergetic network model | Ecological communities are undeniably diverse, both in terms of the species that compose them as well as the type of interactions that link species to each other. Despite this long recognition of the coexistence of multiple interaction types in nature, little is known about the consequences of this diversity for commun... | The question of how species diversity contributes to the functioning of ecological communities has intrigued ecologists for decades, and is especially relevant in the current context of species extinctions. Ecological communities are not only diverse in terms of the species that compose them but also in terms of the wa... | Despite the wide recognition of the coexistence of multiple interaction types linking species in nature [1–3], research on ecological networks has been massively dominated by studies on a single interaction at a time (e.g. trophic, competitive or mutualistic; e.g. [4–6]). The implications of the diversity of interactio... |
10.1371/journal.pntd.0001687 | Immunodominant Antigens of Leishmania chagasi Associated with Protection against Human Visceral Leishmaniasis | Protection and recovery from visceral leishmaniasis (VL) have been associated with cell-mediated immune (CMI) responses, whereas no protective role has been attributed to humoral responses against specific parasitic antigens. In this report, we compared carefully selected groups of individuals with distinct responses t... | One of the most striking features of infection by Leishmania chagasi is that infection leads to a spectrum of clinical outcomes ranging from asymptomatic infection to active disease. The existence of asymptomatic infected people has served as an incentive to believe that an effective vaccine is possible, but unfortunat... | Visceral Leishmaniasis (VL) is a potentially fatal disease caused by infection with Leishmania chagasi in the New World and Leishmania donovani or Leishmania infantum in the Old World [1]. Infection leads to a spectrum of clinical outcomes ranging from asymptomatic infection to active disease. The anti-Leishmania immun... |
10.1371/journal.ppat.1001161 | Retention and Loss of RNA Interference Pathways in Trypanosomatid Protozoans | RNA interference (RNAi) pathways are widespread in metaozoans but the genes required show variable occurrence or activity in eukaryotic microbes, including many pathogens. While some Leishmania lack RNAi activity and Argonaute or Dicer genes, we show that Leishmania braziliensis and other species within the Leishmania ... | RNAi interference pathways play fundamental roles in eukaryotes and provide important methods for the analysis of gene function. Occasionally RNAi has been lost, precluding its use as a tool, as well as raising the question of what forces could lead to loss of such a key pathway. Genomic and functional studies previous... | In metazoans, RNAi interference and related pathways play many key roles including regulation of mRNA levels and translation, chromatin silencing, programmed DNA rearrangements, genome surveillance, and defense against invading viruses. The phylogenetic distribution of key genes required for RNA interference such as Ar... |
10.1371/journal.pcbi.1002832 | Phylogenetic Diversity Theory Sheds Light on the Structure of Microbial Communities | Microbial communities are typically large, diverse, and complex, and identifying and understanding the processes driving their structure has implications ranging from ecosystem stability to human health and well-being. Phylogenetic data gives us a new insight into these processes, providing a more informative perspecti... | Microbial diversity analyses have revolutionized our knowledge of the microscopic world, from terrestrial and marine to human and urban environments. This growing field rests on the evolutionary relatedness of organisms, and at its frontier is the inference of ecological processes from phylogenetic diversity. However, ... | Microbial ecology has been advancing at a rapid pace, but understanding the processes driving microbial community structure remains a challenge [1]. The first step towards identifying these processes has been to document microbial biodiversity, and the use of phylogenetic methods has been stimulated by the abundance of... |
10.1371/journal.pgen.1003851 | A Critical Role for PDGFRα Signaling in Medial Nasal Process Development | The primitive face is composed of neural crest cell (NCC) derived prominences. The medial nasal processes (MNP) give rise to the upper lip and vomeronasal organ, and are essential for normal craniofacial development, but the mechanism of MNP development remains largely unknown. PDGFRα signaling is known to be critical ... | Craniofacial anomalies, including cleft lip and palate, are frequent birth defects. Although these are often associated with defects in neural crest development, the more severe phenotypic manifestations of midline defects is facial clefting, which is poorly understood. In this work, we show that the facial clefting ph... | Neural crest cells (NCCs) are a transient and multipotent cell population unique to vertebrates. During development, NCCs give rise to a broad variety of cell types, which contribute to the formation of the peripheral nervous system, cardiac outflow tract, pigment cells, and the majority of craniofacial bones and carti... |
10.1371/journal.pgen.1008142 | An integrative association method for omics data based on a modified Fisher’s method with application to childhood asthma | The development of high-throughput biotechnologies allows the collection of omics data to study the biological mechanisms underlying complex diseases at different levels, such as genomics, epigenomics, and transcriptomics. However, each technology is designed to collect a specific type of omics data. Thus, the associat... | In this research, we developed a statistical approach using a modified Fisher’s method (denoted as Omnibus-Fisher) to combine separate p-values of association testing for a trait and SNPs, DNA methylation markers, and RNA sequencing, calculated by kernel machine regression into an overall gene-level p-value to account ... | Because of major advances in high-throughput biotechnologies, large amounts of omics data have been collected to study the biological mechanisms underlying complex diseases at different levels, such as genomics, epigenomics, and transcriptomics. Such different types of omics data can help us understand a disease from s... |
10.1371/journal.pntd.0000859 | Insecticide Susceptibility of Phlebotomus argentipes in Visceral Leishmaniasis Endemic Districts in India and Nepal | To investigate the DDT and deltamethrin susceptibility of Phlebotomus argentipes, the vector of Leishmania donovani, responsible for visceral leishmaniasis (VL), in two countries (India and Nepal) with different histories of insecticide exposure.
Standard WHO testing procedures were applied using 4% DDT and 0.05% delta... | Visceral leishmaniasis (VL), also know as kala azar, is one of the major public health concerns India, Nepal and Bangladesh. In the Indian subcontinent, VL is caused by Leishmania donovani which is transmitted by Phlebotomus argentipes. To date, Indoor Residual Spraying (IRS) campaigns have been unable to control the d... | Approximately 200 million people are at risk of visceral leishmaniasis (VL) – also known as kala-azar – in Bangladesh, India and Nepal [1]. In South East Asia, VL is caused by Leishmania donovani Laveran & Mesnil (Kinetoplastida: Trypanosomatidae) which is transmitted by Phlebotomus argentipes Annandale & Brunneti (Dip... |
10.1371/journal.pgen.1005349 | In vivo Modeling Implicates APOL1 in Nephropathy: Evidence for Dominant Negative Effects and Epistasis under Anemic Stress | African Americans have a disproportionate risk for developing nephropathy. This disparity has been attributed to coding variants (G1 and G2) in apolipoprotein L1 (APOL1); however, there is little functional evidence supporting the role of this protein in renal function. Here, we combined genetics and in vivo modeling t... | African Americans have a disproportionate risk for developing chronic kidney disease compared to European Americans. Previous studies have identified a region on chromosome 22 containing two genes, MYH9 and APOL1, which likely accounts for nearly all of this difference. Previous reports provided strong statistical evid... | Chronic kidney disease (CKD) is an acute public health problem world-wide. Within the United States alone, it affects up to 14% of the adult population and is associated with both high costs and poor clinical outcomes[1]. Compared with European Americans, African Americans have a disproportionate risk for several forms... |
10.1371/journal.pcbi.1000359 | Polymorphism Data Can Reveal the Origin of Species Abundance Statistics | What is the underlying mechanism behind the fat-tailed statistics observed for species abundance distributions? The two main hypotheses in the field are the adaptive (niche) theories, where species abundance reflects its fitness, and the neutral theory that assumes demographic stochasticity as the main factor determini... | One purchases 100 wineglasses and 100 pairs of pants. After one year, 10 glasses and 10 pants survive. What can be said about the relative quality of the survivors? Well, clothes “die” as a result of accumulated wear; the surviving items are of better quality. The breaking of a wineglass is an external, random event: h... | One of the most interesting peculiarities of mother nature is the large variance in abundance of otherwise similar species. In the tropical rainforest, for example, there are differences of 4–5 orders of magnitude in the observed abundance of tropical trees [1]–[5]. Moreover, the abundance distribution admits a fat tai... |
10.1371/journal.pntd.0002027 | How Effective Is School-Based Deworming for the Community-Wide Control of Soil-Transmitted Helminths? | The London Declaration on neglected tropical diseases was based in part on a new World Health Organization roadmap to “sustain, expand and extend drug access programmes to ensure the necessary supply of drugs and other interventions to help control by 2020”. Large drug donations from the pharmaceutical industry form th... | Large donations of drugs to treat soil-transmitted helminths (STHs, intestinal worms) means that many more school-aged children will be treated, improving their well-being and development. These children will have to be repeatedly treated since reinfection will occur due to contaminated environments in the absence of i... | In January 2012, a high-level meeting brought together 13 pharmaceutical companies and the global health community in London, UK to announce a new public-private partnership to eliminate or control the seven preventable neglected tropical diseases (NTDs) by 2020, based largely on a new NTD roadmap from the World Health... |
10.1371/journal.ppat.0030062 | Impact of Mycobacterium ulcerans Biofilm on Transmissibility to Ecological Niches and Buruli Ulcer Pathogenesis | The role of biofilms in the pathogenesis of mycobacterial diseases remains largely unknown. Mycobacterium ulcerans, the etiological agent of Buruli ulcer, a disfiguring disease in humans, adopts a biofilm-like structure in vitro and in vivo, displaying an abundant extracellular matrix (ECM) that harbors vesicles. The c... | Mycobacterium ulcerans is the etiologic agent of Buruli ulcer, a necrotic skin disease affecting humans living close to wetlands in tropical countries. This mycobacteria resides in water where it could colonize many ecological niches such as aquatic plants, herbivorous animals, and water bugs. The latter were shown to ... | Mycobacterium ulcerans is the etiologic agent of Buruli ulcer, a necrotic skin disease affecting humans living close to wetlands in tropical countries. The natural history and transmission of this mycobacteria are still obscure. Epidemiological studies suggest that swampy areas, and more specifically, aquatic environme... |
10.1371/journal.pgen.1005767 | Iterative Usage of Fixed and Random Effect Models for Powerful and Efficient Genome-Wide Association Studies | False positives in a Genome-Wide Association Study (GWAS) can be effectively controlled by a fixed effect and random effect Mixed Linear Model (MLM) that incorporates population structure and kinship among individuals to adjust association tests on markers; however, the adjustment also compromises true positives. The m... | Genome-Wide Association Studies (GWAS) can reveal genetic-phenotypic relationships, but have limitations. To control false positives, population structure and kinship are incorporated in a fixed and random effect Mixed Linear Model (MLM). However, because of the confounding between population structure, kinship, and qu... | Genome-Wide Association Studies (GWAS) use direct statistical tests as opposed to direct genetic inferences carried out in linkage analyses. Associations between a genetic marker and a phenotype happen for many reasons in addition to the genetic linkage between the tested genetic markers and functional causal polymorph... |
10.1371/journal.ppat.1003273 | A Ubiquitin-specific Protease Possesses a Decisive Role for Adenovirus Replication and Oncogene-mediated Transformation | Adenoviral replication depends on viral as well as cellular proteins. However, little is known about cellular proteins promoting adenoviral replication. In our screens to identify such proteins, we discovered a cellular component of the ubiquitin proteasome pathway interacting with the central regulator of adenoviral r... | Adenoviral infections can result in severe outcomes leading to mortality especially in children undergoing immunosuppressive therapies. Unfortunately, no specific anti-adenoviral treatments are available to treat disseminated adenoviral infections. We have set out to identify host factors promoting adenoviral growth an... | Human adenoviruses constitute a group of more than 60 adenovirus types. In general, adenoviruses cause self-limiting infections of the eye, or gastrointestinal and respiratory tract, which can lead to epidemic keratoconjunctivitis, diarreah, and severe acute respiratory diseases [1]–[9]. However, with increasing preval... |
10.1371/journal.pgen.1005784 | Mutations of the Calcium Channel Gene cacophony Suppress Seizures in Drosophila | Bang sensitive (BS) Drosophila mutants display characteristic seizure-like phenotypes resembling, in some aspects, those of human seizure disorders such as epilepsy. The BS mutant parabss1, caused by a gain-of-function mutation of the voltage-gated Na+ channel gene, is extremely seizure-sensitive with phenotypes that h... | Seizure disorders, such as epilepsy, are a serious health concern because of the large number of patients affected and a limited availability of treatment options. About 10% of the population will have at least one seizure during their lifetime, and 1% will experience persistent, recurrent epileptic seizures. Moreover,... | Human seizure disorders are a substantial neurological health problem because of the large number of affected individuals, and heterogeneity underlying the many syndromes. An estimated 1% of the U.S. population, nearly 3 million Americans, is affected by the more than 40 different syndromes that comprise the epilepsies... |
10.1371/journal.pgen.1001259 | Ancestral Regulatory Circuits Governing Ectoderm Patterning Downstream of Nodal and BMP2/4 Revealed by Gene Regulatory Network Analysis in an Echinoderm | Echinoderms, which are phylogenetically related to vertebrates and produce large numbers of transparent embryos that can be experimentally manipulated, offer many advantages for the analysis of the gene regulatory networks (GRN) regulating germ layer formation. During development of the sea urchin embryo, the ectoderm ... | Echinoderms (sea urchins, starfish, etc.) are marine invertebrates that share a close ancestry with vertebrates. Their embryos offer many advantages for the analysis of transcriptional circuits that control developmental programs. During early development of the common sea urchin Paracentrotus lividus, a signaling cent... | It is becoming increasingly apparent that most developmental processes are controlled by dozens or hundreds of regulatory genes assembled into complex gene regulatory networks (GRNs), rather than by a small number of master genes. By describing the functional relationships between these genes, GRNs allow integration of... |
10.1371/journal.pgen.1002497 | Contrasting Properties of Gene-Specific Regulatory, Coding, and Copy Number Mutations in Saccharomyces cerevisiae: Frequency, Effects, and Dominance | Genetic variation within and between species can be shaped by population-level processes and mutation; however, the relative impact of “survival of the fittest” and “arrival of the fittest” on phenotypic evolution remains unclear. Assessing the influence of mutation on evolution requires understanding the relative rate... | Genetic dissection of phenotypic differences within and between species has shown that mutations affecting either the expression or function of a gene product can contribute to phenotypic evolution; mutations that alter gene copy number have also been shown to be an important source of phenotypic variation. Predicting ... | Mutations are the ultimate source of genetic variation, thus understanding the properties of new mutations is important for both medical and evolutionary genetics. Large-scale sequencing surveys have recently measured mutation rates for different types of DNA lesions (e.g., transitions, transversions, indels, rearrange... |
10.1371/journal.ppat.1005725 | Molecular Mechanisms for Drug Hypersensitivity Induced by the Malaria Parasite’s Chloroquine Resistance Transporter | Mutations in the Plasmodium falciparum ‘chloroquine resistance transporter’ (PfCRT) confer resistance to chloroquine (CQ) and related antimalarials by enabling the protein to transport these drugs away from their targets within the parasite’s digestive vacuole (DV). However, CQ resistance-conferring isoforms of PfCRT (... | In acquiring resistance to one drug, many pathogens and cancer cells become hypersensitive to other drugs. This phenomenon could be exploited to combat existing drug resistance and to delay the emergence of resistance to new drugs. However, much remains to be understood about the mechanisms that underlie drug hypersens... | Originally identified as the protein responsible for conferring resistance to the ‘wonder-drug’ chloroquine (CQ) [1, 2], the Plasmodium falciparum ‘chloroquine resistance transporter’ (PfCRT) has become a key player in the malaria parasite’s steadily expanding resistance to drugs [3–5]. The isoforms of PfCRT that confe... |
10.1371/journal.pgen.1006915 | The population genetics of human disease: The case of recessive, lethal mutations | Do the frequencies of disease mutations in human populations reflect a simple balance between mutation and purifying selection? What other factors shape the prevalence of disease mutations? To begin to answer these questions, we focused on one of the simplest cases: recessive mutations that alone cause lethal diseases ... | What determines the frequencies of disease mutations in human populations? To begin to answer this question, we focus on one of the simplest cases: mutations that cause completely recessive, lethal Mendelian diseases. We first review theory about what to expect from mutation and selection in a population of finite size... | New disease mutations arise in heterozygotes and either drift to higher frequencies or are rapidly purged from the population, depending on the strength of selection and the demographic history of the population [1–6]. Elucidating the relative contributions of mutation, natural selection and genetic drift will help to ... |
10.1371/journal.ppat.1000141 | Phosphoinositide-3 Kinase-Akt Pathway Controls Cellular Entry of Ebola Virus | The phosphoinositide-3 kinase (PI3K) pathway regulates diverse cellular activities related to cell growth, migration, survival, and vesicular trafficking. It is known that Ebola virus requires endocytosis to establish an infection. However, the cellular signals that mediate this uptake were unknown for Ebola virus as w... | Each year, filoviruses such as Ebola virus claim many human lives and decimate gorilla populations in Africa. Infection results in an acute fever often associated with profuse internal and external bleeding and death rates of up to 90%. Due to these symptoms and high pathogenicity, these viruses have been heavily publi... | Ebola virus, a member of the family Filoviridae, is an emerging infectious agent that causes severe and often fatal hemorrhagic fever in humans and nonhuman primates. In many outbreaks, especially those caused by Zaire Ebola virus (ZEBOV), mortality rates close to 90% have been reported [1]. Currently, no vaccine or th... |
10.1371/journal.pntd.0000611 | Distinct Genetic Diversity of Oncomelania hupensis, Intermediate Host of Schistosoma japonicum in Mainland China as Revealed by ITS Sequences | Oncomelania hupensis is the unique intermediate host of Schistosoma japonicum, which causes schistosomiasis endemic in the Far East, and especially in mainland China. O. hupensis largely determines the parasite's geographical range. How O. hupensis's genetic diversity is distributed geographically in mainland China has... | The intermediate host of Schistosoma japonicum in Asia is the snail Oncomelania hupensis, which can be separated phenotypically into ribbed- and smooth-shelled morphotypes. In China, the typical morphotype is ribbed-shelled, with its distribution restricted to mainland China. Smooth-shelled snails with varix are also d... | The snail Oncomelania hupensis, the only intermediate host of Schistosoma japonicum, has been found in China, and also in Japan, Philippines and Indonesian island of Sulawesi. Over the past a few decades, the taxonomy of O. hupensis has been a dispute due to the variation in morphological characters such as shell sculp... |
10.1371/journal.pbio.2006229 | Low-intensity electromagnetic fields induce human cryptochrome to modulate intracellular reactive oxygen species | Exposure to man-made electromagnetic fields (EMFs), which increasingly pollute our environment, have consequences for human health about which there is continuing ignorance and debate. Whereas there is considerable ongoing concern about their harmful effects, magnetic fields are at the same time being applied as therap... | Repetitive low-intensity magnetic stimulation has been used in the treatment of disease for over 50 years. Associated benefits have included alleviation of depression, memory loss, and symptoms of Parkinson disease, as well as accelerated bone and wound healing and the treatment of certain cancers, independently of sur... | Weak electromagnetic radiation (μT-mT), which increasingly pollutes our environment, has been associated with dual and seemingly contradictory effects on human health. On the one hand, possibly deleterious public health consequences have elicited considerable debate on safety and exposure limits to electromagnetic fiel... |
10.1371/journal.pgen.1000713 | E Unibus Plurum: Genomic Analysis of an Experimentally Evolved Polymorphism in Escherichia coli | Microbial populations founded by a single clone and propagated under resource limitation can become polymorphic. We sought to elucidate genetic mechanisms whereby a polymorphism evolved in Escherichia coli under glucose limitation and persisted because of cross-feeding among multiple adaptive clones. Apart from a 29 kb... | Experimental evolution of asexual species has shown that multiple genotypes can arise from a single ancestor and stably coexist (e unibus plurum). Although facilitated by environmental heterogeneity, this phenomenon also occurs in simple, homogeneous environments provisioned with a single limiting nutrient. We sought t... | Evolutionary biologists have long sought to understand mechanistically how adaptive genetic variation arises and persists. Experimental studies using model organisms such as Drosophila [1]–[3] and C. elegans [4]–[6] transformed the search for such mechanisms from a retrospective to a prospective endeavor. But, long gen... |
10.1371/journal.pcbi.1000307 | Probabilistic Interaction Network of Evidence Algorithm and its Application to Complete Labeling of Peak Lists from Protein NMR Spectroscopy | The process of assigning a finite set of tags or labels to a collection of observations, subject to side conditions, is notable for its computational complexity. This labeling paradigm is of theoretical and practical relevance to a wide range of biological applications, including the analysis of data from DNA microarra... | What mathematicians call the “labeling problem” underlies difficulties in interpreting many classes of complex biological data. To derive valid inferences from multiple, noisy datasets, one must consider all possible combinations of the data to find the solution that best matches the experimental evidence. Exhaustive s... | Labeling a set of fixed data with another representative set is the generic description for a large family of problems. This family includes clustering and dimensionality reduction, an approach in which the original dataset is represented by a set of typically far lower dimension (the representative set). The represent... |
10.1371/journal.pntd.0001017 | Trypanosoma brucei Glycogen Synthase Kinase-3, A Target for Anti-Trypanosomal Drug Development: A Public-Private Partnership to Identify Novel Leads | Trypanosoma brucei, the causative agent of Human African Trypanosomiasis (HAT), expresses two proteins with homology to human glycogen synthase kinase 3β (HsGSK-3) designated TbruGSK-3 short and TbruGSK-3 long. TbruGSK-3 short has previously been validated as a potential drug target and since this enzyme has also been ... | Over 60 million people in sub-Saharan Africa are at risk of infection with the parasite Trypanosoma brucei which causes Human African Trypanosomiasis (HAT), also known as sleeping sickness. The disease results in systemic and neurological disability to its victims. At present, only four drugs are available for treatmen... | Human African trypanosomiasis (HAT) and the lack of effective therapy constitute a health concern in 36 countries of sub-Saharan Africa [1]. The disease affects predominantly poor populations and transmission has been attributed to exposure during activities such as agriculture, animal husbandry, or hunting [2], which ... |
10.1371/journal.pcbi.1003078 | Coordination of Rapid Sphingolipid Responses to Heat Stress in Yeast | The regulatory roles of sphingolipids in diverse cell functions have been characterized extensively. However, the dynamics and interactions among the different sphingolipid species are difficult to assess, because de novo biosynthesis, metabolic inter-conversions, and the retrieval of sphingolipids from membranes form ... | Sphingolipids play dual roles by serving as components of membrane rafts and by regulating numerous key cell functions. Although sphingolipids have been studied extensively, the details of their functioning are difficult to understand, because their synthesis, pathways of inter-conversion, and utilization constitute a ... | Cells and organisms are regularly exposed to small fluctuations in their environments and have developed effective mechanisms of tolerance. Stronger perturbations lead to stresses, which are not as easily tolerated and require the cells to mount well-coordinated, multi-scale responses. These stress responses are very i... |
10.1371/journal.pgen.1005001 | Discovery of CTCF-Sensitive Cis-Spliced Fusion RNAs between Adjacent Genes in Human Prostate Cells | Genes or their encoded products are not expected to mingle with each other unless in some disease situations. In cancer, a frequent mechanism that can produce gene fusions is chromosomal rearrangement. However, recent discoveries of RNA trans-splicing and cis-splicing between adjacent genes (cis-SAGe) support for other... | Genes are considered the units of hereditary information; thus, neither genes nor their encoded products are expected to mingle with each other unless in some disease situations. However, the genes are not alone in the genome. Genes have neighbors, some close, some far. With RNA-seq, many fusion RNAs involving neighbor... | The traditional thinking is that gene fusions and their fusion products are caused by chromosomal rearrangement at the DNA level. However, a few isolated reports of RNA trans-splicing provide support for additional mechanisms for fusion RNA production in humans [1–4]. In prostate cancer, the SLC45A3-ELK4 fusion has rec... |
10.1371/journal.pgen.1004890 | Altered Chromatin Occupancy of Master Regulators Underlies Evolutionary Divergence in the Transcriptional Landscape of Erythroid Differentiation | Erythropoiesis is one of the best understood examples of cellular differentiation. Morphologically, erythroid differentiation proceeds in a nearly identical fashion between humans and mice, but recent evidence has shown that networks of gene expression governing this process are divergent between species. We undertook ... | The process whereby blood progenitor cells differentiate into red blood cells, known as erythropoiesis, is very similar between mice and humans. Yet, while studies of this process in mouse have substantially improved our knowledge of human erythropoiesis, recent work has shown a significant divergence in global gene ex... | Red blood cell (RBC) production (erythropoiesis) is one of the best understood examples of lineage commitment and cellular differentiation [1]–[4]. This process begins as multipotent hematopoietic stem cells (HSCs) differentiate into lineage committed erythroid progenitors, losing multipotency in intermediate progenito... |
10.1371/journal.pgen.1000007 | Genome-Wide Assessments Reveal Extremely High Levels of Polymorphism of Two Active Families of Mouse Endogenous Retroviral Elements | Endogenous retroviral elements (ERVs) in mice are significant genomic mutagens, causing ∼10% of all reported spontaneous germ line mutations in laboratory strains. The majority of these mutations are due to insertions of two high copy ERV families, the IAP and ETn/MusD elements. This significant level of ongoing retrot... | The laboratory mouse is the most widely used mammal for biological research. Hundreds of inbred mouse strains have been developed that vary in characteristics such as susceptibility to cancer or other diseases. There is much interest in uncovering differences between strains that result in different traits and, to aid ... | The laboratory mouse is the model of choice for mammalian biological research and a plethora of mouse genomic resources and databases now exist [1]. Notably, fueled by availability of genomic sequence for the common strain C57BL/6J (B6)[2], several groups have documented genetic variation among strains using single nuc... |
10.1371/journal.pgen.1005863 | UPF2-Dependent Nonsense-Mediated mRNA Decay Pathway Is Essential for Spermatogenesis by Selectively Eliminating Longer 3'UTR Transcripts | During transcription, most eukaryotic genes generate multiple alternative cleavage and polyadenylation (APA) sites, leading to the production of transcript isoforms with variable lengths in the 3’ untranslated region (3’UTR). In contrast to somatic cells, male germ cells, especially pachytene spermatocytes and round sp... | 3’UTR length control has been identified as a critical mechanism through which the cell establishes and maintains its functional identity. Developing male germ cells, especially spermatocytes and spermatids, display a transcriptome enriched in short 3’UTR transcripts, which has been demonstrated to be essential for spe... | Spermatogenesis is a complex cellular differentiation process through which male germline stem cells develop sequentially into spermatogonia, spermatocytes, spermatids, and eventually spermatozoa [1]. Both meiosis (i.e. spermatocyte development) and spermiogenesis (i.e. spermatid differentiation into spermatozoa) are u... |
10.1371/journal.pcbi.1004017 | Metadynamics Simulations Reveal a Na+ Independent Exiting Path of Galactose for the Inward-Facing Conformation of vSGLT | Sodium-Galactose Transporter (SGLT) is a secondary active symporter which accumulates sugars into cells by using the electrochemical gradient of Na+ across the membrane. Previous computational studies provided insights into the release process of the two ligands (galactose and sodium ion) into the cytoplasm from the in... | Membrane proteins are crucial for the communication of the cell with the environment. Among these, symporters are in charge of the transport of molecules (like sugars, amino acids, osmolytes) inside the cells, exploiting the concentration gradient of an ion to perform the task. Here we investigate by atomistic simulati... | Secondary active transporters are membrane proteins involved in the translocation of small organic molecules across the cellular membrane using the energy stored as transmembrane electrochemical gradient of ions (mostly Na+ or H+). Sodium symporters in particular use this alkali metal ion to cotransport a variety of su... |
10.1371/journal.pcbi.1002165 | Monkeys and Humans Share a Common Computation for Face/Voice Integration | Speech production involves the movement of the mouth and other regions of the face resulting in visual motion cues. These visual cues enhance intelligibility and detection of auditory speech. As such, face-to-face speech is fundamentally a multisensory phenomenon. If speech is fundamentally multisensory, it should be r... | The evolution of speech is one of our most fascinating and enduring mysteries—enduring partly because all the critical features of speech (brains, vocal tracts, ancestral speech-like sounds) do not fossilize. Furthermore, it is becoming increasingly clear that speech is, by default, a multimodal phenomenon: we use both... | When we speak, our face moves and deforms the mouth and other regions [1], [2], [3], [4], [5]. These dynamics and deformations lead to a variety of visual motion cues (“visual speech”) related to the auditory components of speech and are integral to face-to-face communication. In noisy, real world environments, visual ... |
10.1371/journal.pgen.1005721 | Origins of De Novo Genes in Human and Chimpanzee | The birth of new genes is an important motor of evolutionary innovation. Whereas many new genes arise by gene duplication, others originate at genomic regions that did not contain any genes or gene copies. Some of these newly expressed genes may acquire coding or non-coding functions and be preserved by natural selecti... | For the past 20 years scientists have puzzled over a strange-yet-ubiquitous genomic phenomenon; in every genome there are sets of genes which are unique to that particular species i.e. lacking homologues in any other species. How have these genes originated? The advent of massively parallel RNA sequencing (RNA-Seq) has... | New genes continuously arise in genomes. Recent evolutionary 'inventions' include small proteins that have functions related to the adaptation to the environment, such as antimicrobial peptides or antifreeze proteins, which have independently evolved in different groups of organisms [1,2]. A well-studied process for th... |
10.1371/journal.pntd.0001514 | Molecular Mechanisms of Drug Resistance in Natural Leishmania Populations Vary with Genetic Background | The evolution of drug-resistance in pathogens is a major global health threat. Elucidating the molecular basis of pathogen drug-resistance has been the focus of many studies but rarely is it known whether a drug-resistance mechanism identified is universal for the studied pathogen; it has seldom been clarified whether ... | Drug resistance is a serious problem that strikes at the core of infectious disease control. The mechanisms developed by pathogens to become resistant against existing drug treatments have been studied for many years but these studies have frequently scrutinized a few lines of the pathogen and rarely is it known whethe... | Leishmania, a protozoan parasite transmitted by phlebotomine sand flies, causes a neglected infectious disease commonly referred to as leishmaniasis. The species Leishmania (Leishmania) donovani is the causative agent of visceral leishmaniasis (VL) or kala-azar, the most severe form of leishmaniasis which is lethal if ... |
10.1371/journal.pgen.0030205 | Forty Years of Erratic Insecticide Resistance Evolution in the Mosquito Culex pipiens | One view of adaptation is that it proceeds by the slow and steady accumulation of beneficial mutations with small effects. It is difficult to test this model, since in most cases the genetic basis of adaptation can only be studied a posteriori with traits that have evolved for a long period of time through an unknown s... | Adaptation is not always a straightforward process, and often results from natural selection tinkering with available variation. We present in this study just such a tortuous natural selection pathway, which allows the mosquito Culex pipiens to resist organophosphorous insecticides. In the Montpellier area, following t... | Adaptation is often envisioned as a slow and regular improvement, a view embodied by Fisher's geometrical model of adaptation, whereby mutations fix if they bring the current phenotype closer to an optimum [1,2]. However, the trajectory towards the optimum can take a truly tortuous path [3], as adaptation uses almost a... |
10.1371/journal.ppat.1000442 | CAR-Associated Vesicular Transport of an Adenovirus in Motor Neuron Axons | Axonal transport is responsible for the movement of signals and cargo between nerve termini and cell bodies. Pathogens also exploit this pathway to enter and exit the central nervous system. In this study, we characterised the binding, endocytosis and axonal transport of an adenovirus (CAV-2) that preferentially infect... | Adenoviruses commonly cause subclinical morbidity in the ocular, respiratory, and gastrointestinal tracts, and less frequently, adenovirus-induced disease can be fatal for newborns and immunocompromised hosts. In addition, adenoviruses can reach the central nervous system (CNS) and cause associated encephalitis and tum... | Adenoviridae is a family of greater than 150 nonenveloped double-stranded DNA viruses that infect all vertebrate classes. Whilst adenoviruses (Ads) are commonly associated with respiratory, ocular and gastrointestinal tract infections, many serotypes cause clinical manifestations in other tissues, including the central... |
10.1371/journal.pcbi.1002360 | Early Warning Signals for Critical Transitions: A Generalized Modeling Approach | Critical transitions are sudden, often irreversible, changes that can occur in a large variety of complex systems; signals that warn of critical transitions are therefore highly desirable. We propose a new method for early warning signals that integrates multiple sources of information and data about the system through... | Fisheries, coral reefs, productive farmland, planetary climate, neural activity in the brain, and financial markets are all complex systems that can be susceptible to sudden changes leading to drastic re-organization or collapse. A variety of signals based on analysis of time-series data have been proposed that would p... | Critical transitions are sudden, long-term changes in complex systems that occur when a threshold is crossed [1]. Many systems are known to be at risk of such transitions, including systems in ecology [2], climate research [3], economics [4], sociology [5] and human physiology [6]. Examples of critical transitions in e... |
10.1371/journal.pcbi.1000639 | An Integrative -omics Approach to Identify Functional Sub-Networks in Human Colorectal Cancer | Emerging evidence indicates that gene products implicated in human cancers often cluster together in “hot spots” in protein-protein interaction (PPI) networks. Additionally, small sub-networks within PPI networks that demonstrate synergistic differential expression with respect to tumorigenic phenotypes were recently s... | Intensive research on cancer has led to an understanding of many individual genes that may be important for the initiation and progression of tumors. However, since cancer is a progressive disease that results from accumulation of multiple mutations likely acting in concert, individual markers can only provide limited ... | Colorectal cancer (CRC) is the second leading cause of cancer death in adult Americans [1]. Interest in this complex disease is represented by a very mature body of research, much of it at the genomic level. Yet the identification and verification of proteins that have a functional role in the patho-physiology of CRC r... |
10.1371/journal.pgen.1007472 | Duplication of a Pks gene cluster and subsequent functional diversification facilitate environmental adaptation in Metarhizium species | The ecological importance of the duplication and diversification of gene clusters that synthesize secondary metabolites in fungi remains poorly understood. Here, we demonstrated that the duplication and subsequent diversification of a gene cluster produced two polyketide synthase gene clusters in the cosmopolitan funga... | In fungi, gene clusters that synthesize secondary metabolites are hotspots for the generation of fungal metabolic diversity through gene duplication, but their ecological importance remains poorly understood. Metarhizium species are adapted to life as insect pathogens, plant symbionts and saprophytes, enabling the func... | Metabolic gene clusters are hotspots for the generation of fungal metabolic diversity through gene duplication, but the ecological importance of these gene clusters remains poorly understood [1]. Gene clusters that biosynthesize secondary metabolites (SMs) are particularly challenging, because they are often lineage-sp... |
10.1371/journal.pbio.2006057 | Cross-resistance is modular in bacteria–phage interactions | Phages shape the structure of natural bacterial communities and can be effective therapeutic agents. Bacterial resistance to phage infection, however, limits the usefulness of phage therapies and could destabilise community structures, especially if individual resistance mutations provide cross-resistance against multi... | Phage therapy is a promising alternative to antibiotics for treating bacterial infections. Yet as with antibiotics, bacteria readily evolve resistance to phage attack, including cross-resistance that protects against multiple phages at once and so limits the usefulness of phage cocktails. Here we show, using laboratory... | Natural microbial communities are comprised of complex networks of species interactions, wherein each species may be engaged in ecological interactions with many other species [1–3]. In this community context, the evolutionary response of a focal species to a given pairwise species interaction can promote an ‘evolution... |
10.1371/journal.pgen.1000951 | Characterization of Oxidative Guanine Damage and Repair in Mammalian Telomeres | 8-oxo-7,8-dihydroguanine (8-oxoG) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG) are among the most common oxidative DNA lesions and are substrates for 8-oxoguanine DNA glycosylase (OGG1)–initiated DNA base excision repair (BER). Mammalian telomeres consist of triple guanine repeats and are subject to oxidativ... | It has been proposed that oxidative DNA damage compromises telomere integrity. However, neither the types nor the consequences of oxidative DNA damage in telomeres have been fully explored. Oxidative base lesions, especially 8-oxoG and FapyG are among the most common oxidative DNA damage. These guanine lesions are exci... | Telomeres are chromosome end nucleoprotein structures that are composed of telomere associated proteins and TTAGGG repeats in mammals [1]. Telomeres cap chromosome ends and prevent them from being recognized as broken DNA. Dysfunctional telomeres, emanating from loss of telomere repeats and/or loss of protection by tel... |
10.1371/journal.pgen.1000763 | Elevated Levels of the Polo Kinase Cdc5 Override the Mec1/ATR Checkpoint in Budding Yeast by Acting at Different Steps of the Signaling Pathway | Checkpoints are surveillance mechanisms that constitute a barrier to oncogenesis by preserving genome integrity. Loss of checkpoint function is an early event in tumorigenesis. Polo kinases (Plks) are fundamental regulators of cell cycle progression in all eukaryotes and are frequently overexpressed in tumors. Through ... | Double strand DNA breaks (DSBs) are dangerous chromosomal lesions that can lead to genome rearrangements, genetic instability, and cancer if not accurately repaired. Eukaryotes activate a surveillance mechanism, called DNA damage checkpoint, to arrest cell cycle progression and facilitate DNA repair. Several factors ar... | Saccharomyces cerevisiae cells suffering a double stranded DNA break (DSB) activate a robust Mec1-dependent checkpoint response when DSB ends are processed to expose single-stranded DNA (ssDNA), and progression through the cell cycle is arrested prior to anaphase. Several well conserved factors are recruited at the DSB... |
10.1371/journal.pgen.1004880 | Syd/JIP3 and JNK Signaling Are Required for Myonuclear Positioning and Muscle Function | Highlighting the importance of proper intracellular organization, many muscle diseases are characterized by mispositioned myonuclei. Proper positioning of myonuclei is dependent upon the microtubule motor proteins, Kinesin-1 and cytoplasmic Dynein, and there are at least two distinct mechanisms by which Kinesin and Dyn... | A common pathology found in numerous cases of muscle diseases, including congenital myopathies and muscular dystrophies, is aberrantly located nuclei within individual multinucleated muscle cells. However, whether or not mispositioned myonuclei are a cause or consequence of muscle disease states is currently debated. H... | The intracellular location of the multiple nuclei within muscle cells has recently gained traction as a potential contributing factor to muscle disease. Improper myonuclear position strongly correlates with muscle disease [1], [2] and muscle weakness [3]–[5]; yet, the mechanisms of myonuclear movement and positioning h... |
10.1371/journal.pntd.0002929 | Transcriptomic Evidence for a Dramatic Functional Transition of the Malpighian Tubules after a Blood Meal in the Asian Tiger Mosquito Aedes albopictus | The consumption of a vertebrate blood meal by adult female mosquitoes is necessary for their reproduction, but it also presents significant physiological challenges to mosquito osmoregulation and metabolism. The renal (Malpighian) tubules of mosquitoes play critical roles in the initial processing of the blood meal by ... | The Asian tiger mosquito Aedes albopictus is a vector of several medically-important arboviruses and one of the most invasive mosquito species in the world. Existing control measures for mosquitoes are presently being challenged by the emergence of resistance to insecticides that target the nervous system. Thus, it is ... | The Asian tiger mosquito Aedes albopictus is considered one of the most invasive mosquito species in the world; since 1979 it has spread to over 28 countries outside of its native range in Asia and Southeast Asia, aided by the international trade of used automobile tires [1], [2]. Within the United States, the mosquito... |
10.1371/journal.pcbi.1005717 | Domain-based prediction of the human isoform interactome provides insights into the functional impact of alternative splicing | Alternative splicing is known to remodel protein-protein interaction networks (“interactomes”), yet large-scale determination of isoform-specific interactions remains challenging. We present a domain-based method to predict the isoform interactome from the reference interactome. First, we construct the domain-resolved ... | Protein-protein interaction networks have been extensively used in systems biology to study the role of proteins in cell function and disease. However, current network biology studies typically assume that one gene encodes one protein isoform, ignoring the effect of alternative splicing. Alternative splicing allows a g... | Protein-protein interaction (PPI) networks (also known as interactome networks) have been extensively studied in systems biology to understand genotype-phenotype relationships and several have been constructed for different model organisms such as human, yeast and bacteria [1–10]. The increase in the number of interact... |
10.1371/journal.pntd.0005323 | Characterizing Antibody Responses to Plasmodium vivax and Plasmodium falciparum Antigens in India Using Genome-Scale Protein Microarrays | Understanding naturally acquired immune responses to Plasmodium in India is key to improving malaria surveillance and diagnostic tools. Here we describe serological profiling of immune responses at three sites in India by probing protein microarrays consisting of 515 Plasmodium vivax and 500 Plasmodium falciparum prote... | Although malaria deaths have fallen by 60% worldwide since 2000, the disease remains a significant public health problem. India has the highest burden of malaria in the South-East Asia Region, where Plasmodium vivax and Plasmodium falciparum are its main causes. While the two major malaria parasite species co-occur in ... | The burden of malaria in India has halved over the last 15 years, yet India continues to account for over 70% of malaria cases in South East Asia [1]. The ‘National Framework for Malaria Elimination in India 2016–2030’ has two aims: eliminating malaria throughout the country by 2030 and maintaining malaria–free status ... |
10.1371/journal.pgen.1001345 | Environmental Sex Determination in the Branchiopod Crustacean Daphnia magna: Deep Conservation of a Doublesex Gene in the Sex-Determining Pathway | Sex-determining mechanisms are diverse among animal lineages and can be broadly divided into two major categories: genetic and environmental. In contrast to genetic sex determination (GSD), little is known about the molecular mechanisms underlying environmental sex determination (ESD). The Doublesex (Dsx) genes play an... | Sex determination is a fundamental biological process that can be broadly divided into two major categories. In genetic sex determination (GSD), sex-specific differentiation results from intrinsic genetic differences between males and females, whereas environmental sex determination (ESD) relies on environmental signal... | Sex determination is a fundamental biological process. It affects not only the sexual differentiation of gonads, but also the development of most organs, and leads to sex-specific differences in behavior, physiology and morphology. Organisms have evolved a variety of different sex-determining systems [1], [2] that can ... |
10.1371/journal.pbio.1000101 | Visualisation and Quantification of Morphogen Gradient Formation in the Zebrafish | During embryonic development, signalling molecules known as morphogens act in a concentration-dependent manner to provide positional information to responding tissues. In the early zebrafish embryo, graded signalling by members of the nodal family induces the formation of mesoderm and endoderm, thereby patterning the e... | One of the earliest events in vertebrate embryonic development is the patterning of the embryo into three germ layers: the ectoderm, mesoderm, and endoderm. Morphogens are signalling molecules that act in a concentration-dependent manner to induce the formation of different cell types. Members of the nodal family are t... | During embryonic development, secreted molecules known as morphogens generate a concentration gradient of positional information that instructs developing tissues to adopt particular cell fates [1]. One example of this phenomenon is the patterning of the early zebrafish embryo by the nodal/TGF-β signalling pathway [2].... |
10.1371/journal.pgen.1001301 | Prevalence of Epistasis in the Evolution of Influenza A Surface Proteins | The surface proteins of human influenza A viruses experience positive selection to escape both human immunity and, more recently, antiviral drug treatments. In bacteria and viruses, immune-escape and drug-resistant phenotypes often appear through a combination of several mutations that have epistatic effects on pathoge... | Epistasis describes non-additive interactions among genetic sites: the consequence of a mutation at one site may depend on the status of the genome at other sites. In an extreme case, a mutation may have no effect if it arises on one genetic background, but a strong effect on another background. Epistatic mutations in ... | Influenza A is among the most extensively studied viruses, owing to its importance as a human pathogen [1]–[6]. With a large, public database of genetic sequences, influenza viruses also offer a model system for studying molecular evolution in general. The evolution of influenza viruses is characterized by frequent rea... |
10.1371/journal.pgen.1008175 | A statistical model for reference-free inference of archaic local ancestry | Statistical analyses of genomic data from diverse human populations have demonstrated that archaic hominins, such as Neanderthals and Denisovans, interbred or admixed with the ancestors of present-day humans. Central to these analyses are methods for inferring archaic ancestry along the genomes of present-day individua... | Recent analyses of modern human genomes have shown that archaic hominins like Neanderthals and Denisovans contribute a few percentage of ancestry to many populations. These analyses rely on having accurate reference genomes from these archaic populations. Due to the difficulty in sequencing these genomes, we lack a com... | Admixture, the exchange of genes among previously isolated populations, is increasingly being recognized as an important force in shaping genetic variation in natural populations. Analyses of large collections of genome sequences have shown that admixture events have been prevalent throughout human history [1]. These s... |
10.1371/journal.pmed.1002215 | Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach | The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain.
We conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham ... | Genetic sequence variants explain only a modest proportion of the variation in body mass index (BMI) and cardiometabolic disease in the general population.
There is limited understanding of the link of DNA methylation—a well-characterized epigenetic modification—with BMI and cardiometabolic disease in the general popul... | Obesity is highly prevalent in developed nations [1] and contributes to a substantial burden of morbidity and mortality [2,3]. Despite advances in the understanding of genetic variants, lifestyle factors, and gene–environment interactions associated with obesity [4–7], much of the interindividual variation in body weig... |
10.1371/journal.pgen.1001261 | Self-Mating in the Definitive Host Potentiates Clonal Outbreaks of the Apicomplexan Parasites Sarcocystis neurona and Toxoplasma gondii | Tissue-encysting coccidia, including Toxoplasma gondii and Sarcocystis neurona, are heterogamous parasites with sexual and asexual life stages in definitive and intermediate hosts, respectively. During its sexual life stage, T. gondii reproduces either by genetic out-crossing or via clonal amplification of a single str... | The parasites Toxoplasma gondii and Sarcocystis neurona have lifecycles that include a sexual stage in a definitive host and an asexual stage in intermediate hosts. For T. gondii, laboratory studies have demonstrated that the sexual stage can serve the dual purpose of producing new, virulent genotypes through recombina... | Population genetic studies of pathogenic microbes have been paramount to our understanding of disease resulting from emerging and re-emerging infectious organisms [1]. Studies performed to determine the relative contributions of drift and recombination in the production of genetic diversity have identified that most pa... |
10.1371/journal.pntd.0007576 | ParaDB: A manually curated database containing genomic annotation for the human pathogenic fungi Paracoccidioides spp. | The genus Paracoccidioides consists of thermodymorphic fungi responsible for Paracoccidioidomycosis (PCM), a systemic mycosis that has been registered to affect ~10 million people in Latin America. Biogeographical data subdivided the genus Paracoccidioides in five divergent subgroups, which have been recently classifie... | The genus Paracoccidioides comprises fungi responsible for Paracoccidioidomycosis (PCM), a neglected tropical disease prevalent in South America that has been shown to affect approximately 10 million people and has great medical/social impact, since available treatments are poorly effective, frequently leading to relap... | The genus Paracoccidioides includes a series of thermodymorphic fungi responsible for causing a neglected tropical disease known as paracoccidioidomycosis (PCM), which represents one of the most prevalent systemic mycoses in Latin America [1]. In fact, approximately 10 million people have been estimated to be infected ... |
10.1371/journal.pbio.3000156 | Scrutinizing assortative mating in birds | It is often claimed that pair bonds preferentially form between individuals that resemble one another. Such assortative mating appears to be widespread throughout the animal kingdom. Yet it is unclear whether the apparent ubiquity of assortative mating arises primarily from mate choice (“like attracts like”), which can... | Research on mate choice in birds has attracted much attention, partly because many birds form monogamous pair bonds like humans do. Human mate choice is characterized by the phenomenon of “like attracts like,” meaning that partners resemble each other in multiple ways (“assortative mating”). Assortative mating is also ... | Members of a pair often resemble each other. For instance, in humans, partners have similar political attitudes [1, 2], level of education [3, 4], and body height [4–6]. In fact, assortative mating appears to be common across all animal taxa and across all phenotypic traits that have been investigated [7]. However, in ... |
10.1371/journal.pbio.1001438 | Crag Is a GEF for Rab11 Required for Rhodopsin Trafficking and Maintenance of Adult Photoreceptor Cells | Rhodopsins (Rhs) are light sensors, and Rh1 is the major Rh in the Drosophila photoreceptor rhabdomere membrane. Upon photoactivation, a fraction of Rh1 is internalized and degraded, but it remains unclear how the rhabdomeric Rh1 pool is replenished and what molecular players are involved. Here, we show that Crag, a DE... | Animals sense light through receptors called Rhodopsins. These proteins are typically localized to stacked membranes in photoreceptors. In flies, upon light exposure, Rhodopsin undergoes conformational changes and becomes active as metarhodopsin. Metarhodopsin then initiates a signaling cascade that activates the photo... | The Drosophila phototransduction pathway has been extensively studied [1], and most known members of the pathway were isolated in forward genetics screens by means of electroretinogram (ERG) and phototactic assays [2]–[6]. Since vision is not an essential sense, previous screens were performed on homozygous viable muta... |
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