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10.1371/journal.pcbi.1003986 | Hippocampal Remapping Is Constrained by Sparseness rather than Capacity | Grid cells in the medial entorhinal cortex encode space with firing fields that are arranged on the nodes of spatial hexagonal lattices. Potential candidates to read out the space information of this grid code and to combine it with other sensory cues are hippocampal place cells. In this paper, we investigate a populat... | The mammalian brain represents space in the population of hippocampal place cells as well as in the population of medial entorhinal cortex grid cells. Since both populations are active at the same time, space information has to be synchronized between the two. Both brain areas are reciprocally connected, and it is uncl... | The neuronal representation of space that is necessary for navigation and orientation has been traditionally assigned to the hippocampal place cell system [1], where cells fire only at few distinct locations and are silent elsewhere. Since the discovery of grid cells in the medial entorhinal cortex (MEC) [2], [3], whic... |
10.1371/journal.pgen.1004637 | Dominant Sequences of Human Major Histocompatibility Complex Conserved Extended Haplotypes from HLA-DQA2 to DAXX | We resequenced and phased 27 kb of DNA within 580 kb of the MHC class II region in 158 population chromosomes, most of which were conserved extended haplotypes (CEHs) of European descent or contained their centromeric fragments. We determined the single nucleotide polymorphism and deletion-insertion polymorphism allele... | The human major histocompatibility complex (MHC) is a gene-dense region highly enriched in immune response genes. MHC genetic variation is among the highest in the human genome and is associated with both tissue transplant compatibility and many genetic disorders. Long-range (1–3 Mb) MHC haplotypes of essentially ident... | The human major histocompatibility complex (MHC) is a highly polymorphic genomic region of over 3 Mb on chromosome 6p21. MHC polymorphisms include critical determinants for tissue transplantation success and show strong correlation both with many genetic diseases and with ethnic origin. Haplotype analysis of DNA sequen... |
10.1371/journal.pntd.0000948 | Assessment of the Anthelmintic Efficacy of Albendazole in School
Children in Seven Countries Where Soil-Transmitted Helminths Are
Endemic | The three major soil-transmitted helminths (STH) Ascaris
lumbricoides, Trichuris trichiura and
Necator americanus/Ancylostoma duodenale are among the
most widespread parasites worldwide. Despite the global expansion of
... | Soil-transmitted helminths (roundworms, whipworms and hookworms) infect millions
of children in (sub)tropical countries, resulting in malnutrition, growth
stunting, intellectual retardation and cognitive deficits. Currently, there is a
need to closely monitor ... | The three major Soil-Transmitted Helminths (STH), Ascaris
lumbricoides (roundworm), Trichuris trichiura
(whipworm) and Necator americanus/Ancylostoma duodenale (the
hookworms) are amongst the most widespread parasites worldwide. An estimated 4.5
billio... |
10.1371/journal.pbio.0060160 | Human and Drosophila Cryptochromes Are Light Activated by Flavin Photoreduction in Living Cells | Cryptochromes are a class of flavoprotein blue-light signaling receptors found in plants, animals, and humans that control plant development and the entrainment of circadian rhythms. In plant cryptochromes, light activation is proposed to result from photoreduction of a protein-bound flavin chromophore through intramol... | Vision in animals is generally associated with light-sensitive rhodopsin pigments located in the eyes. However, animals ranging from flies to humans also possess ancient visual receptors known as cryptochromes in multiple cell types. In this work, we study the mechanism of light sensing in two representative animal cry... | Cryptochromes are blue-light–absorbing photoreceptors found throughout the biological kingdom, involved in diverse and important signaling roles [1–3]. Cryptochromes were first identified in plants from a mutant of Arabidopsis thaliana (A. thaliana), hy4, which failed to show normal plant growth and developmental respo... |
10.1371/journal.pntd.0002528 | Regulatory T Cells in Peripheral Blood and Cerebrospinal Fluid of Syphilis Patients with and without Neurological Involvement | Syphilis, a sexually transmitted disease caused by spirochetal bacterium Treponema pallidum, can progress to affect the central nervous system, causing neurosyphilis. Accumulating evidence suggest that regulatory T cells (Tregs) may play an important role in the pathogenesis of syphilis. However, little is known about ... | Syphilis, caused by the bacterium Treponema pallidum, can progress to affect the central nervous system (CNS) and cause damage in the brain and spinal cord, which is called neurosyphilis. While many affected neurosyphilis patients may not have any symptoms, some of the patients will develop severe symptoms that can be ... | China has experienced an expanding epidemic of syphilis infection in the last 10 years [1], [2]. In 2011, the national incidence rate was 32.04 per 100,000 population and 429,677 new cases were reported [3]. This sexually transmitted disease has reemerged as a significant public health issue in China due to its serious... |
10.1371/journal.ppat.1003263 | Strongyloidiasis and Infective Dermatitis Alter Human T Lymphotropic Virus-1 Clonality in vivo | Human T-lymphotropic Virus-1 (HTLV-1) is a retrovirus that persists lifelong by driving clonal proliferation of infected T-cells. HTLV-1 causes a neuroinflammatory disease and adult T-cell leukemia/lymphoma. Strongyloidiasis, a gastrointestinal infection by the helminth Strongyloides stercoralis, and Infective Dermatit... | HTLV-1 is a human retrovirus estimated to infect 20 million people world-wide and is causing in a small proportion of the infected individuals an inflammatory disease or a leukemia/lymphoma. HTLV-1 persists lifelong by driving clonal proliferation of infected T-cells. Strongyloidiasis, a gastrointestinal infection by a... | Human T-lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). It has been estimated that 10 to 20 million persons live with HTLV-1 infection worldwide. A small proportion (up to 7%, depending on the area) of HTLV-1-infect... |
10.1371/journal.pntd.0000361 | Prevalence Distribution and Risk Factors for Schistosoma hematobium Infection among School Children in Blantyre, Malawi | Schistosomiasis is a public health problem in Malawi but estimates of its prevalence vary widely. There is need for updated information on the extent of disease burden, communities at risk and factors associated with infection at the district and sub-district level to facilitate effective prioritization and monitoring ... | Schistosoma hematobium infection is a parasitic infection endemic in Malawi. Schistosomiasis usually shows a focal distribution of infection and it is important to identify communities at high risk of infection and assess effectiveness of control programs. We conducted a survey in one district in Malawi to determine pr... | Schistosomiasis remains an important public health problem globally with an estimated 200 million cases reported each year [1]. However, 85% of the cases reported annually occur in sub-Saharan Africa and over 150,000 deaths are attributable to chronic infection with S. haematobium in this region [2],[3]. The eggs of S.... |
10.1371/journal.pntd.0005627 | Expression of inhibitory receptors and polyfunctional responses of T cells are linked to the risk of congenital transmission of T. cruzi | Congenital T. cruzi infections involve multiple factors in which complex interactions between the parasite and the immune system of pregnant women play important roles. In this study, we used an experimental murine model of chronic infection with T. cruzi to evaluate the changes in the expression of inhibitory receptor... | Chagas disease or American trypanosomiasis is a complex parasitic disease caused by the protozoan Trypanosoma cruzi. This disease that affects approximately 10 million people worldwide may be mother-to-child transmitted which is an important public health problem with great relevance in endemic and non-endemic areas an... | Chagas disease, which is caused by the protozoan Trypanosoma cruzi, is a tropical parasitic disease that affects approximately 10 million people worldwide. The disease is primarily transmitted by contact with the infected feces of triatomine bugs [1]. This parasite can also be transmitted by non-vector mechanisms, incl... |
10.1371/journal.ppat.1003440 | The Interactomes of Influenza Virus NS1 and NS2 Proteins Identify New Host Factors and Provide Insights for ADAR1 Playing a Supportive Role in Virus Replication | Influenza A NS1 and NS2 proteins are encoded by the RNA segment 8 of the viral genome. NS1 is a multifunctional protein and a virulence factor while NS2 is involved in nuclear export of viral ribonucleoprotein complexes. A yeast two-hybrid screening strategy was used to identify host factors supporting NS1 and NS2 func... | Viruses are obligate intracellular parasites that rely on cellular functions for efficient replication. As most biological processes are sustained by protein-protein interactions, the identification of interactions between viral and host proteins can provide a global overview about the cellular functions engaged during... | Influenza A viruses are the causative agents of seasonal and pandemic infections and are responsible for the death of at least half a million people worldwide each year. The genome of influenza A viruses is composed of eight negative-sense single-stranded RNAs encoding 13 proteins. NS1 and NS2 are derived from alternat... |
10.1371/journal.pcbi.1003415 | Population Decoding in Rat Barrel Cortex: Optimizing the Linear Readout of Correlated Population Responses | Sensory information is encoded in the response of neuronal populations. How might this information be decoded by downstream neurons? Here we analyzed the responses of simultaneously recorded barrel cortex neurons to sinusoidal vibrations of varying amplitudes preceded by three adapting stimuli of 0, 6 and 12 µm in ampl... | In the natural environment, animals are constantly exposed to sensory stimulation. A key question in systems neuroscience is how attributes of a sensory stimulus can be “read out” from the activity of a population of brain cells. We chose to investigate this question in the whisker-mediated touch system of rats because... | A goal of systems neuroscience is to achieve a quantitative understanding of how cortical neurons report sensory events in their population activity. The interlaced synaptic architecture of neuronal networks provides anatomical evidence for population decoding by downstream neuronal structures. Such a synaptic organiza... |
10.1371/journal.pcbi.1004207 | Thermal Stabilization of Dihydrofolate Reductase Using Monte Carlo Unfolding Simulations and Its Functional Consequences | Design of proteins with desired thermal properties is important for scientific and biotechnological applications. Here we developed a theoretical approach to predict the effect of mutations on protein stability from non-equilibrium unfolding simulations. We establish a relative measure based on apparent simulated melti... | All-atom molecular simulations have provided valuable insight into the workings of molecular machines and the folding and unfolding of proteins. However, commonly employed molecular dynamics simulations suffer from a limitation in accessible time scale, making it difficult to model large-scale unfolding events in a rea... | Protein stability is an important determinant of organismal fitness and is central to the process of enzyme design for industrial applications [1–3]. Most proteins must be folded to carry out their functions in vitro or in vivo. In addition, non-functional aggregation of unfolded or partially-unfolded proteins can have... |
10.1371/journal.ppat.1002847 | The Ebola Virus Glycoprotein Contributes to but Is Not Sufficient for Virulence In Vivo | Among the Ebola viruses most species cause severe hemorrhagic fever in humans; however, Reston ebolavirus (REBOV) has not been associated with human disease despite numerous documented infections. While the molecular basis for this difference remains unclear, in vitro evidence has suggested a role for the glycoprotein ... | Most Ebola virus species cause severe hemorrhagic fevers with high case fatality rates. However, Reston ebolavirus (REBOV) seems to be apathogenic for humans. While the reason for this is unknown, several lines of in vitro research have indicated that the viral glycoprotein (GP) may play a critical role in determining ... | The family Filoviridae, within the order Mononegavirales, contains two genera, Marburgvirus and Ebolavirus (EBOV), with EBOV being currently divided into the species Zaire ebolavirus (ZEBOV), Sudan ebolavirus, TaΪ Forest ebolavirus and Reston ebolavirus (REBOV) [1]. In addition, Bundibugyo ebolavirus is also being prop... |
10.1371/journal.ppat.1002575 | In Situ Microscopy Analysis Reveals Local Innate Immune Response Developed around Brucella Infected Cells in Resistant and Susceptible Mice | Brucella are facultative intracellular bacteria that chronically infect humans and animals causing brucellosis. Brucella are able to invade and replicate in a broad range of cell lines in vitro, however the cells supporting bacterial growth in vivo are largely unknown. In order to identify these, we used a Brucella mel... | Brucella are facultative intracellular bacteria chronically infecting humans and animals causing brucellosis, one of the most common zoonotic disease worldwide which can result in infertility and chronic debilitating disease. The cells supporting Brucella growth in vivo remain largely unknown. In order to identify thes... | Brucella (α-proteobacteria) are facultative intracellular Gram-negative coccobacilli that infect humans as well as domestic (goat, sheep, swine, etc.) and wild type mammals. Animal infection leads to abortion and infertility with dramatic economic costs. Brucellosis is mainly transmitted to humans through the ingestion... |
10.1371/journal.pgen.1002460 | Cohesin Protects Genes against γH2AX Induced by DNA Double-Strand Breaks | Chromatin undergoes major remodeling around DNA double-strand breaks (DSB) to promote repair and DNA damage response (DDR) activation. We recently reported a high-resolution map of γH2AX around multiple breaks on the human genome, using a new cell-based DSB inducible system. In an attempt to further characterize the ch... | Genomic stability requires that deleterious events such as DNA double-strand breaks (DSBs) are precisely repaired. The natural compaction of DNA into chromatin hinders DNA accessibility and break detection. Therefore, cells respond to DSBs by triggering multiple chromatin modifications that promote accessibility and fa... | DNA packaging into chromatin hinders detection and repair of DNA Double Strand Breaks (DSBs), and therefore DSB repair occurs simultaneously with multiple chromatin modifications, including histone acetylation, ubiquitylation and phosphorylation, as well as ATP dependant nucleosome remodelling and chromatin protein dep... |
10.1371/journal.pgen.1004625 | BMPs Regulate msx Gene Expression in the Dorsal Neuroectoderm of Drosophila and Vertebrates by Distinct Mechanisms | In a broad variety of bilaterian species the trunk central nervous system (CNS) derives from three primary rows of neuroblasts. The fates of these neural progenitor cells are determined in part by three conserved transcription factors: vnd/nkx2.2, ind/gsh and msh/msx in Drosophila melanogaster/vertebrates, which are ex... | The trunk nervous system of both vertebrates and invertebrates develops from three primary rows of neural stem cells whose fate is determined by neural identity genes expressed in an evolutionarily conserved dorso-ventral pattern. Establishment of this pattern requires a shared signaling pathway in both groups of anima... | In both Drosophila melanogaster and vertebrates, Bone Morphogenetic Proteins (BMPs) are expressed in the epidermal ectoderm abutting the dorsal border of the neuroectoderm [1]. The genetic network that underlies formation of a centralized nervous system consisting of segregated motor and sensory centers appears to have... |
10.1371/journal.pgen.1005676 | Ectodysplasin/NF-κB Promotes Mammary Cell Fate via Wnt/β-catenin Pathway | Mammary gland development commences during embryogenesis with the establishment of a species typical number of mammary primordia on each flank of the embryo. It is thought that mammary cell fate can only be induced along the mammary line, a narrow region of the ventro-lateral skin running from the axilla to the groin. ... | Mammary glands are the most characteristic feature of all mammals. The successful growth and function of the mammary glands is vital for the survival of offspring since the secreted milk is the main nutritional source of a new-born. Ectodysplasin (Eda) is a signaling molecule that regulates the formation of skin append... | The murine mammary gland development initiates at around embryonic day 10.5 (E10.5) with the establishment of bilateral milk or mammary lines [1]. Between E11-E12, five pairs of mammary placodes, local thickenings of the epithelium, emerge at conserved positions. By E13.5, the placodes have transformed via hillock stag... |
10.1371/journal.pgen.1008119 | Temporal genomic contrasts reveal rapid evolutionary responses in an alpine mammal during recent climate change | Many species have experienced dramatic changes in their abundance and distribution during recent climate change, but it is often unclear whether such ecological responses are accompanied by evolutionary change. We used targeted exon sequencing of 294 museum specimens (160 historic, 134 modern) to generate independent t... | Museum specimens represent an irreplaceable archive that can be used to understand how species respond to rapid environmental change. We recovered genomic data from archived samples spanning a century of climate change in co-distributed declining versus stable species of montane chipmunks. Applying novel statistical me... | Rapid environmental change threatens global biodiversity and has led to population declines in many species [1–5]. Although phenotypic plasticity may enable populations to track rapidly changing climates, evolutionary adaptation will often be essential for long-term persistence [6]. Disentangling plasticity from evolut... |
10.1371/journal.pntd.0001726 | Efficacy of Praziquantel against Schistosoma mekongi and Opisthorchis viverrini: A Randomized, Single-Blinded Dose-Comparison Trial | Schistosomiasis and opisthorchiasis are of public health importance in Southeast Asia. Praziquantel (PZQ) is the drug of choice for morbidity control but few dose comparisons have been made.
Ninety-three schoolchildren were enrolled in an area of Lao PDR where Schistosoma mekongi and Opisthorchis viverrini coexist for ... | Parasitic worm infections are of public health importance in Southeast Asia. Particularly, the blood-dwelling Schistosoma mekongi worm, which is acquired by skin contact with the infectious cercariae in freshwater, can lead to liver enlargement. An infection with Opisthorchis viverrini is obtained by consumption of und... | Schistosomiasis, food-borne trematodiasis, and soil-transmitted helminthiasis are neglected tropical diseases that are of considerable public health relevance in Southeast Asia [1]. In Lao People's Democratic Republic (Lao PDR), approximately 80,000 individuals are at risk for schistosomiasis mekongi, 2 million individ... |
10.1371/journal.pgen.1002617 | The Caenorhabditis elegans HEN1 Ortholog, HENN-1, Methylates and Stabilizes Select Subclasses of Germline Small RNAs | Small RNAs regulate diverse biological processes by directing effector proteins called Argonautes to silence complementary mRNAs. Maturation of some classes of small RNAs involves terminal 2′-O-methylation to prevent degradation. This modification is catalyzed by members of the conserved HEN1 RNA methyltransferase fami... | Small RNAs serve as sentinels of the genome, policing activity of selfish genetic elements, modulating chromatin dynamics, and fine-tuning gene expression. Nowhere is this more important than in the germline, where endogenous small interfering RNAs (endo-siRNAs) and Piwi-interacting RNAs (piRNAs) promote formation of f... | Argonautes are an evolutionarily conserved family of proteins implicated in diverse cellular processes. They function as effector proteins in the RNA-induced silencing complex (RISC), a gene regulatory complex that binds small, non-coding RNAs to target its silencing effects. Small RNAs are broadly segregated into grou... |
10.1371/journal.pntd.0003725 | Overexpression of Cytoplasmic TcSIR2RP1 and Mitochondrial TcSIR2RP3 Impacts on Trypanosoma cruzi Growth and Cell Invasion | Trypanosoma cruzi is a protozoan pathogen responsible for Chagas disease. Current therapies are inadequate because of their severe host toxicity and numerous side effects. The identification of new biotargets is essential for the development of more efficient therapeutic alternatives. Inhibition of sirtuins from Trypan... | Sirtuins are a family of deacetylases, evolutionary conserved from bacteria to mammals. They participate in the regulation of a wide range of nuclear, cytoplasmic and mitochondrial pathways, and are considered pro-life enzymes. In the last years the search for sirtuin inhibitors was a very active field of research, wit... | Acetylation is a ubiquitous protein modification present in prokaryotic and eukaryotic cells that participates in the regulation of many cellular processes. A limited set of acetyltransferases and deacetylases, and of the acetyl-lysine “reading” domain (bromodomain) are the principal components of the acetylation/deace... |
10.1371/journal.pcbi.1000133 | Stroke Rehabilitation Reaches a Threshold | Motor training with the upper limb affected by stroke partially reverses the loss of cortical representation after lesion and has been proposed to increase spontaneous arm use. Moreover, repeated attempts to use the affected hand in daily activities create a form of practice that can potentially lead to further improve... | Stroke often leaves patients with predominantly unilateral functional limitations of the arm and hand. Although recovery of function after stroke is often achieved by compensatory use of the less affected limb, improving use of the more affected limb has been associated with increased quality of life. Here, we develope... | Stroke is the leading cause of disability in the US, and about 65% of stroke survivors experience long-term upper extremity functional limitations [1]. Although patients may regain some motor functions in the months following stroke due to spontaneous recovery, stroke often leaves patients with predominantly unilateral... |
10.1371/journal.pgen.1000917 | Hypomethylation of a LINE-1 Promoter Activates an Alternate Transcript of the MET Oncogene in Bladders with Cancer | It was recently shown that a large portion of the human transcriptome can originate from within repetitive elements, leading to ectopic expression of protein-coding genes. However the mechanism of transcriptional activation of repetitive elements has not been definitively elucidated. For the first time, we directly dem... | A surprisingly large portion of our transcriptome originates within repetitive elements, most commonly LINE-1s. However, the mechanism of activation has not been definitively shown. We directly demonstrate for the first time the causal relationship between DNA hypomethylation and transcriptional activation of LINE-1 pr... | Aberrant DNA methylation is involved in the initiation and progression of carcinogenesis and includes both hypermethylation of CpG islands at gene promoters and global hypomethylation. While a small portion of hypomethylation occurs at gene promoters, resulting in overexpression of certain oncogenes [1], [2], the major... |
10.1371/journal.pcbi.0030200 | Landscape as a Model: The Importance of Geometry | In all models, but especially in those used to predict uncertain processes (e.g., climate change and nonnative species establishment), it is important to identify and remove any sources of bias that may confound results. This is critical in models designed to help support decisionmaking. The geometry used to represent ... | Many different areas of science try to simulate and predict (model) how processes act across virtual landscapes. Sometimes these models are abstract, but often they are based on real-world landscapes and are used to make real-world planning or management decisions. We considered two separate issues: how movement occurs... | The focus of this study is spatially explicit predictive models designed to support decisionmaking (e.g., population establishment and spread, climate change, and flood risk), which should have reliable, probabilistic, and mappable results. In cases in which there are few relevant validation data (e.g., nonnative speci... |
10.1371/journal.pcbi.1007150 | Integrative modeling of the HIV-1 ribonucleoprotein complex | A coarse-grain computational method integrates biophysical and structural data to generate models of HIV-1 genomic RNA, nucleocapsid and integrase condensed into a mature ribonucleoprotein complex. Several hypotheses for the initial structure of the genomic RNA and oligomeric state of integrase are tested. In these mod... | The genome of HIV-1 is composed of two strands of RNA that are packaged in the mature virion as a condensed ribonucleoprotein complex with nucleocapsid, integrase, and other proteins. We have generated models of the HIV-1 ribonucleoprotein that integrate experimental results from multiple structural and biophysical exp... | Electron microscopy of mature HIV-1 shows a condensed ribonucleoprotein (RNP) complex [1] packaged within the cone-shaped capsid, which is thought to include genomic RNA, nucleocapsid, integrase, transfer RNA, reverse transcriptase, and other components [2]. It is formed through a complex, multistep process where genom... |
10.1371/journal.pcbi.1000562 | Discovery of Regulatory Elements is Improved by a Discriminatory Approach | A major goal in post-genome biology is the complete mapping of the gene regulatory networks for every organism. Identification of regulatory elements is a prerequisite for realizing this ambitious goal. A common problem is finding regulatory patterns in promoters of a group of co-expressed genes, but contemporary metho... | In the years following the sequencing of the human genome focus have shifted towards trying to understand how this blueprint results in the diversity of cells that we observe. Part of the answer lies in the regulation of transcription and how the proteins responsible for this recognize where they should attach to the D... | The rapid emergence of experimental techniques that can probe for functional elements at whole-genome scales[1] necessitates computational methods to analyze data in these settings. In particular, methods that locate promoters or measure gene expression on genome-wide scales (e.g. [2],[3]) must be complemented by algor... |
10.1371/journal.pmed.1002463 | Treatment eligibility and retention in clinical HIV care: A regression discontinuity study in South Africa | Loss to follow-up is high among HIV patients not yet receiving antiretroviral therapy (ART). Clinical trials have demonstrated the clinical efficacy of early ART; however, these trials may miss an important real-world consequence of providing ART at diagnosis: its impact on retention in care.
We examined the effect of ... | Starting antiretroviral therapy (ART) at HIV diagnosis has health benefits relative to deferring therapy.
Understanding the magnitude of these benefits is important for countries expanding treatment eligibility.
Clinical trials may underestimate the real-world benefits of immediate ART, because in such trials, patients... | Mass provision of HIV treatment has improved life expectancy in southern Africa [1–3], yet HIV remains the leading cause of death and disability [4]. Recent clinical trials show health benefits to antiretroviral therapy (ART) at high CD4 counts [5–7]; WHO now recommends starting HIV patients on ART at diagnosis [8], an... |
10.1371/journal.pntd.0006159 | Barriers of attendance to dog rabies static point vaccination clinics in Blantyre, Malawi | Rabies is a devastating yet preventable disease that causes around 59,000 human deaths annually. Almost all human rabies cases are caused by bites from rabies-infected dogs. A large proportion of these cases occur in Sub Saharan Africa (SSA). Annual vaccination of at least 70% of the dog population is recommended by th... | Rabies is a devastating yet preventable disease that causes around 59,000 human deaths annually of which a large proportion occurs in Sub Saharan Africa (SSA). In order to eliminate rabies, annual vaccination of at least 70% of the dog population is recommended. In SSA most rabies vaccination programmes use static poin... | Rabies has been estimated to cause around 59,000 human deaths per year [1]. Globally, rabies has been estimated to cause 3.7 million disability-adjusted life years and 8.6 billion US dollars economic losses annually [1]. Almost all human rabies cases are acquired from contact with rabies infected dogs [2]. Case fatalit... |
10.1371/journal.pcbi.1003360 | Dimensionality of Carbon Nanomaterials Determines the Binding and Dynamics of Amyloidogenic Peptides: Multiscale Theoretical Simulations | Experimental studies have demonstrated that nanoparticles can affect the rate of protein self-assembly, possibly interfering with the development of protein misfolding diseases such as Alzheimer's, Parkinson's and prion disease caused by aggregation and fibril formation of amyloid-prone proteins. We employ classical mo... | Investigation of the effects of nanomaterials on biological systems is crucial due to the increasing exposure to nanostructured materials with the growing developments and applications of nanotechnology in everyday life. Nanoparticles have been shown to have an effect on protein structure and interfere with protein sel... | The fast-developing field of nanotechnology has already had a significant impact in numerous areas of science and technology due to the ability to control the properties of nanomaterials with greater precision [1]–[3]. Despite the remarkable speed of developments in nanoscience, little is known about the effects of nan... |
10.1371/journal.pcbi.1003524 | Computational Analyses of Synergism in Small Molecular Network Motifs | Cellular functions and responses to stimuli are controlled by complex regulatory networks that comprise a large diversity of molecular components and their interactions. However, achieving an intuitive understanding of the dynamical properties and responses to stimuli of these networks is hampered by their large scale ... | Cellular responses to stimuli are controlled by complex regulatory networks that comprise many molecular components. Understanding such networks is critical for understanding normal cellular functions and pathological conditions. Because the complexity of these networks often precludes intuitive insights, a useful appr... | Cellular functions are regulated by complex biochemical networks that incorporate large numbers of diverse molecular components and their interactions. The large scale and complexity of these regulatory networks impedes achieving an intuitive understanding of their overall function and responses to stimuli and/or drugs... |
10.1371/journal.pntd.0002504 | Diagnostic Accuracy of Loopamp Trypanosoma brucei Detection Kit for Diagnosis of Human African Trypanosomiasis in Clinical Samples | Molecular methods have great potential for sensitive parasite detection in the diagnosis of human African trypanosomiasis (HAT), but the requirements in terms of laboratory infrastructure limit their use to reference centres. A recently developed assay detects the Trypanozoon repetitive insertion mobile element (RIME) ... | Diagnosis and effective treatment are cornerstones in the control of human African trypanosomiasis (HAT). Molecular tools such as the polymerase chain reaction (PCR) detect the parasite's DNA and are generally very sensitive and specific. However, PCR is not applicable in field settings because it requires a laboratory... | Human African trypanosomiasis (HAT) is a protozoan disease caused by the Trypanosoma brucei species, which are cyclically transmitted by tsetse flies. Two subspecies are pathogenic to man: Trypanosoma brucei (T.b.) gambiense in central and western Africa, and Trypanosoma brucei rhodesiense in east and southern Africa [... |
10.1371/journal.pcbi.1003269 | Catalysis of Protein Folding by Chaperones Accelerates Evolutionary Dynamics in Adapting Cell Populations | Although molecular chaperones are essential components of protein homeostatic machinery, their mechanism of action and impact on adaptation and evolutionary dynamics remain controversial. Here we developed a physics-based ab initio multi-scale model of a living cell for population dynamics simulations to elucidate the ... | Molecular chaperones or heat-shock proteins are essential components of protein homeostatic machinery in all three domains of life, whose role is not only to prevent protein aggregation but also catalyze the protein folding process by decreasing the energetic barrier for folding. Importantly, chaperones have often been... | Evolutionary selection of protein sequences is a complex task whereby several traits such as translation efficiency, structural integrity (i.e. folding stability and kinetics), molecular function, as well as interactions with other proteins in the cellular milieu should be simultaneously optimized. Imposing simultaneou... |
10.1371/journal.pgen.1005528 | Ty3 Retrotransposon Hijacks Mating Yeast RNA Processing Bodies to Infect New Genomes | Retrotransposition of the budding yeast long terminal repeat retrotransposon Ty3 is activated during mating. In this study, proteins that associate with Ty3 Gag3 capsid protein during virus-like particle (VLP) assembly were identified by mass spectrometry and screened for roles in mating-stimulated retrotransposition. ... | Cells undergoing changes in gene expression programs such as nutritional deprivation and other stresses exhibit formation of ribonucleoprotein (RNP) complexes. In Saccharomyces cerevisiae, the majority of investigations to date involve analysis of P-body (PB) and stress-granule RNP formation following nutritional stres... | RNA processing bodies (PB) are ribonucleoprotein (RNP) granules that contain proteins associated with cytoplasmic deadenylation, decapping and 5’ to 3’ degradation of RNAs in eukaryotic cells [reviewed in [1–5]]. In previous work we showed that artificial overexpression of the long-terminal-repeat retrotransposon Ty3 i... |
10.1371/journal.pgen.1002020 | Towards Establishment of a Rice Stress Response Interactome | Rice (Oryza sativa) is a staple food for more than half the world and a model for studies of monocotyledonous species, which include cereal crops and candidate bioenergy grasses. A major limitation of crop production is imposed by a suite of abiotic and biotic stresses resulting in 30%–60% yield losses globally each ye... | A major limitation of crop production is imposed by a suite of abiotic and biotic stresses resulting in 30%–60% yield losses globally each year. In this paper, we used a yeast-based approach to identify rice proteins that govern the rice stress response. We validated the role of these new proteins using additional anal... | A major limitation of crop production is imposed by a suite of abiotic and biotic stresses resulting in 30%–60% yield losses globally each year [1]. The burgeoning field of systems biology provides new methodologies to make sense of plant stress responses, which are often controlled by highly complex signal transductio... |
10.1371/journal.pbio.2005594 | The mammalian decidual cell evolved from a cellular stress response | Among animal species, cell types vary greatly in terms of number and kind. The number of cell types found within an organism differs considerably between species, and cell type diversity is a significant contributor to differences in organismal structure and function. These observations suggest that cell type originati... | Animals consist of a wide variety of cells that serve different functions depending on their location in the body. Cells with similar functions, or cell types, in different animal species are related both by an evolutionary line of descent—similar to the relatedness of species themselves—and by a developmental line of ... | Multicellular organisms consist of numerous specialized cells, or cell types, that play an important role in the structural and functional diversity of organisms. Evolutionary diversification of cell types in metazoans has been a significant source of novelty and was essential to the elaboration of increasingly complex... |
10.1371/journal.ppat.1002142 | Novel Chikungunya Vaccine Candidate with an IRES-Based Attenuation and Host Range Alteration Mechanism | Chikungunya virus (CHIKV) is a reemerging mosquito-borne pathogen that has recently caused devastating urban epidemics of severe and sometimes chronic arthralgia. As with most other mosquito-borne viral diseases, control relies on reducing mosquito populations and their contact with people, which has been ineffective i... | Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has reemerged since 2004 to cause millions of cases of severe and often persistent arthralgia. Because no licensed vaccine exists to prevent this disease, we utilized an attenuation approach to produce a live CHIKV vaccine candidate that elicits a robust, pr... | Chikungunya (CHIK) virus (CHIKV) is a reemerging arboviral pathogen that has recently caused explosive urban outbreaks involving millions of persons in Africa and Asia. The virus was first isolated from a human in Tanzania in 1953 during a major epidemic [1], and derives its name from a Makonde word meaning “that which... |
10.1371/journal.pntd.0002952 | Variability in Dengue Titer Estimates from Plaque Reduction Neutralization Tests Poses a Challenge to Epidemiological Studies and Vaccine Development | Accurate determination of neutralization antibody titers supports epidemiological studies of dengue virus transmission and vaccine trials. Neutralization titers measured using the plaque reduction neutralization test (PRNT) are believed to provide a key measure of immunity to dengue viruses, however, the assay's variab... | Plaque Reduction Neutralization Tests (PRNTs) remain the most popular approach to characterize an individual's ability to neutralize dengue viruses and are widely used in both epidemiological studies and vaccine trials. However, the underlying variability in the assay is poorly understood, hindering the interpretation ... | Dengue remains a substantial public health problem in tropical and subtropical regions [1]. All four serotypes of the mosquito-borne virus are capable of producing significant morbidity and death [2]. As part of efforts to monitor and control the disease, public health agencies and vaccine developers use serological me... |
10.1371/journal.pbio.2002842 | Deconstructing the principles of ductal network formation in the pancreas | The mammalian pancreas is a branched organ that does not exhibit stereotypic branching patterns, similarly to most other glands. Inside branches, it contains a network of ducts that undergo a transition from unconnected microlumen to a mesh of interconnected ducts and finally to a treelike structure. This ductal remode... | In the pancreas of mammals, digestive enzymes are transported from their production site in acini (clusters of cells that secrete the enzymes) to the intestine via a network of ducts. During organ development in fetuses, the ducts initially form by the coordinated polarization of cells to form small holes, which will c... | Branching is a phenomenon that appears everywhere in life. Biological examples include tree leaves and branches [1], the arterial and venous systems [2], the liver [3], lung [4,5], kidney, and several glands such as the pancreas, the mammary [6], salivary [7], lacrimal [8], prostate [9], and meibomian glands [10]. Work... |
10.1371/journal.ppat.1005507 | Promotion of Expansion and Differentiation of Hematopoietic Stem Cells by Interleukin-27 into Myeloid Progenitors to Control Infection in Emergency Myelopoiesis | Emergency myelopoiesis is inflammation-induced hematopoiesis to replenish myeloid cells in the periphery, which is critical to control the infection with pathogens. Previously, pro-inflammatory cytokines such as interferon (IFN)-α and IFN-γ were demonstrated to play a critical role in the expansion of hematopoietic ste... | Emergency myelopoiesis is inflammation-induced hematopoiesis that is critical for controlling infection with pathogens, but the molecular mechanism remains incompletely understood. Here, we clarify that one of the interleukin (IL)-6/IL-12 family cytokines, IL-27, plays an important role in emergency myelopoiesis. Among... | Emergency myelopoiesis is inflammation-induced hematopoiesis, which is critical for controlling systemic infection with pathogens such as a virus, bacteria, or parasite [1,2]. In contrast to adaptive immune cells such as T cells and B cells, which can vigorously proliferate in response to their specific antigens, innat... |
10.1371/journal.pgen.1004253 | Ras GTPase-Like Protein MglA, a Controller of Bacterial Social-Motility in Myxobacteria, Has Evolved to Control Bacterial Predation by Bdellovibrio | Bdellovibrio bacteriovorus invade Gram-negative bacteria in a predatory process requiring Type IV pili (T4P) at a single invasive pole, and also glide on surfaces to locate prey. Ras-like G-protein MglA, working with MglB and RomR in the deltaproteobacterium Myxococcus xanthus, regulates adventurous gliding and T4P-med... | Bacterial cell polarity control is important for maintaining asymmetry of polar components such as flagella and pili. Bdellovibrio bacteriovorus is a predatory deltaproteobacterium which attaches to, and invades, other bacteria using Type IV pili (T4P) extruded from the specialised, invasive, non-flagellar pole of the ... | Bdellovibrio bacteriovorus is a small, predatory deltaproteobacterium which invades other Gram-negative bacteria wherein it replicates. Bdellovibrio can encounter their prey by fast motility, driven by rotation of a single flagellum in liquid environments [1], [2], or by slow gliding motility on solid surfaces [3], but... |
10.1371/journal.pntd.0002032 | African Programme for Onchocerciasis Control 1995–2015: Model-Estimated Health Impact and Cost | Onchocerciasis causes a considerable disease burden in Africa, mainly through skin and eye disease. Since 1995, the African Programme for Onchocerciasis Control (APOC) has coordinated annual mass treatment with ivermectin in 16 countries. In this study, we estimate the health impact of APOC and the associated costs fro... | In 1995, the World Health Organization launched the African Programme for Onchocerciasis Control (APOC) with the aim to control morbidity due to the parasitic infectious disease onchocerciasis (river blindness). APOC aims to set up sustainable national control programs against onchocerciasis in 16 countries in sub-Saha... | Onchocerciasis is caused by Onchocerca volvulus, a filarial nematode restricted to human hosts. The adult female worms reside in subcutaneous nodules where they produce millions of microfilariae during their on-average ten-year life span [1]. The microfilariae are found predominantly migrating through the skin and eyes... |
10.1371/journal.ppat.1002896 | CPSF6 Defines a Conserved Capsid Interface that Modulates HIV-1 Replication | The HIV-1 genome enters cells inside a shell comprised of capsid (CA) protein. Variation in CA sequence alters HIV-1 infectivity and escape from host restriction factors. However, apart from the Cyclophilin A-binding loop, CA has no known interfaces with which to interact with cellular cofactors. Here we describe a nov... | In order to infect a host cell, HIV-1 must interact with and exploit cellular cofactors. Mutations within capsid, the protein shell that surrounds the virus, have been shown to affect virus usage of these cofactors and susceptibility to host antiviral proteins. However, with the exception of the Cyclophilin A-binding l... | The HIV-1 genome enters target cells encapsulated in a fullerene capsid cone composed of capsid (CA) protein. The role of the capsid in early events of the HIV-1 replication cycle is not known, nor is it clear exactly how long the capsid remains associated with the infectious particle, or where the capsid disassembles.... |
10.1371/journal.pgen.1006040 | Testing Rare-Variant Association without Calling Genotypes Allows for Systematic Differences in Sequencing between Cases and Controls | Next-generation sequencing of DNA provides an unprecedented opportunity to discover rare genetic variants associated with complex diseases and traits. However, the common practice of first calling underlying genotypes and then treating the called values as known is prone to false positive findings, especially when geno... | In next-generation sequencing studies, there are typically systematic differences in sequencing qualities (e.g., depth) between cases and controls, because the entire studies are rarely sequenced in exactly the same way. It has long been appreciated that, in the presence of such differences, the standard genotype calli... | Recent technological advances in next-generation sequencing (NGS) have made it possible to conduct association studies on rare variants, which hold great potential to explain the missing heritability of complex traits and diseases [1]. However, it is prohibitively expensive to conduct high-depth, whole-genome sequencin... |
10.1371/journal.pntd.0006071 | A temporal comparison of sex-aggregation pheromone gland content and dynamics of release in three members of the Lutzomyia longipalpis (Diptera: Psychodidae) species complex | Lutzomyia longipalpis is the South American vector of Leishmania infantum, the etiologic agent of visceral leishmaniasis (VL). Male L. longipalpis produce a sex-aggregation pheromone that is critical in mating, yet very little is known about its accumulation over time or factors involved in release. This laboratory stu... | The Dipteran subfamily Phlebotominae includes the genera Lutzomyia and Phlebotomus among which several species are important vectors of parasitic and bacterial pathogens. The sand fly Lutzomyia longipalpis is considered the main vector of visceral leishmaniasis (VL) in the New World. Based on the main component of the ... | There are over 800 known phlebotomine sand fly species, but only approximately 56 Lutzomyia and Phlebotomus species are proven or suspected vectors of human leishmaniasis [1]. Among them, L. longipalpis is the primary vector of Leishmania infantum, the etiological agent of visceral leishmaniasis (VL) in the Americas [2... |
10.1371/journal.pntd.0002119 | Activity of Oxantel Pamoate Monotherapy and Combination Chemotherapy against Trichuris muris and Hookworms: Revival of an Old Drug | It is widely recognized that only a handful of drugs are available against soil-transmitted helminthiasis, all of which are characterized by a low efficacy against Trichuris trichiura, when administered as single doses. The re-evaluation of old, forgotten drugs is a promising strategy to identify alternative anthelmint... | The roundworm Ascaris lumbricoides, the whipworm Trichuris trichiura and the two hookworm species Ancylostoma duodenale and Necator americanus are responsible for the most common infections worldwide and place more than 5 billion people at risk. To control these infections, at risk populations are treated regularly wit... | Infections with the three major soil-transmitted helminth (STH) species, Ascaris lumbricoides, Trichuris trichiura and the hookworms Necator americanus and Ancylostoma duodenale are among the most common parasitic diseases in areas of rural poverty in developing countries [1]. In regions where soil-transmitted helminth... |
10.1371/journal.pntd.0007369 | Tracing the environmental footprint of the Burkholderia pseudomallei lipopolysaccharide genotypes in the tropical “Top End” of the Northern Territory, Australia | The Tier 1 select agent Burkholderia pseudomallei is an environmental bacterium that causes melioidosis, a high mortality disease. Variably present genetic markers used to elucidate strain origin, relatedness and virulence in B. pseudomallei include the Burkholderia intracellular motility factor A (bimA) and filamentou... | Burkholderia pseudomallei is a pathogenic soil bacterium that causes the disease melioidosis, which occurs in many tropical regions globally and in recent years has emerged in non-tropical regions. Melioidosis has been predicted to affect 165,000 people every year resulting in an estimated 89,000 deaths. Person to pers... | Burkholderia pseudomallei is the causative agent of melioidosis, an often fatal disease that is endemic in tropical regions globally, including the “Top End” of the Northern Territory, Australia [1]. Clinical presentations of melioidosis are highly varied [2–5] with pneumonia being the most common presentation [6]. Mel... |
10.1371/journal.ppat.1003761 | The Type-Specific Neutralizing Antibody Response Elicited by a Dengue Vaccine Candidate Is Focused on Two Amino Acids of the Envelope Protein | Dengue viruses are mosquito-borne flaviviruses that circulate in nature as four distinct serotypes (DENV1-4). These emerging pathogens are responsible for more than 100 million human infections annually. Severe clinical manifestations of disease are predominantly associated with a secondary infection by a heterotypic D... | Despite decades of research, there remains a critical need for a dengue virus (DENV) vaccine. Vaccine development efforts are complicated by a requirement to protect against four DENV serotypes (DENV1-4), and incomplete immunity as a risk factor for severe disease. Antibodies play a major protective role against DENV. ... | Dengue virus (DENV) is a mosquito-transmitted flavivirus responsible for 390 million human infections each year [1]. Four related serotypes (DENV1-4) circulate in virtually all tropical and sub-tropical regions of the world [2]. While DENV infection is often subclinical, clinical symptoms of dengue fever (DF) include a... |
10.1371/journal.pntd.0003404 | Genome and Phylogenetic Analyses of Trypanosoma evansi Reveal Extensive Similarity to T. brucei and Multiple Independent Origins for Dyskinetoplasty | Two key biological features distinguish Trypanosoma evansi from the T. brucei group: independence from the tsetse fly as obligatory vector, and independence from the need for functional mitochondrial DNA (kinetoplast or kDNA). In an effort to better understand the molecular causes and consequences of these differences,... | The single-cell parasite Trypanosoma evansi is the disease-causing trypanosome with the widest geographical distribution. The disease, called surra, has significant economic impact primarily due to infections of cattle, horses, and camels. Morphologically the parasite is indistinguishable from bloodstream stage T. bruc... | Trypanosomatid parasites Trypanosoma evansi and T. equiperdum are responsible for animal diseases with extensive pathological and economic impact and closely related to the T. brucei group [1], [2]. The latter includes three subspecies: the human parasite T. b. rhodesiense, the zoonotic parasite T. b. gambiense, and th... |
10.1371/journal.pgen.1007212 | Genetic compensation triggered by actin mutation prevents the muscle damage caused by loss of actin protein | The lack of a mutant phenotype in homozygous mutant individuals’ due to compensatory gene expression triggered upstream of protein function has been identified as genetic compensation. Whilst this intriguing process has been recognized in zebrafish, the presence of homozygous loss of function mutations in healthy human... | Many healthy individuals carry loss of function mutations in essential genes that would normally be deleterious for survival. Intriguingly, it may be the presence of the genomic lesion itself in these individuals that triggers the compensatory pathways. It is not known how widespread this phenomenon is in vertebrate po... | Genetic compensation exists as a mechanism to buffer the organism against gene loss that would otherwise be deleterious to survival. Whilst this term has been used to describe dosage compensation, evolution resulting in reversion to ancestral phenotypes, and gene duplication compensating for mutation, in the present st... |
10.1371/journal.ppat.1006026 | Transcriptomic Analysis Implicates the p53 Signaling Pathway in the Establishment of HIV-1 Latency in Central Memory CD4 T Cells in an In Vitro Model | The search for an HIV-1 cure has been greatly hindered by the presence of a viral reservoir that persists despite antiretroviral therapy (ART). Studies of HIV-1 latency in vivo are also complicated by the low proportion of latently infected cells in HIV-1 infected individuals. A number of models of HIV-1 latency have b... | The major hindrance to an HIV cure is the ability of the virus to persist in a latent state despite antiretroviral therapy. It is difficult to study this latent state in the HIV-infected patient because only a small proportion of cells in the body are affected and current technologies are not able to identify these cel... | A major obstacle to the eradication of HIV-1 is the persistence of the latent viral reservoir. While antiretroviral therapy (ART) has been extremely effective at suppressing viral replication, it has not eradicated this reservoir [1]. Upon the removal of ART, HIV-1 emerges from the latent state and replicates to levels... |
10.1371/journal.pcbi.1002054 | A Role for Both Conformational Selection and Induced Fit in Ligand Binding by the LAO Protein | Molecular recognition is determined by the structure and dynamics of both a protein and its ligand, but it is difficult to directly assess the role of each of these players. In this study, we use Markov State Models (MSMs) built from atomistic simulations to elucidate the mechanism by which the Lysine-, Arginine-, Orni... | Protein-ligand interactions are crucial to chemistry, biology and medicine. Many studies have been conducted to probe the mechanism of protein-ligand binding, leading to the development of the induced fit and conformational selection models. Unfortunately, experimentally probing the atomistic details of protein-ligand ... | Molecular recognition plays important roles in many biological processes. For example, enzymes must recognize their substrates and drugs must be designed to have specific binding partners. Unfortunately, our understanding of how ligand binding occurs remains incomplete. In particular, the role that protein dynamics pla... |
10.1371/journal.pntd.0007417 | Oral immunization with a probiotic cholera vaccine induces broad protective immunity against Vibrio cholerae colonization and disease in mice | Oral cholera vaccines (OCVs) are being increasingly employed, but current killed formulations generally require multiple doses and lack efficacy in young children. We recently developed a new live-attenuated OCV candidate (HaitiV) derived from a Vibrio cholerae strain isolated during the 2010 Haiti cholera epidemic. Ha... | Oral cholera vaccines are increasingly used as public health tools for prevention of cholera and curtailing the spread of outbreaks. However, current killed vaccines provide minimal protection in young children, who are especially susceptible to this diarrheal disease, and require ~7–14 days between vaccination and dev... | The bacterial pathogen Vibrio cholerae causes the severe human diarrheal disease cholera, a potentially fatal illness characterized by rapid-onset of fluid loss and dehydration. Recent estimates place the global burden of cholera at ~3 million cases per year, and over 1.3 billion people are at risk of this disease [1].... |
10.1371/journal.pntd.0005123 | Blood Transcriptional Profiling Reveals Immunological Signatures of Distinct States of Infection of Humans with Leishmania infantum | Visceral leishmaniasis (VL) can be lethal if untreated; however, the majority of human infections with the etiological agents are asymptomatic. Using Illumina Bead Chip microarray technology, we investigated the patterns of gene expression in blood of active VL patients, asymptomatic infected individuals, patients unde... | Infections of humans with the protozoan parasites L. donvani and L. infantum can lead to the development of the disease visceral leishmaniasis, but also to an asymptomatic status. However, the mechanisms that result in these clinical outcomes after infection are poorly understood. In this study, we applied a data-drive... | Infections with the protozoan parasites Leishmania donovani or L. infantum (chagasi) result in clinical outcomes that range from asymptomatic infection to active visceral leishmaniasis (VL). When disease occurs, symptoms often include fever, hepatosplenomegaly, cachexia, pancytopenia and hypergammaglobulinemia [1], whi... |
10.1371/journal.pcbi.1002211 | Neural Dynamics as Sampling: A Model for Stochastic Computation in Recurrent Networks of Spiking Neurons | The organization of computations in networks of spiking neurons in the brain is still largely unknown, in particular in view of the inherently stochastic features of their firing activity and the experimentally observed trial-to-trial variability of neural systems in the brain. In principle there exists a powerful comp... | It is well-known that neurons communicate with short electric pulses, called action potentials or spikes. But how can spiking networks implement complex computations? Attempts to relate spiking network activity to results of deterministic computation steps, like the output bits of a processor in a digital computer, are... | Attempts to understand the organization of computations in the brain from the perspective of traditional, mostly deterministic, models of computation, such as attractor neural networks or Turing machines, have run into problems: Experimental data suggests that neurons, synapses, and neural systems are inherently stocha... |
10.1371/journal.pmed.1002223 | Master Regulators of Oncogenic KRAS Response in Pancreatic Cancer: An Integrative Network Biology Analysis | KRAS is the most frequently mutated gene in pancreatic ductal adenocarcinoma (PDAC), but the mechanisms underlying the transcriptional response to oncogenic KRAS are still not fully understood. We aimed to uncover transcription factors that regulate the transcriptional response of oncogenic KRAS in pancreatic cancer an... | Outcomes for patients diagnosed with pancreatic cancer are very poor because surgical approaches plus other current treatments are often inadequate to treat this disease.
Previous efforts have been made to subtype the disease in an effort to identify more clinically relevant groups for tailored treatment.
To improve on... | Pancreatic ductal adenocarcinoma (PDAC) is the most lethal human malignancy, with a 5-y survival of 4% [1]. There are very few treatment options, with the only chance of a cure being surgical resection if the tumour is detected at an early, confined stage. Chemotherapeutic options are used in the palliative setting but... |
10.1371/journal.pmed.1002898 | Early occupational intervention for people with low back pain in physically demanding jobs: A randomized clinical trial | Occupational medicine seeks to reduce sick leave; however, evidence for an add-on effect to usual care is sparse. The objective of the GOBACK trial was to test whether people with low back pain (LBP) in physically demanding jobs and at risk of sick leave gain additional benefit from a 3-month complex intervention that ... | Individuals with low back pain (LBP), especially those in physically demanding jobs, are at risk of taking sick leave.
The resultant loss of productivity adds to the already considerable socioeconomic burden of LBP.
While occupational medicine interventions can help to reduce sick leave, there is limited evidence avail... | The lifetime prevalence of low back pain (LBP) is about 70% [1]. In the US alone, an estimated $87 billion is spent annually on healthcare for individuals with back pain, which has been one of the fastest growing healthcare expenses [2]. Sick leave and productivity loss add to this considerable socioeconomic burden [3]... |
10.1371/journal.ppat.1007802 | Strength of T cell signaling regulates HIV-1 replication and establishment of latency | A major barrier to curing HIV-1 is the long-lived latent reservoir that supports re-emergence of HIV-1 upon treatment interruption. Targeting this reservoir will require mechanistic insights into the establishment and maintenance of HIV-1 latency. Whether T cell signaling at the time of HIV-1 infection influences produ... | Activation of CD4+ T cells facilitates HIV-1 infection; however, whether there are minimal signals required for the establishment of infection, replication, and latency has not been explored. To determine how T cell signaling influences HIV-1 infection and the generation of latently infected cells, we used chimeric ant... | HIV-1 persists in a transcriptionally silent latent state in long-lived memory T cells. Although antiretroviral therapies (ART) suppress HIV-1 replication, interruption of treatment results in rapid viral rebound. Therefore, HIV-1 patients must remain on ART indefinitely, despite long-term side effects, development of ... |
10.1371/journal.pntd.0004677 | The wMel Strain of Wolbachia Reduces Transmission of Chikungunya Virus in Aedes aegypti | New approaches to preventing chikungunya virus (CHIKV) are needed because current methods are limited to controlling mosquito populations, and they have not prevented the invasion of this virus into new locales, nor have they been sufficient to control the virus upon arrival. A promising candidate for arbovirus control... | New approaches to preventing chikungunya virus (CHIKV) infection are needed because the endemic range of this virus is expanding and because current methods are limited to controlling mosquito populations, and this approach has not effectively controlled this virus. A promising candidate for arbovirus control and preve... | Chikungunya virus (CHIKV; Togaviridae, Alphavirus) has recently re-emerged out of Africa and caused explosive outbreaks of arthritic disease in Southeast Asia, India, Europe and currently the Americas [1–4]. The current outbreak in the Americas is cause for great concern because CHIKV is spreading nearly uncontrolled w... |
10.1371/journal.pntd.0003636 | Validation of a Microsphere Immunoassay for Serological Leptospirosis Diagnosis in Human Serum by Comparison to the Current Gold Standard | A microsphere immunoassay (MIA) utilising Luminex xMap technology that is capable of determining leptospirosis IgG and IgM independently was developed. The MIA was validated using 200 human samples submitted for routine leptospirosis serology testing. The traditional microscopic agglutination (MAT) method (now 100 year... | Leptospirosis is a zoonotic disease caused by spirochaetes of the genus Leptospira and affects millions of people, worldwide, each year. Laboratory diagnosis of leptospirosis currently relies on methods that are flawed in many areas. Current methods are outdated, time consuming and expensive. They rely on a continuous ... | Leptospirosis is considered to be the most widespread zoonotic disease in the world [1] with clinical diagnosis proving challenging due to the non-specific nature of symptoms associated with the disease. There are some 300 leptospiral serovars belonging to a number of different serogroups. Currently there are 24 sero-g... |
10.1371/journal.pntd.0002180 | False Positivity of Non-Targeted Infections in Malaria Rapid Diagnostic Tests: The Case of Human African Trypanosomiasis | In endemic settings, diagnosis of malaria increasingly relies on the use of rapid diagnostic tests (RDTs). False positivity of such RDTs is poorly documented, although it is especially relevant in those infections that resemble malaria, such as human African trypanosomiasis (HAT). We therefore examined specificity of m... | Rapid diagnostic tests (RDT) for malaria are currently rolled-out as the backbone of parasite-based diagnosis, and their diagnostic accuracy is sufficiently high to substitute microscopy. One decade ago, attention has been given to occurrence of limited false positivity in a number of malaria RDTs, but false positivity... | Traditional diagnosis of malaria relies on microscopic detection of Plasmodium in thick blood films, which is labour-intensive, time-consuming and requires technical skills. Malaria rapid diagnostic tests (RDT) offer an attractive alternative for microscopy. They detect parasite antigens in blood through an antibody-an... |
10.1371/journal.pbio.2004867 | Dependence of innate lymphoid cell 1 development on NKp46 | NKp46, a natural killer (NK) cell–activating receptor, is involved in NK cell cytotoxicity against virus-infected cells or tumor cells. However, the role of NKp46 in other NKp46+ non-NK innate lymphoid cell (ILC) populations has not yet been characterized. Here, an NKp46 deficiency model of natural cytotoxicity recepto... | Group 1 innate lymphoid cells (ILCs) comprise two subsets: natural killer (NK) cells and ILC1s. Although NK cells and ILC1s are functionally distinct, a factor that regulates one subset but not the other has not been identified. In the current study, we discovered that NKp46, a marker expressed by both NK cells and ILC... | Natural cytotoxicity receptor NKp46, encoded by the Ncr1 gene, is a natural killer (NK) cell–activating receptor that plays roles in regulating the NK cell’s clearance of virus and rejection of tumor [1]. Following binding to its putative ligands, the receptor activates intracellular signaling through immune-receptor t... |
10.1371/journal.pgen.1005686 | Comparative Genomic Analyses of the Human NPHP1 Locus Reveal Complex Genomic Architecture and Its Regional Evolution in Primates | Many loci in the human genome harbor complex genomic structures that can result in susceptibility to genomic rearrangements leading to various genomic disorders. Nephronophthisis 1 (NPHP1, MIM# 256100) is an autosomal recessive disorder that can be caused by defects of NPHP1; the gene maps within the human 2q13 region ... | Genomic instability due to the intrinsic sequence architecture of the genome, such as low copy repeats (LCRs), is a major contributor to de novo mutations that can occur in the process of human genome evolution. LCRs can mediate genomic rearrangements associated with genomic disorders by acting as substrates for nonall... | Genomic instability is a major contributor to de novo mutations that can occur in the process of human genome evolution [1–3]. Genomic rearrangements can be mediated by various mechanisms, including nonallelic homologous recombination (NAHR), nonhomologous end joining, mobile element insertion (e.g. long interspersed e... |
10.1371/journal.pgen.1007914 | RPGRIP1L is required for stabilizing epidermal keratinocyte adhesion through regulating desmoglein endocytosis | Cilia-related proteins are believed to be involved in a broad range of cellular processes. Retinitis pigmentosa GTPase regulator interacting protein 1-like (RPGRIP1L) is a ciliary protein required for ciliogenesis in many cell types, including epidermal keratinocytes. Here we report that RPGRIP1L is also involved in th... | The desmosome is a type of intercellular junction, essential for cells to adhere to one another. Abnormalities in desmosomes can cause disorders in the hair, skin, and heart, some of which are severe or even fatal. Here, we discovered that RPGRIP1L, a protein known to regulate cilia formation and function, is essential... | Retinitis pigmentosa GTPase regulator interacting protein 1-like (RPGRIP1L, also known as NPHP8, MKS5, KIAA1005, or Ftm in mouse) is a transition zone protein that has important roles in regulating cilia formation and function [1–5]. Mutations in the RPGRIP1L gene cause Joubert syndrome (JBTS) and Meckel syndrome (MKS)... |
10.1371/journal.pntd.0001311 | Preexisting Japanese Encephalitis Virus Neutralizing Antibodies and Increased Symptomatic Dengue Illness in a School-Based Cohort in Thailand | Dengue viruses (DENVs) and Japanese encephalitis virus (JEV) have significant cross-reactivity in serological assays; the clinical implications of this remain undefined. An improved understanding of whether and how JEV immunity modulates the clinical outcome of DENV infection is important as large-scale DENV vaccine tr... | Dengue viruses (DENVs) and Japanese encephalitis virus (JEV) have significant cross-reactivity in serological assays, but the possible clinical implications of this remain poorly understood. Interactions between these flaviviruses are potentially important for public health because wild-type JEV continues to co-circula... | The dengue viruses (DENV) and Japanese encephalitis virus (JEV) are closely-related members of the virus family Flaviviridae. DENV and JEV co-circulate in the Indian subcontinent and in Southeast Asia, where they are important causes of human disease and mortality. The co-occurrence of JEV and DENV has been documented ... |
10.1371/journal.pbio.1000595 | Genome-Wide and Phase-Specific DNA-Binding Rhythms of BMAL1 Control Circadian Output Functions in Mouse Liver | The mammalian circadian clock uses interlocked negative feedback loops in which the heterodimeric basic helix-loop-helix transcription factor BMAL1/CLOCK is a master regulator. While there is prominent control of liver functions by the circadian clock, the detailed links between circadian regulators and downstream targ... | The circadian clock is a timing system that allows organisms to keep behavioral, physiological, and cellular rhythms in resonance with daily environmental cycles. In mammals, such clocks use transcriptional regulatory loops in which the heterodimeric transcription factor BMAL1/CLOCK plays a central role. While defects ... | Circadian clocks provide higher organisms with cell-autonomous and organ-based metronomes that control temporally gated and tissue-specific gene expression or metabolic programs [1]–[4]. In the liver, such programs have been implicated in detoxification [5], glucose homeostasis [6],[7], cholesterol biosynthesis [8],[9]... |
10.1371/journal.pntd.0001652 | Multispacer Sequence Typing Relapsing Fever Borreliae in Africa | In Africa, relapsing fevers are neglected arthropod-borne infections caused by closely related Borrelia species. They cause mild to deadly undifferentiated fever particularly severe in pregnant women. Lack of a tool to genotype these Borrelia organisms limits knowledge regarding their reservoirs and their epidemiology.... | In Africa, relapsing fevers are caused by four cultured species: Borrelia crocidurae, Borrelia duttonii, Borrelia hispanica and Borrelia recurrentis. These borreliae are transmitted by the bite of Ornithodoros soft ticks except for B. recurrentis which is transmitted by louse Pediculus humanus. They cause potentially u... | In Africa, relapsing fevers (RF) are arthropod-borne diseases caused by four cultured species Borrelia crocidurae, Borrelia duttonii, Borrelia hispanica and Borrelia recurrentis [1]. Transmission is by the bite of Ornithodoros soft ticks for the first three species whereas Pediculus humanus louse feces transmit B. recu... |
10.1371/journal.pntd.0007322 | Geographic shifts in Aedes aegypti habitat suitability in Ecuador using larval surveillance data and ecological niche modeling: Implications of climate change for public health vector control | Arboviral disease transmission by Aedes mosquitoes poses a major challenge to public health systems in Ecuador, where constraints on health services and resource allocation call for spatially informed management decisions. Employing a unique dataset of larval occurrence records provided by the Ecuadorian Ministry of He... | The yellow fever mosquito (Aedes aegypti) is a medically important vector of arboviral diseases in Ecuador, such as dengue fever and chikungunya. Managing Ae. aegypti is a challenge to public health agencies in Latin America, where the use of limited resources must be planned in an efficient, targeted manner. The spati... | Mosquito-borne disease transmission poses an ongoing challenge to global public health. This is especially true in much of Latin America, where arboviral disease management is complicated by the proliferation of mosquito vectors in tropical conditions, frequently coupled with limited resources for medical care and comp... |
10.1371/journal.pbio.1002039 | Composition, Formation, and Regulation of the Cytosolic C-ring, a Dynamic Component of the Type III Secretion Injectisome | Many gram-negative pathogens employ a type III secretion injectisome to translocate effector proteins into eukaryotic host cells. While the structure of the distal “needle complex” is well documented, the composition and role of the functionally important cytosolic complex remain less well understood. Using functional ... | The type III secretion system, also known as the injectisome, is a key virulence factor in many gram-negative bacteria, and is responsible for the transmission of bacterial proteins directly into host cells. While some elements of the system are well characterized, the cytosolic components involved in substrate recogni... | Bacteria that live in close contact with eukaryotic cells are frequently able to modulate host cell behavior. Various Gram-negative species employ a molecular syringe, the type III secretion system (T3SS) or injectisome [1, 2], to translocate effector proteins from the bacterial cytosol into the host cell. T3SSs are of... |
10.1371/journal.pntd.0005546 | Tiger on the prowl: Invasion history and spatio-temporal genetic structure of the Asian tiger mosquito Aedes albopictus (Skuse 1894) in the Indo-Pacific | Within the last century, increases in human movement and globalization of trade have facilitated the establishment of several highly invasive mosquito species in new geographic locations with concurrent major environmental, economic and health consequences. The Asian tiger mosquito, Aedes albopictus, is an extremely in... | The Asian tiger mosquito, Aedes albopictus, is an aggressive mosquito that has expanded globally in the last century, chiefly due to the increase of human movements. It is a major public health concern due to its role in transmitting dengue, chikungunya and Zika viruses. Understanding how populations of Ae. albopictus ... | Many species of mosquitoes are amongst the most invasive pests in the world. They have a long history of human-mediated introductions [1, 2] that have resulted in the spread of major epidemics (malaria, dengue, Zika, etc.) and the establishment of invading mosquitoes as a biting nuisance. The Asian tiger mosquito, Aede... |
10.1371/journal.pgen.1003167 | Mutational Spectrum Drives the Rise of Mutator Bacteria | Understanding how mutator strains emerge in bacterial populations is relevant both to evolutionary theory and to reduce the threat they pose in clinical settings. The rise of mutator alleles is understood as a result of their hitchhiking with linked beneficial mutations, although the factors that govern this process re... | Natural and laboratory populations of bacteria can readily give rise to strains with high mutation rates. The evolution of these mutator bacteria—of particular concern in clinical situations—has been understood exclusively in terms of their increased capacity to generate beneficial mutations, such as those that confer ... | Despite their increased load of deleterious mutations [1], [2], mutator strains of bacteria are isolated routinely in laboratory and clinical settings [3]–[8]. Theory [9]–[11] and experiments [5], [12], [13] explain these observations as a consequence of genetic hitchhiking, whereby mutator alleles reach high frequency... |
10.1371/journal.pmed.1002230 | Clinical applicability and cost of a 46-gene panel for genomic analysis of solid tumours: Retrospective validation and prospective audit in the UK National Health Service | Single gene tests to predict whether cancers respond to specific targeted therapies are performed increasingly often. Advances in sequencing technology, collectively referred to as next generation sequencing (NGS), mean the entire cancer genome or parts of it can now be sequenced at speed with increased depth and sensi... | Healthcare planners and oncologists require real world evidence that next generation sequencing (NGS) technologies improve gene mutation detection and enable more appropriate use of targeted drug therapies.
With a range of genomic testing options available for cancer patients, we need to know whether healthcare systems... | Historically, the standard approach to testing for somatic mutations in cancers has been single gene testing using methods such as Sanger sequencing. With such methods, candidate genes are examined for mutations, and, as a result, patients may become eligible to enter a clinical trial or receive targeted drug therapies... |
10.1371/journal.pbio.0060033 | A Global Assessment of Salmon Aquaculture Impacts on Wild Salmonids | Since the late 1980s, wild salmon catch and abundance have declined dramatically in the North Atlantic and in much of the northeastern Pacific south of Alaska. In these areas, there has been a concomitant increase in the production of farmed salmon. Previous studies have shown negative impacts on wild salmonids, but th... | The impact of salmon farming on wild salmon and trout is a hotly debated issue in all countries where salmon farms and wild salmon coexist. Studies have clearly shown that escaped farm salmon breed with wild populations to the detriment of the wild stocks, and that diseases and parasites are passed from farm to wild sa... | Since the late 1970s, salmon aquaculture has grown into a global industry, producing over 1 million tonnes of salmon per year [1]. The majority of this biomass is held in open net pens in coastal areas through which wild salmon migrate on their way to and from the ocean. A number of studies have predicted or evaluated ... |
10.1371/journal.pntd.0005992 | Candidate genes-based investigation of susceptibility to Human African Trypanosomiasis in Côte d’Ivoire | Human African Trypanosomiasis (HAT) or sleeping sickness is a Neglected Tropical Disease. Long regarded as an invariably fatal disease, there is increasing evidence that infection by T. b. gambiense can result in a wide range of clinical outcomes, including latent infections, which are long lasting infections with no p... | Since it was first identified, human African trypanosomiasis (HAT) or sleeping sickness has been described as invariably fatal. Recent data however suggest that infection by T. b. gambiense can result in a wide range of clinical outcomes in its human host including long lasting infections, that can be detected by the p... | Sleeping sickness, or human African Trypanosomiasis (HAT), is caused by Trypanosoma brucei gambiense and T.b. rhodesiense and is transmitted by tsetse flies (Glossina spp). T. b. gambiense is associated with a more chronic disease that can take decades to become patent, and T.b. rhodesiense causes an acute disease with... |
10.1371/journal.pntd.0000612 | Asymptomatic Renal Colonization of Humans in the Peruvian Amazon by Leptospira | Renal carriage and shedding of leptospires is characteristic of carrier or maintenance animal hosts. Sporadic reports indicate that after infection, humans may excrete leptospires for extended periods. We hypothesized that, like mammalian reservoir hosts, humans develop asymptomatic leptospiruria in settings of high di... | Leptospirosis is a bacterial disease commonly transmitted from animals to humans. The more than 200 types of spiral-shaped bacteria (spirochetes) in the genus Leptospira are classified as pathogenic, intermediately pathogenic, or saprophytic (meaning not causing infection in any mammal) based on their ability to cause ... | Leptospirosis is a zoonotic disease caused by spirochetes of the genus Leptospira. Found worldwide, leptospirosis is more common in tropical and sub-tropical areas where environmental and socioeconomic conditions favor its transmission. It has been identified in recent years as a global public health problem because of... |
10.1371/journal.pntd.0001473 | Successful Outcomes with Oral Fluoroquinolones Combined with Rifampicin in the Treatment of Mycobacterium ulcerans: An Observational Cohort Study | The World Health Organization currently recommends combined streptomycin and rifampicin antibiotic treatment as first-line therapy for Mycobacterium ulcerans infections. Alternatives are needed when these are not tolerated or accepted by patients, contraindicated, or neither accessible nor affordable. Despite in vitro ... | Buruli ulcer is a necrotizing infection of skin and subcutaneous tissue caused by Mycobacterium ulcerans and is the third most common mycobacterial disease worldwide (after tuberculosis and leprosy). In recent years its treatment has radically changed, evolving from a predominantly surgically to a predominantly medical... | In recent years the treatment of Mycobacterium ulcerans (M. ulcerans) has radically changed, evolving from a predominantly surgically [1], [2] to a predominantly medically treated disease [3]. This resulted from clinical experience supported by scientific data showing superior outcomes when antibiotics were used alone ... |
10.1371/journal.pbio.0050007 | Drug Export Pathway of Multidrug Exporter AcrB Revealed by DARPin Inhibitors | The multidrug exporter AcrB is the inner membrane component of the AcrAB-TolC drug efflux system in Escherichia coli and is responsible for the resistance of this organism to a wide range of drugs. Here we describe the crystal structure of the trimeric AcrB in complex with a designed ankyrin-repeat protein (DARPin) inh... | Bacterial resistance to antibiotics is a major challenge for the current treatment of infectious diseases. One way bacteria can escape destruction is by pumping out administered drugs through specific transporter proteins that span the cell membrane. We used designer proteins that bind to and stabilize proteins of inte... | Drug resistance is a medical problem, ranging from cancer cells evading chemotherapy to bacteria surviving antibiotic treatment. Efflux pumps represent one class of integral membrane transport proteins in bacteria that confer antibiotic resistance [1]. These proteins actively detoxify the intracellular space by exporti... |
10.1371/journal.pgen.1003033 | Stimulation of Gross Chromosomal Rearrangements by the Human CEB1 and CEB25 Minisatellites in Saccharomyces cerevisiae Depends on G-Quadruplexes or Cdc13 | Genomes contain tandem repeats that are at risk of internal rearrangements and a threat to genome integrity. Here, we investigated the behavior of the human subtelomeric minisatellites HRAS1, CEB1, and CEB25 in Saccharomyces cerevisiae. In mitotically growing wild-type cells, these GC–rich tandem arrays stimulate the r... | All genomes contain particular DNA sequences that are prone to break and rearrange. They can be lost or rescued at the expense of sequence variations and complex rearrangements. Using a sensitive yeast model system, we examined the fragility of the HRAS1, CEB1, and CEB25 GC-rich human minisatellites (tandem repetition ... | Some chromosomal regions are more prone to rearrangement than others and thus are the source of genetic diseases and cancer. Among “at risk” sequences, tandem repeats like microsatellites and minisatellites that differ by the length of their repeat unit (1–10 nt and 10–100 nt, respectively) are prone to changes in repe... |
10.1371/journal.pgen.1006512 | Extensive Regulation of Diurnal Transcription and Metabolism by Glucocorticoids | Altered daily patterns of hormone action are suspected to contribute to metabolic disease. It is poorly understood how the adrenal glucocorticoid hormones contribute to the coordination of daily global patterns of transcription and metabolism. Here, we examined diurnal metabolite and transcriptome patterns in a zebrafi... | Glucocorticoids, steroid hormones of the adrenal gland, are important regulators of metabolism and the stress response. They are also widely used as anti-inflammatory drugs. Production and release of glucocorticoids show a diurnal pattern regulated by the circadian clock. Importantly, altered daily patterns of hormone ... | The circadian clock is an endogenous oscillator that regulates daily changes of behavior, physiology and metabolism [1]. The molecular basis of the circadian clock is a transcriptional-translational feedback loop, a central part of which are E-box enhancer elements [2]. To generate physiological rhythms, “peripheral” c... |
10.1371/journal.pcbi.0030156 | Mechanisms of Firing Patterns in Fast-Spiking Cortical Interneurons | Cortical fast-spiking (FS) interneurons display highly variable electrophysiological properties. Their spike responses to step currents occur almost immediately following the step onset or after a substantial delay, during which subthreshold oscillations are frequently observed. Their firing patterns include high-frequ... | About 25% of the neurons in the mammalian neocortex are inhibitory, namely reduce the activity of neurons they contact. These inhibitory neurons exhibit diversity of morphological, chemical, and biophysical properties, and their classification has recently been the focus of much debate. Even neurons belonging to a sing... | Among inhibitory neurons in the neocortex, the “fast-spiking” (FS) compose the most prominent type. These neurons are characterized by brief action potentials with a width smaller than 0.5 ms followed by a deep monophasic afterhyperpolarization (AHP) [1,2]. Delayed rectifier currents of the types Kv3.1–Kv3.2 are respon... |
10.1371/journal.ppat.1005697 | The WOPR Protein Ros1 Is a Master Regulator of Sporogenesis and Late Effector Gene Expression in the Maize Pathogen Ustilago maydis | The biotrophic basidiomycete fungus Ustilago maydis causes smut disease in maize. Hallmarks of the disease are large tumors that develop on all aerial parts of the host in which dark pigmented teliospores are formed. We have identified a member of the WOPR family of transcription factors, Ros1, as major regulator of sp... | The fungus Ustilago maydis is a pathogen of maize which induces tumor formation in the infected tissue. In these tumors huge amounts of fungal spores develop. As a biotrophic pathogen, U. maydis establishes itself in the plant with the help of a large number of secreted effector proteins. Many effector proteins are imp... | The basidiomycete Ustilago maydis is a biotrophic pathogen colonizing maize. The resulting disease, the so-called smut disease, is characterized by the formation of large tumors on all aerial parts of the plant. In these tumors fungal hyphae proliferate profusely and eventually produce massive amounts of dark pigmented... |
10.1371/journal.ppat.1002958 | Molecular Basis for Genetic Resistance of Anopheles gambiae to Plasmodium: Structural Analysis of TEP1 Susceptible and Resistant Alleles | Thioester-containing protein 1 (TEP1) is a central component in the innate immune response of Anopheles gambiae to Plasmodium infection. Two classes of TEP1 alleles, TEP1*S and TEP1*R, are found in both laboratory strains and wild isolates, related by a greater or lesser susceptibility, respectively to both P. berghei ... | Anopheles mosquitoes transmit malaria, the world's most devastating parasitic disease, of which Anopheles gambiae is the principal vector for malaria in Sub-Saharan Africa. Different populations of mosquitoes vary widely in how readily they become infected with malaria parasites, while some strains do not transmit mala... | Thioester-containing proteins (TEPs) are a major component of the innate immune response of insects to invasion by bacteria and protozoa [1], [2]. Anopheles gambiae thioester-containing protein 1 (TEP1) is a complement-like protein that plays a central role in the opsonization of gram-negative bacteria in the hemolymph... |
10.1371/journal.ppat.1006168 | Identification of several high-risk HPV inhibitors and drug targets with a novel high-throughput screening assay | Human papillomaviruses (HPVs) are oncogenic viruses that cause numerous different cancers as well as benign lesions in the epithelia. To date, there is no effective cure for an ongoing HPV infection. Here, we describe the generation process of a platform for the development of anti-HPV drugs. This system consists of en... | Human papillomaviruses are causative agents of many different cancers; they are most commonly associated with cervical cancer which leads to about quarter of a million deaths each year. Regardless of extensive studies for decades there is no specific cure against HPV infection. During this research, we have engineered ... | Human papillomaviruses (HPVs) are small, double-stranded DNA viruses that infect the epithelium of the skin and mucosa. To date, at least 202 HPVs have been characterized, but studies suggest that the true number is considerably higher[1,2]. HPVs induce benign lesions in the mucosal and cutaneous epithelia, and most of... |
10.1371/journal.ppat.1002063 | Suboptimal Activation of Antigen-Specific CD4+
Effector Cells Enables Persistence of M. tuberculosis In
Vivo | Adaptive immunity to Mycobacterium tuberculosis controls
progressive bacterial growth and disease but does not eradicate infection. Among
CD4+ T cells in the lungs of M.
tuberculosis-infected mice, we observed that few produced IFN-γ
... | Mycobacterium tuberculosis causes persistent infection even in
human or animal hosts that develop antigen-specific CD4+ and
CD8+ T cell responses. To understand this phenomenon, we
tested the hypothesis that the CD4+ effector T cells that are
... | Even though its etiologic agent was discovered over 125 years ago, tuberculosis
remains a global scourge, killing 1.7 million people in 2009, at least ¾ of
whom were immunocompetent [1]. Long-term persistence of Mycobacterium
tuberculosis, which resides principally in... |
10.1371/journal.pntd.0001974 | Leishmania donovani Develops Resistance to Drug Combinations | Drug combinations for the treatment of leishmaniasis represent a promising and challenging chemotherapeutic strategy that has recently been implemented in different endemic areas. However, the vast majority of studies undertaken to date have ignored the potential risk that Leishmania parasites could develop resistance ... | Leishmania is a protozoan parasite that infects human macrophages to produce the neglected tropical disease known as leishmaniasis. Chemotherapy is currently the only treatment option for leishmaniasis. First-line therapies include pentavalent antimonials, except in some regions in the Indian subcontinent, the liposoma... | The use of drug combinations, either in co-formulations or co-administrations, is an established approach for the treatment of several infectious diseases including malaria and tuberculosis [1]. This approach has also recently become a priority for other tropical parasitic diseases, such as visceral leishmaniasis [2]–[... |
10.1371/journal.pcbi.1006571 | powerTCR: A model-based approach to comparative analysis of the clone size distribution of the T cell receptor repertoire | Sequencing of the T cell receptor (TCR) repertoire is a powerful tool for deeper study of immune response, but the unique structure of this type of data makes its meaningful quantification challenging. We introduce a new method, the Gamma-GPD spliced threshold model, to address this difficulty. This biologically interp... | A more detailed understanding of the immune response can unlock critical information concerning diagnosis and treatment of disease. Here, in particular, we study T cells through T cell receptor sequencing, as T cells play a vital role in immune response. One important feature of T cell receptor sequencing data is the f... | Recent advances in high-throughput sequencing of the T cell receptor (TCR) repertoire provide a new, detailed characterization of the immune system. T cells, each displaying a unique TCR, are capable of responding to presented antigens and initiating an adaptive immune response. An immune response is described by rapid... |
10.1371/journal.pgen.1002232 | Frequent Beneficial Mutations during Single-Colony Serial Transfer of Streptococcus pneumoniae | The appearance of new mutations within a population provides the raw material for evolution. The consistent decline in fitness observed in classical mutation accumulation studies has provided support for the long-held view that deleterious mutations are more common than beneficial mutations. Here we present results of ... | Beneficial mutations have long been considered extremely rare events and were thought to occur with a frequency of approximately one out of a billion times that a bacterium replicates its genome. Rare beneficial mutations would then be amplified by natural selection from the more frequent background of harmful mutation... | Spontaneous mutations provide the underlying variability on which selection acts to drive evolution. Among newly-arising mutations that impact fitness, the balance between those that are beneficial and those that are deleterious has appeared to be heavily skewed toward maladaptive changes. This view has been supported ... |
10.1371/journal.pbio.2002458 | Identifying genetic variants that affect viability in large cohorts | A number of open questions in human evolutionary genetics would become tractable if we were able to directly measure evolutionary fitness. As a step towards this goal, we developed a method to examine whether individual genetic variants, or sets of genetic variants, currently influence viability. The approach consists ... | Our global understanding of adaptation in humans is limited to indirect statistical inferences from patterns of genetic variation, which are sensitive to past selection pressures. We introduced a method that allowed us to directly observe ongoing selection in humans by identifying genetic variants that affect survival ... | A number of central questions in evolutionary genetics remain open, in particular for humans. Which types of variants affect fitness? Which components of fitness do they affect? What is the relative importance of directional and balancing selection in shaping genetic variation? Part of the difficulty is that our unders... |
10.1371/journal.ppat.1000745 | Protection of Mice against Lethal Challenge with 2009 H1N1 Influenza A Virus by 1918-Like and Classical Swine H1N1 Based Vaccines | The recent 2009 pandemic H1N1 virus infection in humans has resulted in nearly 5,000 deaths worldwide. Early epidemiological findings indicated a low level of infection in the older population (>65 years) with the pandemic virus, and a greater susceptibility in people younger than 35 years of age, a phenomenon correlat... | Influenza A viruses generally infect individuals of all ages and cause severe respiratory disease in very young children and elderly people (>65 years). However, the 2009 pandemic H1N1 virus infection is predominantly seen in children and adults (<35 years of age), but rarely in people older than 65 years of age. Recen... | Influenza A viruses (IAV), members of the Orthomyxoviridae family, cause severe respiratory diseases in humans with an average mortality rate of 36,000/year in the United States alone [1]. Apart from yearly seasonal outbreaks, IAV can cause frequent epidemics and occasional pandemics in humans [2],[3]. Vaccination has ... |
10.1371/journal.pntd.0004401 | Yeast-Based High-Throughput Screens to Identify Novel Compounds Active against Brugia malayi | Lymphatic filariasis is caused by the parasitic worms Wuchereria bancrofti, Brugia malayi or B. timori, which are transmitted via the bites from infected mosquitoes. Once in the human body, the parasites develop into adult worms in the lymphatic vessels, causing severe damage and swelling of the affected tissues. Accor... | We have developed and validated a yeast-based high-throughput screening assay for the identification of specific inhibitors of filarial targets. We engineered yeast strains to functionally express parasite and human enzymes, labeling these with fluorescent proteins and growing them in competition in the presence of tes... | Lymphatic filariasis is a neglected tropical disease caused primarily by the parasitic nematodes Wuchereria bancrofti and Brugia malayi. The painful and disfiguring manifestations of this disease, also known as elephantiasis, can lead to permanent disability, causing an annual loss of approximately 5.5 million disabili... |
10.1371/journal.pbio.2001220 | Smek promotes corticogenesis through regulating Mbd3’s stability and Mbd3/NuRD complex recruitment to genes associated with neurogenesis | The fate of neural progenitor cells (NPCs) during corticogenesis is determined by a complex interplay of genetic or epigenetic components, but the underlying mechanism is incompletely understood. Here, we demonstrate that Suppressor of Mek null (Smek) interact with methyl-CpG–binding domain 3 (Mbd3) and the complex pla... | Neural progenitor cells are self-renewing, multipotent cells that generate major neural cell types, including neurons and glia. Their fate during development of the cerebral cortex is determined by a complex interplay of genetic and epigenetic components. It has been shown that Suppressor of Mek null (Smek) proteins—wh... | Neural stem cells (NSCs) are self-renewing, multipotent cells that generate major neural cell types, including neurons and glia, in the developing central nervous system (CNS) [1,2]. During neurogenesis, NSCs are derived from neuroepithelial cells (NECs), which first divide symmetrically to expand the population and th... |
10.1371/journal.ppat.1006951 | Host shifts result in parallel genetic changes when viruses evolve in closely related species | Host shifts, where a pathogen invades and establishes in a new host species, are a major source of emerging infectious diseases. They frequently occur between related host species and often rely on the pathogen evolving adaptations that increase their fitness in the novel host species. To investigate genetic changes in... | Host shifts, where a pathogen jumps from one host species to another, are a major source of infectious disease. Hosts shifts are more likely to occur between related host species and often rely on the pathogen evolving adaptations that increase their fitness in the novel host. Here we have investigated how viruses evol... | Host shifts–where a pathogen jumps into and establishes in a new host species–are a major source of emerging infectious diseases. RNA viruses seem particularly prone to host shift [1–4], with HIV, Ebola virus and SARS coronavirus all having been acquired by humans from other host species [5–7]. Whilst some pathogens ma... |
10.1371/journal.pbio.1000365 | Sex and the Single Cell. II. There Is a Time and Place for Sex | The Drosophila melanogaster sex hierarchy controls sexual differentiation of somatic cells via the activities of the terminal genes in the hierarchy, doublesex (dsx) and fruitless (fru). We have targeted an insertion of GAL4 into the dsx gene, allowing us to visualize dsx-expressing cells in both sexes. Developmentally... | Morphologically, fruit flies are either male or female. The specification of sex is a multi-step process that depends on whether the fertilized egg has only one X chromosome (will develop as male) or two X chromosomes (will develop as female). This initial assessment of sex activates a cascade of regulatory genes that ... | A single, multi-branched regulatory hierarchy specifies all somatic sexual differences in Drosophila melanogaster [1]–[5]. The fly sex hierarchy is of great intrinsic interest as a model developmental system to dissect both how information is passed through a molecular network and how the actions of the terminal regula... |
10.1371/journal.ppat.1005210 | Perivascular Arrest of CD8+ T Cells Is a Signature of Experimental Cerebral Malaria | There is significant evidence that brain-infiltrating CD8+ T cells play a central role in the development of experimental cerebral malaria (ECM) during Plasmodium berghei ANKA infection of C57BL/6 mice. However, the mechanisms through which they mediate their pathogenic activity during malaria infection remain poorly u... | Cerebral malaria is the most severe complication of Plasmodium falciparum infection. Utilizing the murine experimental model of cerebral malaria (ECM), it has been found that CD8+ T cells are a key immune cell type responsible for development of cerebral pathology during malaria infection. To identify how CD8+ T cells ... | Malaria remains a significant global health problem with 207 million cases, resulting in 584,000–1,238,000 deaths, annually [1, 2]. A high proportion of these deaths are due to cerebral malaria (CM), a neuropathology induced primarily by the species Plasmodium falciparum [2]. Current treatment of cerebral malaria is li... |
10.1371/journal.pbio.1001839 | A Novel Protein, CHRONO, Functions as a Core Component of the Mammalian Circadian Clock | Circadian rhythms are controlled by a system of negative and positive genetic feedback loops composed of clock genes. Although many genes have been implicated in these feedback loops, it is unclear whether our current list of clock genes is exhaustive. We have recently identified Chrono as a robustly cycling transcript... | The circadian clock has a fundamental role in regulating biological temporal rhythms in organisms, and it is tightly controlled by a molecular circuit consisting of positive and negative regulatory feedback loops. Although many of the clock genes comprising this circuit have been identified, there are still some critic... | Circadian rhythms with a period of approximately 24 h endow organisms with the ability to adapt to changes of solar light following earth's rotation. The mammalian circadian clock system consists of inputs from light and feeding, a core pacemaker located in a paired nuclei, called suprachiasmatic nucleus (SCN), and out... |
10.1371/journal.pgen.1008325 | NKILA represses nasopharyngeal carcinoma carcinogenesis and metastasis by NF-κB pathway inhibition | The role of long non-coding RNA (lncRNA) in the progression of Nasopharyngeal carcinoma (NPC) has not been fully elucidated. The study was designed to explore the functional role of NKILA, a newly identified lncRNA, in the progression of NPC. We performed a lncRNA expression profile microarray using four NPC and paired... | NF-κB is a pivotal link between NPC and inflammation. Importantly, NF-κB was found to be overexpressed in nearly all NPC tissues, and inflammatory cytokines have also been observed in NPC tissues. Inflammatory cytokines promote the susceptibility of NPC cells to metastasize via constant NF-κB activation. Here, we found... | Nasopharyngeal carcinoma (NPC), a metastasis-prone cancer, which is particularly common in southeast Asia and southern China [1–4]. Due to the high radiosensitivity, radiotherapy has become the main treatment for locoregional NPC. Radiation oncology has improved the locoregional control(the tumor control of nasopharynx... |
10.1371/journal.ppat.0030064 | Identification of a Novel Polyomavirus from Patients with Acute Respiratory Tract Infections | We report the identification of a novel polyomavirus present in respiratory secretions from human patients with symptoms of acute respiratory tract infection. The virus was initially detected in a nasopharyngeal aspirate from a 3-year-old child from Australia diagnosed with pneumonia. A random library was generated fro... | We have identified a novel virus, referred to as WU virus, in the family Polyomaviridae by screening of human respiratory secretions. Two human polyomaviruses, BK and JC, were identified in 1971 and infect the majority of humans around the world. These two viruses are closely related to each other and are both are path... | Viral infections of the respiratory tract are responsible for significant mortality and morbidity worldwide [1]. Despite extensive studies in the past decades that have identified a number of etiologic agents, including rhinoviruses, coronaviruses, influenzaviruses, parainfluenzaviruses, respiratory syncytial virus, an... |
10.1371/journal.pcbi.1000114 | Probing the Extent of Randomness in Protein Interaction Networks | Protein–protein interaction (PPI) networks are commonly explored for the identification of distinctive biological traits, such as pathways, modules, and functional motifs. In this respect, understanding the underlying network structure is vital to assess the significance of any discovered features. We recently demonstr... | A protein–protein interaction network represents the set of pair-wise associations that have been discerned between the constituent proteins of an organism. There are three main types of such networks: (i) those determined from a single high-throughput experiment; (ii) curated, where interactions are compiled from the ... | Protein interaction networks are key to the understanding and modeling of many biological processes. At the highest level, networks enable the conceptualization of the different physiological, biological, and chemical functions that typically occur in a cell. At the core of a network description lie the connections, or... |
10.1371/journal.pntd.0006540 | Quantification of dengue virus specific T cell responses and correlation with viral load and clinical disease severity in acute dengue infection | In order to understand the role of dengue virus (DENV) specific T cell responses that associate with protection, we studied their frequency and phenotype in relation to clinical disease severity and resolution of viraemia in a large cohort of patients with varying severity of acute dengue infection.
Using ex vivo IFNγ ... | In order to understand the role of dengue virus (DENV) specific T cell responses in protection against infection, we studied T cell cytokine production in relation to clinical disease severity and resolution of viraemia in a large cohort of patients with varying severity of acute dengue infection. We found that DENV-sp... | Dengue virus is the cause of the most common mosquito-borne viral infection worldwide, indeed over half of the global population live in areas where there is intense dengue transmission putting them at risk of dengue infection [1]. Dengue virus causes 390 million infections annually, of which nearly a quarter are clini... |
10.1371/journal.ppat.1007504 | Immune-inducible non-coding RNA molecule lincRNA-IBIN connects immunity and metabolism in Drosophila melanogaster | Non-coding RNAs have important roles in regulating physiology, including immunity. Here, we performed transcriptome profiling of immune-responsive genes in Drosophila melanogaster during a Gram-positive bacterial infection, concentrating on long non-coding RNA (lncRNA) genes. The gene most highly induced by a Micrococc... | Drosophila melanogaster is a powerful genetic model for studying the innate immune mechanisms conserved from flies to humans. With recent methodology, such as whole transcriptome analyses, novel non-protein coding genes in addition to protein coding genes are being increasingly identified. These long and short non-codi... | The fruit fly Drosophila melanogaster (D. melanogaster) is a widely used model system in immunological studies [1]. Drosophila has an elegant innate immune response that includes both the cellular and the humoral arms [2,3]. Activation of the cellular immune response involves mechanisms such as recognition, phagocytosi... |
10.1371/journal.ppat.1006040 | The Two-Component System ArlRS and Alterations in Metabolism Enable Staphylococcus aureus to Resist Calprotectin-Induced Manganese Starvation | During infection the host imposes manganese and zinc starvation on invading pathogens. Despite this, Staphylococcus aureus and other successful pathogens remain capable of causing devastating disease. However, how these invaders adapt to host-imposed metal starvation and overcome nutritional immunity remains unknown. W... | The ubiquitous pathogen Staphylococcus aureus is a serious threat to human health due to the continued spread of antibiotic resistance. This spread has made it challenging to treat staphylococcal infections and led to the call for new approaches to treat this devastating pathogen. One approach is to disrupt the ability... | Staphylococcus aureus is a ubiquitous pathogen that colonizes 30% of the population at any given time and can infect virtually every human tissue [1]. These facts and the continued spread of antibiotic resistance have led both the Centers for Disease Control and the World Health Organization to state that S. aureus pos... |
10.1371/journal.ppat.1007094 | Listeria monocytogenes InlP interacts with afadin and facilitates basement membrane crossing | During pregnancy, the placenta protects the fetus against the maternal immune response, as well as bacterial and viral pathogens. Bacterial pathogens that have evolved specific mechanisms of breaching this barrier, such as Listeria monocytogenes, present a unique opportunity for learning how the placenta carries out it... | Infections during pregnancy can lead to infections of the placenta, spread to the fetus, and cause fetal damage and death. Improving maternal-child heath is a global heath priority. Yet, progress to prevent and treat pregnancy-related diseases has lagged behind other medical fields. Using pregnant guinea pigs, which ha... | During pregnancy, the consequences of placental infection can be severe, ranging from maternal sepsis to miscarriage, and can lead to pre-term birth and lifelong disability [1]. Fortunately, such infections are relatively rare–which stands as a testament to the strength of the feto-maternal barrier. Despite serving suc... |
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