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10.1371/journal.ppat.1000612 | Transcriptional Regulation of Carbohydrate Metabolism in the Human Pathogen Candida albicans | Glycolysis is a metabolic pathway that is central to the assimilation of carbon for either respiration or fermentation and therefore is critical for the growth of all organisms. Consequently, glycolytic transcriptional regulation is important for the metabolic flexibility of pathogens in their attempts to colonize dive... | Pathogens must be able to assimilate the carbon sources in their environment to generate sufficient energy and metabolites to survive. Since glycolysis is a central metabolic pathway, it is important for this metabolic flexibility. The most commonly isolated agent in human fungal infections, Candida albicans, depends u... | In order to grow and thrive in a wide range of hosts, pathogens not only depend on certain virulence factors but also metabolic flexibility; therefore, they must be able to assimilate various carbon sources. Carbohydrates are the primary and preferred source of metabolic carbon for most organisms, and are used for gene... |
10.1371/journal.pgen.1005005 | Autoselection of Cytoplasmic Yeast Virus Like Elements Encoding Toxin/Antitoxin Systems Involves a Nuclear Barrier for Immunity Gene Expression | Cytoplasmic virus like elements (VLEs) from Kluyveromyces lactis (Kl), Pichia acaciae (Pa) and Debaryomyces robertsiae (Dr) are extremely A/T-rich (>75%) and encode toxic anticodon nucleases (ACNases) along with specific immunity proteins. Here we show that nuclear, not cytoplasmic expression of either immunity gene (P... | The rather wide-spread and extremely A/T rich yeast virus like elements (VLEs, also termed linear plasmids) which encode toxic anticodon nucleases (ACNases) ensure autoselection in the cytoplasm by preventing functional nuclear capture of the cognate immunity genes, but how? When expressed in the nucleus, the mRNA of t... | Pichia acaciae and Kluyveromyces lactis each contain two cytoplasmic virus-like elements (VLEs, also known as linear plasmids); i.e. pPac1-1 (12.6 kb), pPac1-2 (6.8 kb) and pGKL2 (13.5 kb), pGKL1 (8.9 kb) respectively [1,2]. The respective larger elements display substantial similarities to each other in terms of organ... |
10.1371/journal.ppat.1001089 | The Canine Papillomavirus and Gamma HPV E7 Proteins Use an Alternative Domain to Bind and Destabilize the Retinoblastoma Protein | The high-risk HPV E6 and E7 proteins cooperate to immortalize primary human cervical cells and the E7 protein can independently transform fibroblasts in vitro, primarily due to its ability to associate with and degrade the retinoblastoma tumor suppressor protein, pRb. The binding of E7 to pRb is mediated by a conserved... | Human papillomaviruses (HPVs) are estimated to cause the most common sexually transmitted infection in the world, and these infections are recognized as the major cause of cervical cancer. One of the papillomavirus oncoproteins, E7, plays a major role in both the viral life cycle and progression to cancer. In cells E7 ... | Human papillomaviruses (HPVs) mediate the initiation and maintenance of cervical cancer [1], [2]. Based upon DNA sequence homology, there are more than 150 different HPV genotypes, 40 of which infect anogenital and oral mucosa [3]. In addition to genotyping, HPVs can also be classified as low-risk and high-risk based o... |
10.1371/journal.pgen.1000293 | The Genomic Analysis of Lactic Acidosis and Acidosis Response in Human Cancers | The tumor microenvironment has a significant impact on tumor development. Two important determinants in this environment are hypoxia and lactic acidosis. Although lactic acidosis has long been recognized as an important factor in cancer, relatively little is known about how cells respond to lactic acidosis and how that... | It is well recognized that tumor microenvironments play an important role in modulating tumor progression in human cancers. Although previous studies have highlighted the importance of hypoxia, there is limited knowledge on the effects of other components in tumor microenvironments. Therefore, we use gene expression to... | The tumor microenvironment is characterized by oxygen depletion (hypoxia), high lactate and extracellular acidosis (lactic acidosis) as well as glucose and energy deprivation [1]. These changes are largely caused by a combination of poor tissue perfusion, abnormal tumor vasculature, uncontrolled proliferation and dysre... |
10.1371/journal.pntd.0003549 | In-vitro Activity of Avermectins against Mycobacterium ulcerans | Mycobacterium ulcerans causes Buruli ulcer (BU), a debilitating infection of subcutaneous tissue. There is a WHO-recommended antibiotic treatment requiring an 8-week course of streptomycin and rifampicin. This regime has revolutionized the treatment of BU but there are problems that include reliance on daily streptomyc... | Neglected tropical diseases such as Buruli ulcer predominantly afflict the poorest populations in the world and reduce quality of life. Buruli ulcer is a necrotising infection that destroys the skin and soft tissue, frequently presenting as nodules or open ulcers. Buruli ulcer is treated with antibiotics and sometimes ... | Buruli ulcer (BU) is a neglected tropical disease that presents as skin nodules, plaques or oedematous lesions that can progress to open ulcers [1]. BU is caused by infection with Mycobacterium ulcerans, a mycobacterium that is related to the causative agents of tuberculosis and leprosy [2]. Most BU patients are childr... |
10.1371/journal.ppat.1001203 | Fcγ Receptor I Alpha Chain (CD64) Expression in Macrophages Is Critical for the Onset of Meningitis by Escherichia coli K1 | Neonatal meningitis due to Escherichia coli K1 is a serious illness with unchanged morbidity and mortality rates for the last few decades. The lack of a comprehensive understanding of the mechanisms involved in the development of meningitis contributes to this poor outcome. Here, we demonstrate that depletion of macrop... | Escherichia coli K1 is the most common cause of meningitis in premature infants; the mortality rate of this disease ranges from 5% to 30%. A better understanding of the pathogenesis of E. coli K1 meningitis is needed to develop new preventative strategies. We have shown that outer membrane protein A (OmpA) of E. coli K... | Professional phagocytes, including neutrophils and macrophages (MØ) express a specific set of phagocytic receptors that recognize, bind to and mediate internalization of microbial pathogens [1], [2], [3]. Although MØ receptor-mediated phagocytosis generally leads to the destruction of the pathogen, certain receptor-lig... |
10.1371/journal.pntd.0003170 | Nematode-Induced Interference with Vaccination Efficacy Targets Follicular T Helper Cell Induction and Is Preserved after Termination of Infection | One-third of the human population is infected with parasitic worms. To avoid being eliminated, these parasites actively dampen the immune response of their hosts. This immune modulation also suppresses immune responses to third-party antigens such as vaccines. Here, we used Litomosoides sigmodontis-infected BALB/c mice... | Parasitic worms, called helminths, infect one-third of the world population. Despite exposure to their host's immune system many helminths establish chronic infections and survive several years within their host. They avoid elimination by dampening the immune response of their hosts. This immune suppression also affect... | More than 1 billion people are infected with helminths worldwide, predominantly in the tropics and subtropics [1]. To avoid their elimination and to limit pathology, helminths have developed sophisticated strategies to dampen the immune response of their hosts [2], [3]. This helminth-induced immune suppression also aff... |
10.1371/journal.pgen.1001069 | A Global Overview of the Genetic and Functional Diversity in the Helicobacter pylori cag Pathogenicity Island | The Helicobacter pylori cag pathogenicity island (cagPAI) encodes a type IV secretion system. Humans infected with cagPAI–carrying H. pylori are at increased risk for sequelae such as gastric cancer. Housekeeping genes in H. pylori show considerable genetic diversity; but the diversity of virulence factors such as the ... | Most humans are infected with Helicobacter pylori. The H. pylori cag pathogenicity island (cagPAI) encodes a secretion apparatus that can translocate the CagA protein into host cells. Humans infected with cagPAI–carrying H. pylori are at increased risk of severe disease, including gastric cancer. We analyzed the nucleo... | Helicobacter pylori persistently infects more than one half of all humans, and can cause ulcer disease, gastric cancer, and MALT lymphoma [1]. The H. pylori cag pathogenicity island (cagPAI) is an intriguing virulence module of this obligate host-associated bacterium [2]–[4]. H. pylori strains that possess a functional... |
10.1371/journal.pntd.0005271 | High Incidence of Human Rabies Exposure in Northwestern Tigray, Ethiopia: A Four-Year Retrospective Study | Rabies is a fatal zoonotic disease that has been known in Ethiopia for centuries in society as “Mad Dog Disease”. It is an important disease with veterinary and public health significance in the North western zone of Tigray where previous studies have not been conducted. Frequent occurrence of outbreaks in the area led... | Rabies is a deadly disease of human and animals. The disease has been recognized in Ethiopia for centuries, but its impact remained underestimated. This limitation masks the true magnitude of rabies incidence and has been a stumbling block for its prevention and control. The aim of the study was to determine the incide... | Rabies is a fatal and one of the most important reemerging zoonotic diseases throughout the world, caused by RNA viruses that affect the central nervous system of all warm-blooded animals, including humans [1, 2]. Carnivores are one of the primary virus reservoirs and rabid dogs pose the greatest hazard of rabies world... |
10.1371/journal.pntd.0001271 | Male Mating Competitiveness of a Wolbachia-Introgressed Aedes polynesiensis Strain under Semi-Field Conditions | Lymphatic filariasis (LF), a global public health problem affecting approximately 120 million people worldwide, is a leading cause of disability in the developing world including the South Pacific. Despite decades of ongoing mass drug administration (MDA) in the region, some island nations have not yet achieved the thr... | Aedes polynesiensis is the primary mosquito vector of lymphatic filariasis (LF) in the island nations of the South Pacific. Control of LF in this region of the world is difficult due to the unique biology of the mosquito vector. A proposed method to control LF in the Pacific is through the release of male mosquitoes th... | Lymphatic filariasis (LF) is a mosquito-borne disease that can lead to gross disfigurement (lymphedema and elephantiasis) and disability. In addition to the severe pain that often accompanies LF, many affected individuals suffer psychological distress due to associated social stigmas. In severe cases, individuals may b... |
10.1371/journal.pntd.0003392 | Transcriptome Profiles of the Protoscoleces of Echinococcus granulosus Reveal that Excretory-Secretory Products Are Essential to Metabolic Adaptation | Cystic hydatid disease (CHD) is caused by the larval stages of the cestode and affects humans and domestic animals worldwide. Protoscoleces (PSCs) are one component of the larval stages that can interact with both definitive and intermediate hosts. Previous genomic and transcriptomic data have provided an overall snaps... | The successful infection establishment of parasites depends on their ability to combat their host's immune system while maintaining metabolic adaptation to their hosts. The mechanisms of these processes are not well understood. We used the protoscoleces (PSCs) of E. granulosus as a model system to study this complex ho... | Cystic hydatid disease (CHD) is a serious parasitic zoonosis that is caused by the larval stages of Echinococcus granulosus, a cestode that poses a threat to public health as well as significant economic losses [1], [2], [3]. At present, more than 3 million people are infected with this parasite [4], [5], and the preva... |
10.1371/journal.pntd.0003921 | A Spatio-temporal Model of African Animal Trypanosomosis Risk | African animal trypanosomosis (AAT) is a major constraint to sustainable development of cattle farming in sub-Saharan Africa. The habitat of the tsetse fly vector is increasingly fragmented owing to demographic pressure and shifts in climate, which leads to heterogeneous risk of cyclical transmission both in space and ... | African animal trypanosomosis (AAT) is a major constraint to sustainable development of cattle farming in sub-Saharan Africa. The habitat of the tsetse fly vector is increasingly fragmented owing to demographic pressure and shifts in climate, which leads to heterogeneous risk of transmission both in space and time. In ... | In sub-Saharan Africa, African animal trypanosomosis (AAT) is one of the main constraints to the sustainable development of cattle farming [1]. In recent years, the habitat of tsetse fly vector (genus Glossina) has undergone significant modifications due to demographic and climatic pressures. Landscape fragmentation is... |
10.1371/journal.pntd.0006889 | A highly multiplexed broad pathogen detection assay for infectious disease diagnostics | Rapid pathogen identification during an acute febrile illness is a critical first step for providing appropriate clinical care and patient isolation. Primary screening using sensitive and specific assays, such as real-time PCR and ELISAs, can rapidly test for known circulating infectious diseases. If the initial testin... | Identifying the causative agent in an acute febrile illness can be challenging diagnostically, especially when organisms in a particular region have overlapping clinical presentation or when that pathogen’s presence is unexpected. Ebola virus, for example, was not considered in an acute febrile illness differential dia... | Appropriate diagnostic assay selection for infectious diseases depends on multiple parameters including clinical presentation and endemic pathogens known to circulate within a specific geographic region. Rapid point-of-care PCR [1, 2] and lateral flow immunoassays [3, 4] as well as more complex PCR [5–7] and laboratory... |
10.1371/journal.pcbi.1006092 | Interactions of spatial strategies producing generalization gradient and blocking: A computational approach | We present a computational model of spatial navigation comprising different learning mechanisms in mammals, i.e., associative, cognitive mapping and parallel systems. This model is able to reproduce a large number of experimental results in different variants of the Morris water maze task, including standard associativ... | We present a computational model of navigation that successfully reproduces a set of different experiments involving cognitive mapping and associative phenomena during spatial learning. The key ingredients of the model that are responsible for this achievement are (i) the coordination of different navigation strategies... | Neurobehavioral evidence supports a prominent role for interactions between multiple anatomically distinct memory systems in the mammalian brain underlying the coordination of different behavioral strategies during learning (e.g., [1]): A cognitive memory system, relying on a network comprising the hippocampus, prefron... |
10.1371/journal.pcbi.1002769 | Functional Analysis of Metabolic Channeling and Regulation in Lignin Biosynthesis: A Computational Approach | Lignin is a polymer in secondary cell walls of plants that is known to have negative impacts on forage digestibility, pulping efficiency, and sugar release from cellulosic biomass. While targeted modifications of different lignin biosynthetic enzymes have permitted the generation of transgenic plants with desirable tra... | The organization of cooperating enzymes into complexes is a pervasive feature of metabolism. In particular, this phenomenon has been shown to participate in the regulation of flux through the networks of both primary and secondary metabolism in plants. It remains a challenging task to unravel the organizing principles ... | Lignin is a phenolic heteropolymer in the secondary cell walls of vascular plants. It is derived mainly from three hydroxycinnamyl alcohol monomers, namely p-coumaryl, coniferyl, and sinapyl alcohols, which, when incorporated into the lignin polymer, give rise to p-hydroxyphenyl (H), guaiacyl (G), and syringyl (S) subu... |
10.1371/journal.pbio.1000351 | Environmental Change Enhances Cognitive Abilities in Fish | Flexible or innovative behavior is advantageous, especially when animals are exposed to frequent and unpredictable environmental perturbations. Improved cognitive abilities can help animals to respond quickly and adequately to environmental dynamics, and therefore changing environments may select for higher cognitive a... | Animals with higher cognitive abilities should be better capable of producing new, modified, or innovative behaviors as this ability could allow them to cope better with unpredictable environmental changes. Changing environments may hence select for higher cognitive abilities. Similarly, changing conditions during onto... | The ability of adapting to changes in the environment is an important driving force of evolution, as recognized already by Darwin in his famous quote: “It is not the strongest of the species that survives…it is the one that is the most adaptable to change” [1]. Animals may adapt by altering their behavior, physiology, ... |
10.1371/journal.pcbi.1004606 | A Model of Drosophila Larva Chemotaxis | Detailed observations of larval Drosophila chemotaxis have characterised the relationship between the odour gradient and the runs, head casts and turns made by the animal. We use a computational model to test whether hypothesised sensorimotor control mechanisms are sufficient to account for larval behaviour. The model ... | The larvae of the fruitfly are attracted to many odours. We use a computational model in which simulated larvae stop, start and redirect their crawling behaviour in response to their experience of changes in odour. We show that three simple rules for switching between behaviours are sufficient to produce larva-like res... | It is well established that Drosophila larvae perform chemotaxis towards a wide range of odourants (e.g. [1]). Our aim in this paper is to examine what sensorimotor mechanism(s) account for larval chemotaxis, looking for a minimal model that captures observed phenomena. This will allow us to examine the nature of senso... |
10.1371/journal.pgen.1007227 | Dek overexpression in murine epithelia increases overt esophageal squamous cell carcinoma incidence | Esophageal cancer occurs as either squamous cell carcinoma (ESCC) or adenocarcinoma. ESCCs comprise almost 90% of cases worldwide, and recur with a less than 15% five-year survival rate despite available treatments. The identification of new ESCC drivers and therapeutic targets is critical for improving outcomes. Here ... | The DEK oncogene is overexpressed in nearly all human cancers and portends a poor prognosis for many cancer types. High DEK expression causes cancer related phenotypes such as increased cellular proliferation, migration, and invasion in vitro. Despite the well documented link between high DEK expression and cancer, the... | The human DEK oncoprotein is a predominantly chromatin-bound factor that regulates nuclear processes such as chromatin architecture, epigenetics, transcription and DNA repair [1–18]. DEK was originally identified as a fusion protein with the CAN/NUP214 nucleoporin in a patient with acute myeloid leukemia harboring the ... |
10.1371/journal.ppat.1002755 | Structural and Functional Insights into the Malaria Parasite Moving Junction Complex | Members of the phylum Apicomplexa, which include the malaria parasite Plasmodium, share many features in their invasion mechanism in spite of their diverse host cell specificities and life cycle characteristics. The formation of a moving junction (MJ) between the membranes of the invading apicomplexan parasite and the ... | Malaria arises from infection of erythrocytes by single-cell parasites belonging to the genus Plasmodium, the species P. falciparum causing the most severe forms of the disease. The formation of a moving junction (MJ) between the membranes of the parasite and its host cell is essential for invasion. Two important compo... | Plasmodium spp., and P. falciparum in particular, are devastating global pathogens that place nearly half the human population at risk to malaria, leading to more than 250 million cases yearly and over one million deaths [1]. The success of the malaria parasite can be attributed to its intracellular lifestyle, invading... |
10.1371/journal.pgen.1000753 | Accelerated Evolution of the Prdm9 Speciation Gene across Diverse Metazoan Taxa | The onset of prezygotic and postzygotic barriers to gene flow between populations is a hallmark of speciation. One of the earliest postzygotic isolating barriers to arise between incipient species is the sterility of the heterogametic sex in interspecies' hybrids. Four genes that underlie hybrid sterility have been ide... | Speciation, the process by which one species splits into two, involves reproductive barriers between previously interbreeding populations. The question of how speciation occurs has rightly occupied the attention of biologists since before Darwin's “On the Origin of Species.” Studies of recently diverged species have re... | The question of how two species originate from one has fascinated biologists since before Darwin's iconic treatise on the subject [1]. Postzygotic reproductive barriers between species are thought to result from the acquisition of genetic incompatibilities as an incidental by-product of divergence between two populatio... |
10.1371/journal.pntd.0004910 | Economic Analysis of the Impact of Overseas and Domestic Treatment and Screening Options for Intestinal Helminth Infection among US-Bound Refugees from Asia | Many U.S.-bound refugees travel from countries where intestinal parasites (hookworm, Trichuris trichuria, Ascaris lumbricoides, and Strongyloides stercoralis) are endemic. These infections are rare in the United States and may be underdiagnosed or misdiagnosed, leading to potentially serious consequences. This evaluati... | Intestinal parasites including hookworm, Strongyloides stercoralis, Ascaris lumbricoides and Trichuris trichuria have been found to be prevalent in refugee populations. More than 50,000 refugees resettle in the United States annually. Since parasitic disease associated with these infections are rare in the United State... | More than 50,000 refugees resettle in the United States annually [1] and often arrive with much higher prevalence rates of parasitic infections than is seen in the general U.S. population. [2–5] Since parasitic diseases are rare in the United States, there have been delays in diagnosis or inappropriate treatment [6–10]... |
10.1371/journal.pcbi.1006412 | Maintaining maximal metabolic flux by gene expression control | One of the marvels of biology is the phenotypic plasticity of microorganisms. It allows them to maintain high growth rates across conditions. Studies suggest that cells can express metabolic enzymes at tuned concentrations through adjustment of gene expression. The associated transcription factors are often regulated b... | To attain high growth rates, microorganisms need to sustain high activities of metabolic reactions. Since the catalysing enzymes are in finite supply, cells need to carefully tune their concentrations. When conditions change, cells need to adjust those concentrations. How cells maintain high metabolism rates across con... | Microbes need to grow fast to outcompete others. They therefore have to maintain high growth rates in changing environments. To achieve this specific metabolic fluxes (metabolic rates per unit of expended enzyme) need to be kept as high as possible. Since metabolic enzymes are a limited resource, cells should behave ec... |
10.1371/journal.pntd.0001302 | Meningococcal Factor H Binding Proteins in Epidemic Strains from Africa: Implications for Vaccine Development | Factor H binding protein (fHbp) is an important antigen for vaccines against meningococcal serogroup B disease. The protein binds human factor H (fH), which enables the bacteria to resist serum bactericidal activity. Little is known about the vaccine-potential of fHbp for control of meningococcal epidemics in Africa, w... | Epidemics of meningococcal meningitis are common in sub-Saharan Africa. Most are caused by encapsulated serogroup A strains, which rarely cause disease in industrialized countries. A serogroup A polysaccharide protein conjugate vaccine recently was introduced in some countries in sub-Saharan Africa. The antibodies indu... | For more than 100 years devastating epidemics of meningococcal disease have occurred in sub-Saharan Africa [1]. In the decade 1988 to 1997, more than 700,000 cases and over 100,000 deaths were reported. Public health responses were limited by scarce resources [2]. Further, the only vaccines available, un-conjugated (pl... |
10.1371/journal.ppat.1002648 | The Transcription Factor AmrZ Utilizes Multiple DNA Binding Modes to Recognize Activator and Repressor Sequences of Pseudomonas aeruginosa Virulence Genes | AmrZ, a member of the Ribbon-Helix-Helix family of DNA binding proteins, functions as both a transcriptional activator and repressor of multiple genes encoding Pseudomonas aeruginosa virulence factors. The expression of these virulence factors leads to chronic and sustained infections associated with worsening prognosi... | The bacterium Pseudomonas aeruginosa causes a variety of human infections and is the leading cause of death in patients with cystic fibrosis. The main reason for the severity of these infections arises from the ability of P. aeruginosa to express virulence factors that protect it from the host immune system. Several of... | Pseudomonas aeruginosa is an opportunistic, Gram negative bacterium that causes a variety of infections, mainly in immune-challenged patients [1]–[3]. More notably, chronic lung infection by P. aeruginosa is the leading cause of death in patients with the autosomal recessive disorder cystic fibrosis (CF) [4]. The under... |
10.1371/journal.pmed.1002699 | Deep-learning-assisted diagnosis for knee magnetic resonance imaging: Development and retrospective validation of MRNet | Magnetic resonance imaging (MRI) of the knee is the preferred method for diagnosing knee injuries. However, interpretation of knee MRI is time-intensive and subject to diagnostic error and variability. An automated system for interpreting knee MRI could prioritize high-risk patients and assist clinicians in making diag... | We wanted to see if a deep learning model could succeed in the clinically important task of detecting disorders in knee magnetic resonance imaging (MRI) scans.
We wanted to determine whether a deep learning model could improve the diagnostic accuracy, specificity, or sensitivity of clinical experts, including general r... | Magnetic resonance imaging (MRI) of the knee is the standard-of-care imaging modality to evaluate knee disorders, and more musculoskeletal (MSK) MRI examinations are performed on the knee than on any other region of the body [1–3]. MRI has repeatedly demonstrated high accuracy for the diagnosis of meniscal and cruciate... |
10.1371/journal.ppat.1000063 | HtrA2/Omi Terminates Cytomegalovirus Infection and Is Controlled by the Viral Mitochondrial Inhibitor of Apoptosis (vMIA) | Viruses encode suppressors of cell death to block intrinsic and extrinsic host-initiated death pathways that reduce viral yield as well as control the termination of infection. Cytomegalovirus (CMV) infection terminates by a caspase-independent cell fragmentation process after an extended period of continuous virus pro... | Cellular suicide is an effective host defense mechanism to control viral infection. Host cells encode proteins that induce infected cell death while viruses encode proteins that prevent death and facilitate viral replication. Human cytomegalovirus encodes vMIA to suppress host-initiated death pathways. Cytomegalovirus ... | Cell death is central to viral infection, as an evolutionarily-conserved means to eliminate intracellular pathogens and as a way that lytic viruses mediate release of progeny. Human cytomegalovirus (CMV), the major infectious cause of birth defects as well as an important cause of opportunistic disease worldwide [1], r... |
10.1371/journal.pgen.1001383 | Identification and Functional Validation of the Novel Antimalarial
Resistance Locus PF10_0355 in Plasmodium
falciparum | The Plasmodium falciparum parasite's ability to adapt to
environmental pressures, such as the human immune system and antimalarial drugs,
makes malaria an enduring burden to public health. Understanding the genetic
basis of these adaptations is critical to int... | Malaria infection with the human pathogen Plasmodium falciparum
results in almost a million deaths each year, mostly in African children.
Efforts to eliminate malaria are underway, but the parasite is adept at eluding
both the human immune response and antimal... | Plasmodium falciparum malaria is a major public health challenge
that contributes significantly to global morbidity and mortality. Efforts to control
and eliminate malaria combine antimalarial drugs, bed nets and indoor residual
spraying, with vaccine development a longer... |
10.1371/journal.pgen.1002011 | FUS Transgenic Rats Develop the Phenotypes of Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration | Fused in Sarcoma (FUS) proteinopathy is a feature of frontotemporal lobar dementia (FTLD), and mutation of the fus gene segregates with FTLD and amyotrophic lateral sclerosis (ALS). To study the consequences of mutation in the fus gene, we created transgenic rats expressing the human fus gene with or without mutation. ... | Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are two related diseases characterized by degeneration of selected groups of neuronal cells. Neither of these diseases has a clear cause, and both are incurable at present. Mutation of the fus gene has recently been linked to these two diseases. Here, ... | Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two common neurodegenerative diseases [1], [2]. ALS is characterized by degeneration of motor neurons, denervation atrophy of skeletal muscles, and progressive paralysis of limbs [3], [4]. FTLD mainly affects cortical neurons and cause... |
10.1371/journal.ppat.0030189 | Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum | Lipoic acid (LA) is an essential cofactor of α-keto acid dehydrogenase complexes (KADHs) and the glycine cleavage system. In Plasmodium, LA is attached to the KADHs by organelle-specific lipoylation pathways. Biosynthesis of LA exclusively occurs in the apicoplast, comprising octanoyl-[acyl carrier protein]: protein N-... | Plasmodium falciparum is the causative agent of severe malaria. The parasites possess two organelles that are integral to their metabolism—the mitochondrion and the apicoplast, a remnant plastid. Both organelles contain enzymes that depend on the attachment of the cofactor lipoic acid for their catalytic activity. Thes... | Lipoic acid (6,8-thioctic acid; LA) is an essential cofactor that is covalently attached to the transacylase subunit (E2-subunit) of α-keto acid dehydrogenase complexes (KADHs), namely pyruvate dehydrogenase (PDH), α-keto glutarate dehydrogenase (KGDH), and branched chain α-keto acid dehydrogenase (BCDH) as well as the... |
10.1371/journal.pgen.1000929 | Genetic Tests for Ecological and Allopatric Speciation in Anoles on an Island Archipelago | From Darwin's study of the Galapagos and Wallace's study of Indonesia, islands have played an important role in evolutionary investigations, and radiations within archipelagos are readily interpreted as supporting the conventional view of allopatric speciation. Even during the ongoing paradigm shift towards other modes... | Over the last 150 years, since Darwin's study of islands and his “Origin of Species,” island archipelagos have played a central role in the understanding of evolution and how species multiply (speciation). Islands epitomise the conventional view of geographic (allopatric) speciation, where genomes diverge in isolation ... | Speciation generates biodiversity and is therefore a key process in evolution and ecology, and the relative importance of factors contributing to speciation in sexually reproducing animals, such as genetic drift in spatial isolation, natural selection, sexual selection and mutation-order, remains an active area of rese... |
10.1371/journal.pntd.0000614 | Bacillus thuringiensis Cry5B Protein Is Highly Efficacious as a Single-Dose Therapy against an Intestinal Roundworm Infection in Mice | Intestinal parasitic nematode diseases are one of the great diseases of our time. Intestinal roundworm parasites, including hookworms, whipworms, and Ascaris, infect well over 1 billion people and cause significant morbidity, especially in children and pregnant women. To date, there is only one drug, albendazole, with ... | Intestinal parasitic nematode diseases infect over one billion people and cause significant disease burden in children (growth and cognitive stunting, malnutrition), in pregnant women, and via their dampening of the immune system in infected individuals. In over thirty years, no new classes of anti-roundworm drugs (ant... | Neglected tropical diseases (NTDs) have a worldwide devastating impact on the lives of billions of people. Helminth infections comprise approximately 85% of the NTD burden [1]. The top three ailments on this list of NTDs are all caused by intestinal nematodes [2]. These infections consist of ascariasis (caused by Ascar... |
10.1371/journal.pmed.1002741 | Lifetime risk and multimorbidity of non-communicable diseases and disease-free life expectancy in the general population: A population-based cohort study | Non-communicable diseases (NCDs) are leading causes of premature disability and death worldwide. However, the lifetime risk of developing any NCD is unknown, as are the effects of shared common risk factors on this risk.
Between July 6, 1989, and January 1, 2012, we followed participants from the prospective Rotterdam ... | The burden and preventive potential of disease is typically estimated for each non-communicable disease (NCD) separately, yet NCDs often co-occur, which hampers reliable quantification of their overall burden as well as the potential to prevent NCDs jointly in the general population.
Smoking, hypertension, and overweig... | Non-communicable diseases (NCDs), including stroke, heart disease, diabetes, chronic respiratory disease, cancer, and neurodegenerative disease, are the most frequent causes of prolonged disability and premature death worldwide [1–3]. Major changes in lifestyle and medicine over the past decades have led to significant... |
10.1371/journal.pbio.1001258 | Genome-Wide Analysis of the World's Sheep Breeds Reveals High Levels of Historic Mixture and Strong Recent Selection | Through their domestication and subsequent selection, sheep have been adapted to thrive in a diverse range of environments. To characterise the genetic consequence of both domestication and selection, we genotyped 49,034 SNP in 2,819 animals from a diverse collection of 74 sheep breeds. We find the majority of sheep po... | During the process of domestication, mankind recruited animals from the wild into a captive environment, changing their morphology, behaviour, and genetics. In the case of sheep, domestication and subsequent selection by their animal handlers over thousands of years has produced a spectrum of breeds specialised for the... | Man's earliest agricultural systems were based on the captive management of sheep and goats. The transition from hunting to animal husbandry involved human control over the reproduction, diet, and protection of animals. The process of domestication was initiated approximately 11,000 years ago in the Fertile Crescent [1... |
10.1371/journal.ppat.1006678 | Single-cell analysis identifies cellular markers of the HIV permissive cell | Cellular permissiveness to HIV infection is highly heterogeneous across individuals. Heterogeneity is also found across CD4+ T cells from the same individual, where only a fraction of cells gets infected. To explore the basis of permissiveness, we performed single-cell RNA-seq analysis of non-infected CD4+ T cells from... | CD4+ T cells are the main target of human immunodeficiency virus (HIV) infection. However, CD4+ T cells are not equally permissive to infection, varying between individuals and across cells isolated from the same individual. We explored cellular heterogeneity by analyzing the transcriptome profile of CD4+ T cells at si... | In vivo and in vitro data indicates that only a small fraction of the CD4+ T cell population is successfully infected by HIV. Cellular permissiveness to HIV infection differs between cell lines originating from different tissues, between T cell lines [1], between primary CD4+ T cells isolated from different HIV-negativ... |
10.1371/journal.pbio.2006250 | A Notch-mediated, temporal asymmetry in BMP pathway activation promotes photoreceptor subtype diversification | Neural progenitors produce neurons whose identities can vary as a function of the time that specification occurs. Here, we describe the heterochronic specification of two photoreceptor (PhR) subtypes in the zebrafish pineal gland. We find that accelerating PhR specification by impairing Notch signaling favors the early... | A major goal in the field of developmental neurobiology is to identify the mechanisms that underly the diversification of the subtypes of neurons that are needed for the function of the nervous system. When investigating these mechanisms, time is an often-overlooked variable. Here, we show that in the zebrafish pineal ... | The development of a functional nervous system requires the production of an amazing diversity of cell types. The precise identity of each neuron is acquired through a complex process referred to as neuronal subtype specification. Although different molecular mechanisms have been reported to control the specification o... |
10.1371/journal.pmed.1002185 | Lifestyle Advice Combined with Personalized Estimates of Genetic or Phenotypic Risk of Type 2 Diabetes, and Objectively Measured Physical Activity: A Randomized Controlled Trial | Information about genetic and phenotypic risk of type 2 diabetes is now widely available and is being incorporated into disease prevention programs. Whether such information motivates behavior change or has adverse effects is uncertain. We examined the effect of communicating an estimate of genetic or phenotypic risk o... | Despite questions regarding their clinical validity and utility, genetic tests aimed at predicting risk of type 2 diabetes are now widely available.
Some researchers and direct-to-consumer genetic testing companies are optimistic that personalized genetic information will encourage people at risk to adopt healthier beh... | The prevalence of type 2 diabetes is increasing worldwide, and primary prevention of the disease is a global priority [1]. Evidence from randomized controlled trials shows that positive changes in health behavior can significantly reduce the incidence of type 2 diabetes among those considered high-risk [2,3]. However, ... |
10.1371/journal.pcbi.1006888 | Predicting synthetic lethal interactions using conserved patterns in protein interaction networks | In response to a need for improved treatments, a number of promising novel targeted cancer therapies are being developed that exploit human synthetic lethal interactions. This is facilitating personalised medicine strategies in cancers where specific tumour suppressors have become inactivated. Mainly due to the constra... | Our new algorithm SLant, uses artificial intelligence to help target future cancer drug research. In healthy cells tens of thousands of proteins work together forming large interaction networks. However, in cancerous cells genetic damage means that many of these proteins are disabled. Basic functions like DNA repair an... | Despite sustained global efforts to develop effective therapies, cancer is now responsible for more than 15% of the world’s annual deaths. There are over 12 million newly diagnosed cases per annum and this figure continues to grow [1]. Standard chemotherapy involves non-selective, cytotoxic agents that often have limit... |
10.1371/journal.ppat.1002416 | Autophagy Protein Atg3 is Essential for Maintaining Mitochondrial Integrity and for Normal Intracellular Development of Toxoplasma gondii Tachyzoites | Autophagy is a cellular process that is highly conserved among eukaryotes and permits the degradation of cellular material. Autophagy is involved in multiple survival-promoting processes. It not only facilitates the maintenance of cell homeostasis by degrading long-lived proteins and damaged organelles, but it also pla... | Autophagy is a catabolic process involved in maintaining cellular homeostasis in eukaryotic cells, while coping with their changing environmental conditions. Mechanistically, it is also a process of considerable complexity involving multiple protein factors and implying numerous protein-protein and protein-membrane int... | Proteolysis is very important to eukaryotic cells and occurs at a considerable constitutive rate. Base line degradation regulates the levels of numerous proteins and removes misfolded proteins. Mechanistically, this process can be separated into two main pathways: one pathway mediated by the proteasome and the other pa... |
10.1371/journal.ppat.1000853 | Three Members of the 6-cys Protein Family of Plasmodium Play a Role in Gamete Fertility | The process of fertilization is critically dependent on the mutual recognition of gametes and in Plasmodium, the male gamete surface protein P48/45 is vital to this process. This protein belongs to a family of 10 structurally related proteins, the so called 6-cys family. To identify the role of additional members of th... | Sexual reproduction for malaria parasites is an essential process and is necessary for parasite transmission between hosts. Fertilisation between female and male gametes occurs in the midgut of the mosquito and proteins on the surface of gametes are principle targets in transmission blocking strategies. Despite their i... | Sexual reproduction is an obligate process in the Plasmodium life cycle and is required for transmission of the parasites between the vertebrate and mosquito hosts. The sexual phase is initiated by the formation of male and female cells (gametocytes) in the blood of the vertebrate host. Gametocytes are the precursors t... |
10.1371/journal.pntd.0005217 | In vivo Distribution and Clearance of Purified Capsular Polysaccharide from Burkholderia pseudomallei in a Murine Model | Burkholderia pseudomallei is the causative agent of melioidosis, a severe infection prominent in northern Australia and Southeast Asia. The “gold standard” for melioidosis diagnosis is bacterial isolation, which takes several days to complete. The resulting delay in diagnosis leads to delayed treatments, which could re... | An outer membrane component, capsular polysaccharide (CPS), is a virulence factor expressed by many Gram-negative bacteria including Burkholderia pseudomallei, the causative agent of melioidosis. Recently, B. pseudomallei CPS was identified as a useful diagnostic biomarker, leading to the development of a lateral flow ... | Burkholderia pseudomallei is a Gram-negative, soil-dwelling bacillus and the etiologic pathogen of melioidosis, a severe infection endemic in tropical areas with the highest incidence in Southeast Asia and northern Australia [1]. In early 2016, it was predicted that approximately 165,000 individuals worldwide would suf... |
10.1371/journal.pbio.2006134 | KDM5 histone demethylases repress immune response via suppression of STING | Cyclic GMP-AMP (cGAMP) synthase (cGAS) stimulator of interferon genes (STING) senses pathogen-derived or abnormal self-DNA in the cytosol and triggers an innate immune defense against microbial infection and cancer. STING agonists induce both innate and adaptive immune responses and are a new class of cancer immunother... | Pathogens often find ways to turn down cell-intrinsic antipathogen immune responses by the host. Similarly, cancer cells use various mechanisms to evade attack by immune cells. One of the common mechanisms is suppression of the stimulator of interferon genes (STING)-dependent innate immune response. Using potent and sp... | Evasion from immunosurveillance by cancer cells is a major cancer hallmark [1], and restoration of immunosurveillance has been demonstrated as an effective antitumor strategy. For example, antibodies targeting inhibitory checkpoint molecules, including programmed cell death protein 1 (PD-1) and cytotoxic T-cell lymphoc... |
10.1371/journal.pbio.2005372 | Is the sky the limit? On the expansion threshold of a species’ range | More than 100 years after Grigg’s influential analysis of species’ borders, the causes of limits to species’ ranges still represent a puzzle that has never been understood with clarity. The topic has become especially important recently as many scientists have become interested in the potential for species’ ranges to s... | The flow of genetic diversity across environments has conflicting effects. On the beneficial side, it increases the genetic variation that is necessary for adaptation and counters the loss of genetic diversity due to genetic drift. However, it may also swamp adaptation to local conditions. This interplay is crucial for... | Species’ borders are not just determined by the limits of their ecological niche [1, 2]. A species’ edge is typically sharper than would be implied by continuous change in the species’ environment (reviewed in [3, Table 2]). Moreover, although species’ ranges are inherently dynamic, it is puzzling that they typically e... |
10.1371/journal.pgen.1000793 | Inverse Correlation between Promoter Strength and Excision Activity in Class 1 Integrons | Class 1 integrons are widespread genetic elements that allow bacteria to capture and express gene cassettes that are usually promoterless. These integrons play a major role in the dissemination of antibiotic resistance among Gram-negative bacteria. They typically consist of a gene (intI) encoding an integrase (that cat... | Integrons are widespread bacterial genetic elements able to capture and express gene cassettes that often encode antibiotic resistance determinants. Gene cassettes are usually promoterless and are transcribed from a common promoter, Pc. Pc is located within the coding sequence of the integron integrase, IntI, which is ... | Integrons are natural genetic elements that can acquire, exchange and express genes within gene cassettes. The integron platform is composed of a gene, intI, that encodes a site-specific recombinase, IntI, a recombination site, attI, and a functional promoter, Pc, divergent to the integrase gene [1] (Figure 1). Gene ca... |
10.1371/journal.pcbi.1005240 | Impact of Lipid Composition and Receptor Conformation on the Spatio-temporal Organization of μ-Opioid Receptors in a Multi-component Plasma Membrane Model | The lipid composition of cell membranes has increasingly been recognized as playing an important role in the function of various membrane proteins, including G Protein-Coupled Receptors (GPCRs). For instance, experimental and computational evidence has pointed to lipids influencing receptor oligomerization directly, by... | The μ-opioid receptor (MOR) is an important pharmaceutical target in the treatment of pain. In order to develop novel pain therapies, devoid of the serious side-effects of present opioid analgesics, we need to understand the fundamentals of how MOR works on the molecular level. While some studies suggest that oligomers... | Elucidating the impact of the lipid environment on membrane proteins, including G Protein-Coupled Receptors (GPCRs), is increasingly being recognized as a crucial part of understanding how these proteins function. Cholesterol (CHOL), the lipid for which the most is known about its effect on GPCRs, has been shown to aff... |
10.1371/journal.pgen.1004975 | The Arabidopsis DNA Polymerase δ Has a Role in the Deposition of Transcriptionally Active Epigenetic Marks, Development and Flowering | DNA replication is a key process in living organisms. DNA polymerase α (Polα) initiates strand synthesis, which is performed by Polε and Polδ in leading and lagging strands, respectively. Whereas loss of DNA polymerase activity is incompatible with life, viable mutants of Polα and Polε were isolated, allowing the ident... | Three DNA polymerases replicate DNA in Eukaryotes. DNA polymerase α (Polα) initiates strand synthesis, which is performed by Polε and Polδ in leading and lagging strands, respectively. Not only the information encoded in the DNA, but also the inheritance of chromatin states is essential during development. Loss of func... | Arabidopsis is a facultative long-day (LD) plant, meaning that LDs accelerate flowering whereas in short days (SD) flowering is delayed. Flowering in spring (LDs) is therefore promoted by GIGANTEA (GI), CONSTANS (CO) and FLOWERING LOCUS T (FT) which constitute the so called “photoperiod pathway”. GI activates CO which ... |
10.1371/journal.pgen.1001065 | Genome-Wide Profiling of p63 DNA–Binding Sites Identifies an Element that Regulates Gene Expression during Limb Development in the 7q21 SHFM1 Locus | Heterozygous mutations in p63 are associated with split hand/foot malformations (SHFM), orofacial clefting, and ectodermal abnormalities. Elucidation of the p63 gene network that includes target genes and regulatory elements may reveal new genes for other malformation disorders. We performed genome-wide DNA–binding pro... | Mammalian embryonic development requires precise control of gene expression in the right place at the right time. One level of control of gene expression is through cis-regulatory elements controlled by transcription factors. Deregulation of gene expression by mutations in such cis-regulatory elements has been describe... | The p63 protein encoded by the TP63 gene is a transcription factor of the p53 family and functions as a master regulator of ectodermal development. The key function of p63 during ectodermal development is underscored by phenotypic features in p63 knockout mice [1], [2] and in p63 knock-down zebrafish [3], [4]. The deve... |
10.1371/journal.ppat.1005035 | Characterization of a Prefusion-Specific Antibody That Recognizes a Quaternary, Cleavage-Dependent Epitope on the RSV Fusion Glycoprotein | Prevention efforts for respiratory syncytial virus (RSV) have been advanced due to the recent isolation and characterization of antibodies that specifically recognize the prefusion conformation of the RSV fusion (F) glycoprotein. These potently neutralizing antibodies are in clinical development for passive prophylaxis... | Respiratory syncytial virus (RSV) causes significant morbidity and mortality in children, yet an efficacious vaccine remains unavailable. Antibodies that preferentially recognize the prefusion conformation of the fusion (F) glycoprotein, particularly those that bind antigenic site Ø at the membrane-distal apex, potentl... | Respiratory syncytial virus (RSV) is a ubiquitous paramyxovirus that infects nearly all children in the U.S. by two years of age [1]. In infants and young children RSV can cause acute lower respiratory tract infections, leading to bronchiolitis and pneumonia. In 2010, RSV was estimated to cause the deaths of more than ... |
10.1371/journal.pgen.1003443 | Analysis of Rare, Exonic Variation amongst Subjects with Autism Spectrum Disorders and Population Controls | We report on results from whole-exome sequencing (WES) of 1,039 subjects diagnosed with autism spectrum disorders (ASD) and 870 controls selected from the NIMH repository to be of similar ancestry to cases. The WES data came from two centers using different methods to produce sequence and to call variants from it. Ther... | This study evaluates association of rare variants and autism spectrum disorders (ASD) in case and control samples sequenced by two centers. Before doing association analyses, we studied how to combine information across studies. We first harmonized the whole-exome sequence (WES) data, across centers, in terms of the di... | Common and rare variants are important constituents of the genetic architecture of Autism Spectrum Disorders (ASD) [1]–[12]. Nonetheless analysis of rare variants has produced the vast majority of findings that implicate certain genes as playing a role in liability for ASD (i.e., ASD genes). Because of the promise of i... |
10.1371/journal.pmed.1002611 | Sexual transmission of Zika virus and other flaviviruses: A living systematic review | Health authorities in the United States and Europe reported an increasing number of travel-associated episodes of sexual transmission of Zika virus (ZIKV) following the 2015–2017 ZIKV outbreak. This, and other scientific evidence, suggests that ZIKV is sexually transmissible in addition to having its primary mosquito-b... | Sexual transmission of Zika virus (ZIKV) is now documented, but the risks of transmission are not well understood.
It is not known whether other flaviviruses can be transmitted through sexual intercourse.
We developed a sexual transmission framework for ZIKV infection that identified 7 key elements related to ZIKV sexu... | Zika virus (ZIKV) can be transmitted between humans through sexual contact, although it is most commonly transmitted by infected Aedes spp. mosquitoes [1,2]. Sexual transmission of ZIKV has important implications for public health, for people living in endemic regions, and for sexual partners of travellers returning to... |
10.1371/journal.ppat.1007314 | A planarian nidovirus expands the limits of RNA genome size | RNA viruses are the only known RNA-protein (RNP) entities capable of autonomous replication (albeit within a permissive host environment). A 33.5 kilobase (kb) nidovirus has been considered close to the upper size limit for such entities; conversely, the minimal cellular DNA genome is in the 100–300 kb range. This larg... | RNA viruses are the only known RNA-protein (RNP) entities capable of autonomous replication. The upper genome size for such entities was assumed to be <35 kb; conversely, the minimal cellular DNA genome is in the 100–300 kilobase (kb) range. This large difference presents a daunting gap for the proposed evolution of co... | Radiation of primitive life as it took hold on earth was likely accompanied by genome expansion, which was associated with increased complexity and a proposed progression from RNA-based through RNA-protein to DNA-based life [1]. The feasibility of an autonomous ancient RNA genome, and the mechanisms underlying such fat... |
10.1371/journal.pcbi.1006475 | Quasiperiodic rhythms of the inferior olive | Inferior olivary activity causes both short-term and long-term changes in cerebellar output underlying motor performance and motor learning. Many of its neurons engage in coherent subthreshold oscillations and are extensively coupled via gap junctions. Studies in reduced preparations suggest that these properties promo... | Activity of the inferior olive, transmitted via climbing fibers to the cerebellum, regulates initiation and amplitude of movements, signals unexpected sensory feedback, and directs cerebellar learning. It is characterized by widespread subthreshold oscillations and synchronization promoted by strong electrotonic coupli... | A multitude of behavioral studies leave little doubt that the olivo-cerebellar system organizes appropriate timing in motor behavior [1–3], perceptual function [4–6] and motor learning [7–10]. Furthermore, the role of the inferior olive in motor function is evinced in (permanent and transient) clinical manifestations, ... |
10.1371/journal.pcbi.1002040 | Gene Expression in the Rodent Brain is Associated with Its Regional Connectivity | The putative link between gene expression of brain regions and their neural connectivity patterns is a fundamental question in neuroscience. Here this question is addressed in the first large scale study of a prototypical mammalian rodent brain, using a combination of rat brain regional connectivity data with gene expr... | Brain connectivity is believed to be associated with gene expression levels in the developing and the adult animal. Recently, this association has been explored in two model animals: the worm C. elegans at the level of single neurons; and the mouse, where specific subpopulations of neurons in the hippocampus were studi... | Genes play a major role in the formation of the nervous system and in its continuous function. They specify neuronal cell types, help destine neurons into defined neural circuits, and provide important cues determining their connectivity [1]–[2]. Inspired by Roger Sperry's classical chemo-affinity hypothesis that state... |
10.1371/journal.pgen.1002786 | FANCJ/BACH1 Acetylation at Lysine 1249 Regulates the DNA Damage Response | BRCA1 promotes DNA repair through interactions with multiple proteins, including CtIP and FANCJ (also known as BRIP1/BACH1). While CtIP facilitates DNA end resection when de-acetylated, the function of FANCJ in repair processing is less well defined. Here, we report that FANCJ is also acetylated. Preventing FANCJ acety... | The BRCA1–Fanconi anemia (FA) pathway is required for both tumor suppression and cell survival, particularly following treatment with DNA damaging agents that induce DNA interstrand crosslinks (ICLs). ICL processing by the BRCA–FA pathway includes promotion of homologous recombination (HR) and DNA damage tolerance thro... | The hereditary breast cancer associated gene product, BRCA1 is an essential tumor suppressor. To promote genomic stability, BRCA1 interacts with multiple protein partners. In particular, through its C-terminal BRCT repeats, BRCA1 directly interacts with Abraxas, CtIP and FANCJ (also known as BRIP1 or BACH1 (BRCA1-assoc... |
10.1371/journal.pgen.1005423 | SLIRP Regulates the Rate of Mitochondrial Protein Synthesis and Protects LRPPRC from Degradation | We have studied the in vivo role of SLIRP in regulation of mitochondrial DNA (mtDNA) gene expression and show here that it stabilizes its interacting partner protein LRPPRC by protecting it from degradation. Although SLIRP is completely dependent on LRPPRC for its stability, reduced levels of LRPPRC persist in the abse... | Mitochondria provide most of the energy required for key metabolic and cellular processes that are essential for life. The biogenesis of the mitochondrial oxidative phosphorylation system, the site of energy conversion, is dependent on the coordinated expression of the mitochondrial and nuclear genomes. Mitochondrial g... | Mitochondria are double-membrane bound organelles that have fundamental roles in energy metabolism, cell health and death, making them essential for life. The oxidative phosphorylation (OXPHOS) system is the major site of ATP production in mitochondria and is composed of proteins encoded by two genomes, the nuclear gen... |
10.1371/journal.pcbi.1006080 | Bamgineer: Introduction of simulated allele-specific copy number variants into exome and targeted sequence data sets | Somatic copy number variations (CNVs) play a crucial role in development of many human cancers. The broad availability of next-generation sequencing data has enabled the development of algorithms to computationally infer CNV profiles from a variety of data types including exome and targeted sequence data; currently the... | We present Bamgineer, a software program to introduce user-defined, haplotype-specific copy number variants (CNVs) at any frequency into standard Binary Alignment Mapping (BAM) files. Copy number gains are simulated by introducing new DNA sequencing read pairs sampled from existing reads and modified to contain SNPs of... | The emergence and maturation of next-generation sequencing technologies, including whole genome sequencing, whole exome sequencing, and targeted sequencing approaches, has enabled researchers to perform increasingly more complex analysis of copy number variants (CNVs)[1]. While genome sequencing-based methods have long... |
10.1371/journal.pbio.2006738 | Evolutionary emergence of infectious diseases in heterogeneous host populations | The emergence and re-emergence of pathogens remains a major public health concern. Unfortunately, when and where pathogens will (re-)emerge is notoriously difficult to predict, as the erratic nature of those events is reinforced by the stochastic nature of pathogen evolution during the early phase of an epidemic. For i... | The probability that an epidemic will break out is highly dependent on the ability of the pathogen to acquire new adaptive mutations and to induce evolutionary emergence. Forecasting pathogen emergence thus requires a good understanding of the interplay between the epidemiology and evolution taking place at the onset o... | Understanding the factors that govern the ability of pathogens to invade a new host population is of paramount importance to design better surveillance systems and control policies. Mathematical epidemiology can provide key insights into these dynamics [1–4]. For instance, simple deterministic models identified critica... |
10.1371/journal.pgen.1000899 | Chromosome 9p21 SNPs Associated with Multiple Disease Phenotypes Correlate with ANRIL Expression | Single nucleotide polymorphisms (SNPs) on chromosome 9p21 are associated with coronary artery disease, diabetes, and multiple cancers. Risk SNPs are mainly non-coding, suggesting that they influence expression and may act in cis. We examined the association between 56 SNPs in this region and peripheral blood expression... | Genetic variants on chromosome 9p21 have been associated with several important diseases including coronary artery disease, diabetes, and multiple cancers. Most of the risk variants in this region do not alter any protein sequence and are therefore likely to act by influencing the expression of nearby genes. We investi... | The chromosome 9p21.3 region adjacent to the loci encoding the cyclin-dependent kinase inhibitors CDKN2A (ENSG00000147889) and CDKN2B (ENSG00000147883) is an important susceptibility locus for several diseases with a complex genetic background. Recent genome-wide association (GWA) studies have shown that single nucleot... |
10.1371/journal.pcbi.1002764 | Mesoscopic Model of Actin-Based Propulsion | Two theoretical models dominate current understanding of actin-based propulsion: microscopic polymerization ratchet model predicts that growing and writhing actin filaments generate forces and movements, while macroscopic elastic propulsion model suggests that deformation and stress of growing actin gel are responsible... | There are two major ideas about how actin networks generate force against an obstacle: one is that the force comes directly from the elongation and bending of individual actin filaments against the surface of the obstacle; the other is that a growing actin gel can build up stress around the obstacle to squeeze it forwa... | Cell migration is a fundamental phenomenon underlying wound healing and morphogenesis [1]. The first step of migration is protrusion – actin-based extension of the cell's leading edge [2]. Lamellipodial motility [3] and intracellular motility of the bacterium Listeria monocytogenes [4] are two prominent model systems t... |
10.1371/journal.ppat.1003521 | Rational Design of a Live Attenuated Dengue Vaccine: 2′-O-Methyltransferase Mutants Are Highly Attenuated and Immunogenic in Mice and Macaques | Dengue virus is transmitted by Aedes mosquitoes and infects at least 100 million people every year. Progressive urbanization in Asia and South-Central America and the geographic expansion of Aedes mosquito habitats have accelerated the global spread of dengue, resulting in a continuously increasing number of cases. A c... | The four serotypes of dengue virus cause severe outbreaks globally in tropical countries with thousands of patients requiring hospitalization. The health care and indirect economic cost of dengue in endemic countries is huge. Despite this, no clinically approved vaccine or antiviral treatment is currently available. De... | Dengue virus (DENV) is a member of the Flaviviridae family. DENV infection causes dengue fever (DF) and the more severe forms of the disease, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). DENV has four serotypes (DENV-1 to -4), each of which is capable of causing severe disease. The frequency, severit... |
10.1371/journal.ppat.1005038 | Tumor Progression Locus 2 Promotes Induction of IFNλ, Interferon Stimulated Genes and Antigen-Specific CD8+ T Cell Responses and Protects against Influenza Virus | Mitogen-activated protein kinase (MAP) cascades are important in antiviral immunity through their regulation of interferon (IFN) production as well as virus replication. Although the serine-threonine MAP kinase tumor progression locus 2 (Tpl2/MAP3K8) has been implicated as a key regulator of Type I (IFNα/β) and Type II... | Influenza viruses infect millions of people annually causing significant morbidity, mortality and socio-economic burdens. Host immune responses against influenza virus are initiated upon virus recognition by specific intracellular receptors. Signals relayed from these receptors trigger various signaling cascades, which... | Mitogen-activated protein kinase (MAP) cascades represent major intracellular signaling pathways activated in response to a variety of external stimuli. Their activation during infection leads to transcriptional induction of immune and inflammatory mediators. Although MAP kinase signaling is important in eliciting host... |
10.1371/journal.pcbi.1005766 | C-reactive protein upregulates the whole blood expression of CD59 - an integrative analysis | Elevated C-reactive protein (CRP) concentrations in the blood are associated with acute and chronic infections and inflammation. Nevertheless, the functional role of increased CRP in multiple bacterial and viral infections as well as in chronic inflammatory diseases remains unclear. Here, we studied the relationship be... | Chronic inflammation is associated with chronic diseases, morbidity and mortality while lower base inflammation levels are thought to be predictive of healthy aging. Thus, to pursue a long and healthy lifespan, it is essential to understand the inflammatory regulatory mechanisms. To that end, we studied the functional ... | Increased levels of C-reactive protein (CRP) in the blood are associated with tissue injury, infections and inflammation [1]. In addition to acute bacterial and viral infections, chronically elevated CRP levels are predictive of multiple diseases associated with inflammatory processes, e.g. cardiovascular disease (CVD)... |
10.1371/journal.pgen.0030063 | Population Stratification of a Common APOBEC Gene Deletion Polymorphism | The APOBEC3 gene family plays a role in innate cellular immunity inhibiting retroviral infection, hepatitis B virus propagation, and the retrotransposition of endogenous elements. We present a detailed sequence and population genetic analysis of a 29.5-kb common human deletion polymorphism that removes the APOBEC3B gen... | Several recent studies have demonstrated that deletions, duplications, and inversions contribute a substantial fraction of the total amount of variation present in the human genome. In this study, we provide a comprehensive population-genetic analysis of a single deletion previously identified by comparing the genome o... | The APOBEC3 family is known to play a role in innate cellular immunity against retroviral infection. The gene family has undergone an expansion in primates, increasing from a single copy in rodents to at least seven copies in humans [1–3]. Among primates, the APOBEC3 family has been subjected to strong and continuing s... |
10.1371/journal.pntd.0001289 | Efficacy of a Low-Cost, Inactivated Whole-Cell Oral Cholera Vaccine: Results from 3 Years of Follow-Up of a Randomized, Controlled Trial | Killed oral cholera vaccines (OCVs) have been licensed for use in developing countries, but protection conferred by licensed OCVs beyond two years of follow-up has not been demonstrated in randomized, clinical trials.
We conducted a cluster-randomized, placebo-controlled trial of a two-dose regimen of a low-cost killed... | New-generation vaccines against cholera are given orally, to stimulate intestinal immunity. An internationally available oral cholera vaccine (OCV) consists of killed vibrio whole cells together with the B subunit of cholera toxin, is safe, and protects vaccinated individuals against cholera for two years, but this vac... | Cholera is a major global public health problem, causing both epidemic and endemic disease. Although conventional, injectable cholera vaccines have been abandoned as public health tools, modern oral cholera vaccines (OCVs) have been found to be safe and effective [1]. A recently revised World Health Organization (WHO) ... |
10.1371/journal.pgen.1002323 | Positional Cloning of a Type 2 Diabetes Quantitative Trait Locus; Tomosyn-2, a Negative Regulator of Insulin Secretion | We previously mapped a type 2 diabetes (T2D) locus on chromosome 16 (Chr 16) in an F2 intercross from the BTBR T (+) tf (BTBR) Lepob/ob and C57BL/6 (B6) Lepob/ob mouse strains. Introgression of BTBR Chr 16 into B6 mice resulted in a consomic mouse with reduced fasting plasma insulin and elevated glucose levels. We deri... | Humans carry many genetic variants that confer small effects on metabolic traits relevant to type 2 diabetes. These effects are amplified by environmental stressors like obesity. We used morbid obesity as a sensitizer to identify genes that contribute to the diabetes susceptibility of the BTBR mouse strain. Using mappi... | Genetic factors are estimated to contribute approximately 50% towards the risk of developing type 2 diabetes (T2D) [1]. Recent genome-wide association studies have identified a number of “diabetes genes”, gene loci that act in an additive manner and conspire with obesity to augment the risk of T2D. Nearly all of these ... |
10.1371/journal.pgen.1005108 | GAGA Factor Maintains Nucleosome-Free Regions and Has a Role in RNA Polymerase II Recruitment to Promoters | Previous studies have shown that GAGA Factor (GAF) is enriched on promoters with paused RNA Polymerase II (Pol II), but its genome-wide function and mechanism of action remain largely uncharacterized. We assayed the levels of transcriptionally-engaged polymerase using global run-on sequencing (GRO-seq) in control and G... | Transcriptional regulation is critical for proper gene expression in response to environmental changes and developmental programs. Eukaryotes have evolved multiple mechanisms by which transcription factors regulate transcription. One mechanism is the reorganization of chromatin to allow Pol II recruitment. Another is t... | Transcription is controlled by transcription factors (TFs) that modulate various steps in the transcription process. Two major points of transcription regulation are recruitment of Pol II to a preinitiation complex (PIC) and promoter-proximal pausing. PICs form when general transcription factors bind to accessible nucl... |
10.1371/journal.ppat.1006350 | NLRX1 negatively modulates type I IFN to facilitate KSHV reactivation from latency | Kaposi’s sarcoma-associated herpesvirus (KSHV) is a herpesvirus that is linked to Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD). KSHV establishes persistent latent infection in the human host. KSHV undergoes periods of spontaneous reactivation where it can enter the l... | Kaposi’s sarcoma-associated herpesvirus (KSHV) is linked to a number of different human cancers, including Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD). KSHV predominantly establishes life-long latency in the infected host. Lytic reactivation from latency is critical... | Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is a linear double-stranded DNA virus. It is causally linked with Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD) [1, 2]. In the majority of KS lesion cells or PEL cells, KSHV mai... |
10.1371/journal.pntd.0000787 | Arboviral Etiologies of Acute Febrile Illnesses in Western South America, 2000–2007 | Arthropod-borne viruses (arboviruses) are among the most common agents of human febrile illness worldwide and the most important emerging pathogens, causing multiple notable epidemics of human disease over recent decades. Despite the public health relevance, little is know about the geographic distribution, relative im... | Over recent decades, the variety and quantity of diseases caused by viruses transmitted to humans by mosquitoes and other arthropods (also known as arboviruses) have increased around the world. One difficulty in studying these diseases is the fact that the symptoms are often non-descript, with patients reporting such s... | Over the past few decades there has been a global resurgence of arthropod-borne viral pathogens (arboviruses) worldwide [1], [2], particularly those transmitted by mosquitoes. Despite the public health relevance, the geographic range, relative impact, and epidemiologic characteristics associated with arbovirus infectio... |
10.1371/journal.ppat.1000043 | Human-Like Receptor Specificity Does Not Affect the Neuraminidase-Inhibitor Susceptibility of H5N1 Influenza Viruses | If highly pathogenic H5N1 influenza viruses acquire affinity for human rather than avian respiratory epithelium, will their susceptibility to neuraminidase (NA) inhibitors (the likely first line of defense against an influenza pandemic) change as well? Adequate pandemic preparedness requires that this question be answe... | If the avian influenza H5N1 viruses adapt to human hosts, the first step is likely to be a switch in the preference of their viral hemagglutinin (HA) glycoprotein to bind to human rather than avian cell receptors. Such a switch may also alter virus susceptibility to neuraminidase (NA) inhibitors, which are anti-influen... | The spread of highly pathogenic avian influenza A (H5N1) viruses from Asia to the Middle East, Europe, and Africa raises serious concern about a potential human pandemic [1],[2]. H5N1 avian influenza virus has been reported in poultry in 63 countries; 359 human cases have been confirmed in 14 countries, with a mortalit... |
10.1371/journal.ppat.1003189 | Functional Plasticity in the Type IV Secretion System of Helicobacter pylori | Helicobacter pylori causes clinical disease primarily in those individuals infected with a strain that carries the cytotoxin associated gene pathogenicity island (cagPAI). The cagPAI encodes a type IV secretion system (T4SS) that injects the CagA oncoprotein into epithelial cells and is required for induction of the pr... | Helicobacter pylori is a bacterium that colonizes the stomach of about half the world's population, most of whom are asymptomatic. However, some strains of H. pylori express a bacterial secretion system, a sort of molecular syringe that injects a bacterial protein inside the gastric cells and causes inflammation that c... | Helicobacter pylori commonly infects the human gastric epithelium and sometimes causes peptic ulcer disease or gastric cancer, which is the second most common cause of cancer death worldwide. The H. pylori virulence locus most strongly associated with clinical disease, rather than asymptomatic infection, is the cag pat... |
10.1371/journal.pgen.1006799 | Evolutionary forces affecting synonymous variations in plant genomes | Base composition is highly variable among and within plant genomes, especially at third codon positions, ranging from GC-poor and homogeneous species to GC-rich and highly heterogeneous ones (particularly Monocots). Consequently, synonymous codon usage is biased in most species, even when base composition is relatively... | In protein coding genes, base composition strongly varies within and among plant genomes, especially at positions where changes do not alter the coded protein (synonymous variations). Some species, such as the model plant Arabidopsis thaliana, are relatively GC-poor and homogeneous while others, such as grasses, are hi... | Base composition strongly varies across and within plant genomes [1]. This is especially striking at the coding sequence level for synonymous sites where highly contrasted patterns are observed. Most Gymnosperms, basal Angiosperms and Eudicots have relatively GC-poor and homogeneous genomes. In contrast, Monocot specie... |
10.1371/journal.pgen.1007027 | MiR-125a Is a critical modulator for neutrophil development | MicroRNAs are universal post-transcriptional regulators in genomes. They have the ability of buffering gene expressional programs, contributing to robustness of biological systems and playing important roles in development, physiology and diseases. Here, we identified a microRNA, miR-125a, as a positive regulator of gr... | MicroRNAs are critical epigenetic modulators in development, physiology and disease processes. Many miRNAs are involved in immune cell development and function, like miR-150 for B cells, miR-181a for T cells. However, studies of miRNAs involvement in granulocyte development and function and related diseases are still l... | Neutrophils, also known as polymorphonuclear leukocytes (PMNs), are the most abundant granulocytes which play a crucial role in immune defense and inflammatory reaction. Given that the post-mitotic nature of mature neutrophils, they have short lives about only a few days [1] and need to be regenerated constantly throug... |
10.1371/journal.pbio.1000184 | Glia and Muscle Sculpt Neuromuscular Arbors by Engulfing Destabilized Synaptic Boutons and Shed Presynaptic Debris | Synapse remodeling is an extremely dynamic process, often regulated by neural activity. Here we show during activity-dependent synaptic growth at the Drosophila NMJ many immature synaptic boutons fail to form stable postsynaptic contacts, are selectively shed from the parent arbor, and degenerate or disappear from the ... | The synapse is the fundamental unit of communication between neurons and their target cells. As the nervous system matures, synapses often need to be added, removed, or otherwise remodeled to accommodate the changing needs of the circuit. Such changes are often regulated by the activity of the circuit and are thought t... | The wiring of the nervous system, from initial axon sprouting to the formation of specific synaptic connections, represents one of the most dramatic and precise examples of directed cellular outgrowth. Developing axons navigate sometimes tortuous routes as they seek out the appropriate target cells. Once in their targe... |
10.1371/journal.pntd.0006689 | Understanding perceptions on 'Buruli' in northwestern Uganda: A biosocial investigation | An understudied disease, little research thus far has explored responses to Buruli ulcer and quests for therapy from biosocial perspective, despite reports that people seek biomedical treatment too late.
Taking an inductive approach and drawing on long-term ethnographic fieldwork in 2013–14, this article presents persp... | Buruli ulcer, a neglected tropical disease, has been described as an emerging public health problem in parts of sub-Saharan Africa. One of the challenges highlighted by the World Health Organisation (WHO) is improving access to biomedical healthcare. A research priority is thus to determine local understandings of skin... | A so-called neglected tropical diseases, Buruli ulcer occurs in rural areas with limited access to safe water, basic medical care and education [1]. Caused by Mycobacterium ulcerans, similar to mycobacterium that cause leprosy and tuberculosis, people affected develop nodules and other skin lesions typically on exposed... |
10.1371/journal.ppat.1005383 | EBNA3C Directs Recruitment of RBPJ (CBF1) to Chromatin during the Process of Gene Repression in EBV Infected B Cells | It is well established that Epstein-Barr virus nuclear antigen 3C (EBNA3C) can act as a potent repressor of gene expression, but little is known about the sequence of events occurring during the repression process. To explore further the role of EBNA3C in gene repression–particularly in relation to histone modification... | The Epstein-Barr nuclear protein EBNA3C is a well-characterised repressor of host gene expression in B cells growth-transformed by EBV. It is also well established that EBNA3C can interact with the cellular factor RBPJ, a DNA-binding factor in the Notch signalling pathway conserved from worms to humans. However, prior ... | Epstein-Barr virus (EBV) is a large DNA virus that belongs to the gamma subfamily of herpes viruses and infects persistently >90% of the human population. Infection with EBV is aetiologically associated with several types of human cancer, including Burkitt lymphoma, Hodgkin lymphoma, peripheral natural killer/T-cell ly... |
10.1371/journal.pntd.0005591 | An individual-level meta-analysis assessing the impact of community-level sanitation access on child stunting, anemia, and diarrhea: Evidence from DHS and MICS surveys | A lack of access to sanitation is an important risk factor child health, facilitating fecal-oral transmission of pathogens including soil-transmitted helminthes and various causes of diarrheal disease. We conducted a meta-analysis of cross-sectional surveys to determine the impact that community-level sanitation access... | A lack of access to a sanitation facility, i.e. a toilet and/or latrine, leads to numerous health challenges such as parasitic worms and environmental enteropathy. Parasitic worms are transmitted through human feces and cause multiple health complications in children including anemia and child growth stunting. Environm... | An estimated 1 billion people live without access to any type of sanitation facility, i.e. a toilet or latrine [1]. This lack of sanitation access fails to contain human feces, which are responsible for transmission of various diarrheal diseases as well as soil-transmitted helminthes (STH) primarily through the fecal-o... |
10.1371/journal.pcbi.1005631 | Grandmothering and cognitive resources are required for the emergence of menopause and extensive post-reproductive lifespan | Menopause, the permanent cessation of ovulation, occurs in humans well before the end of the expected lifespan, leading to an extensive post-reproductive period which remains a puzzle for evolutionary biologists. All human populations display this particularity; thus, it is difficult to empirically evaluate the conditi... | In all human populations, regardless of environmental and socioeconomic conditions, menopause occurs in women well before the end of their expected lifespan. Conversely, extensive post-reproductive life-span is rare in other species; except in some cetaceans. Evolutionary theory predicts that menopause and extensive po... | Menopause, the permanent cessation of ovulation, occurs in women well before the end of their expected lifespan; reproductive senescence occurs substantially earlier than somatic senescence, leading to a particularly long post-reproductive life [1]. This is a rather uniform pattern across traditional and modern human s... |
10.1371/journal.ppat.1006394 | Molecular basis for the binding and modulation of V-ATPase by a bacterial effector protein | Intracellular pathogenic bacteria evade the immune response by replicating within host cells. Legionella pneumophila, the causative agent of Legionnaires’ Disease, makes use of numerous effector proteins to construct a niche supportive of its replication within phagocytic cells. The L. pneumophila effector SidK was ide... | V-ATPase-driven acidification of lysosomes in phagocytic cells activates enzymes important for killing of phagocytized pathogens. Successful pathogens can subvert host defenses by secreting effectors that target V-ATPases to inhibit lysosomal acidification or lysosomal fusion with other cell compartments. This study re... | Acidification of intracellular compartments by vacuolar-type ATPases (V-ATPases) is crucial for numerous biological processes [1,2]. These processes include glycosylation in the Golgi [3,4], loading of neurotransmitters in secretory vesicles [5,6], protein trafficking in endosomes [7–9], and amino acid sensing in lysos... |
10.1371/journal.ppat.1004510 | Succinate Dehydrogenase is the Regulator of Respiration in Mycobacterium tuberculosis | In chronic infection, Mycobacterium tuberculosis bacilli are thought to enter a metabolic program that provides sufficient energy for maintenance of the protonmotive force, but is insufficient to meet the demands of cellular growth. We sought to understand this metabolic downshift genetically by targeting succinate deh... | This work establishes the principle that Mycobacterium tuberculosis undergoes a metabolic remodeling as oxygen concentrations fall that serves to decrease its rate of oxygen consumption and therefore oxidative phosphorylation. Furthermore, cells can be stimulated to respire, even in low oxygen conditions, by providing ... | The World Health Organization has estimated the prevalence of Tuberculosis (TB) in the human population to be nearly two billion people. Although only a fraction of those individuals will ever display symptoms, TB is still a significant cause of worldwide mortality and was responsible for 1.3 million deaths in 2012 [1]... |
10.1371/journal.pntd.0005253 | Genome-Wide Analyses of Individual Strongyloides stercoralis (Nematoda: Rhabditoidea) Provide Insights into Population Structure and Reproductive Life Cycles | The helminth Strongyloides stercoralis, which is transmitted through soil, infects 30–100 million people worldwide. S. stercoralis reproduces sexually outside the host as well as asexually within the host, which causes a life-long infection. To understand the population structure and transmission patterns of this paras... | Strongyloides stercoralis, one of the most neglected helminths causes strongyloidiasis mainly in tropical and subtropical regions worldwide. The parasite’s complex lifecycle includes sexual and asexual reproduction outside and inside the host, respectively. The parasite can also asexually complete a life cycle within t... | The helminth Strongyloides stercoralis, which is one of the most common and globally distributed human pathogens of clinical importance, infects 30–100 million people worldwide [1,2]. This parasite most often resides in areas with tropical or subtropical climates and less frequently in areas with a temperate climate. I... |
10.1371/journal.pntd.0005372 | Decline in infection-related morbidities following drug-mediated reductions in the intensity of Schistosoma infection: A systematic review and meta-analysis | Since 1984, WHO has endorsed drug treatment to reduce Schistosoma infection and its consequent morbidity. Cross-sectional studies suggest pre-treatment correlation between infection intensity and risk for Schistosoma-related pathology. However, evidence also suggests that post-treatment reduction in intensity may not r... | Schistosomiasis is the disease caused by infection with Schistosoma parasitic flukes. Depending on the infecting species, chronic Schistosoma infection can cause a variety of pathologies including liver and spleen enlargement, fibrosis and hypertension of the portal vein of the liver, or bladder ulceration and deformit... | Schistosomiasis, caused by Schistosoma spp. blood flukes, is one of the most prevalent parasitic diseases in the world, with more than 240 million people infected and 800 million at risk of infection [1]. Chronic schistosomiasis is the form of infection that is predominant in endemic areas, which bear the greatest dise... |
10.1371/journal.pgen.1002536 | The miR-35-41 Family of MicroRNAs Regulates RNAi Sensitivity in Caenorhabditis elegans | RNA interference (RNAi) utilizes small interfering RNAs (siRNAs) to direct silencing of specific genes through transcriptional and post-transcriptional mechanisms. The siRNA guides can originate from exogenous (exo–RNAi) or natural endogenous (endo–RNAi) sources of double-stranded RNA (dsRNA). In Caenorhabditis elegans... | RNA interference (RNAi) has become a widely used approach for silencing genes of interest. This tool is possible because endogenous RNA silencing pathways exist broadly across organisms, including humans, worms, and plants. The general RNAi pathway utilizes small ∼21-nucleotide RNAs to target specific protein-coding ge... | The ability of double stranded RNA (dsRNA) to induce silencing of specific genes was discovered in the nematode Caenorhabditis elegans and dubbed RNA interference (RNAi) [1]. RNAi was subsequently identified in many organisms, including mammals, providing a powerful experimental tool for inactivating specific genes [2]... |
10.1371/journal.ppat.1005487 | The Myeloid LSECtin Is a DAP12-Coupled Receptor That Is Crucial for Inflammatory Response Induced by Ebola Virus Glycoprotein | Fatal Ebola virus infection is characterized by a systemic inflammatory response similar to septic shock. Ebola glycoprotein (GP) is involved in this process through activating dendritic cells (DCs) and macrophages. However, the mechanism is unclear. Here, we showed that LSECtin (also known as CLEC4G) plays an importan... | Ebola virus (EBOV), a highly virulent pathogen, causes a severe hemorrhagic fever syndrome. The fatal infection is characterized by a systemic inflammatory response similar to septic shock. Ebola glycoprotein (GP) is thought to contribute to disease pathogenesis, as high amounts of shed GP from virus-infected cells are... | Ebola virus (EBOV), a member of the family Filoviridae, is the causative agent of severe hemorrhagic fever in humans, which is responsible for the outbreak in West African countries in 2014 [1]. Following EBOV infection, dendritic cells (DCs) and macrophages are the early and preferred replication sites of this virus, ... |
10.1371/journal.ppat.1005019 | Herpesvirus Genome Recognition Induced Acetylation of Nuclear IFI16 Is Essential for Its Cytoplasmic Translocation, Inflammasome and IFN-β Responses | The IL-1β and type I interferon-β (IFN-β) molecules are important inflammatory cytokines elicited by the eukaryotic host as innate immune responses against invading pathogens and danger signals. Recently, a predominantly nuclear gamma-interferon-inducible protein 16 (IFI16) involved in transcriptional regulation has em... | Herpesviruses establish a latent infection in the nucleus of specific cells and reactivation results in the nuclear viral dsDNA replication and infectious virus production. Host innate responses are initiated by the presence of viral genomes and their products, and nucleus associated IFI16 protein has recently emerged ... | Kaposi’s sarcoma associated herpes virus (KSHV), a γ-2 herpesvirus, is etiologically associated with Kaposi’s sarcoma (KS) and primary effusion lymphoma (PEL) [1]. The hallmark of KSHV infection is the establishment of latent infection, reactivation and reinfection, and KS and PEL lesion endothelial and B cells, respec... |
10.1371/journal.pgen.1004905 | An AP Endonuclease Functions in Active DNA Demethylation and Gene Imprinting in Arabidopsis | Active DNA demethylation in plants occurs through base excision repair, beginning with removal of methylated cytosine by the ROS1/DME subfamily of 5-methylcytosine DNA glycosylases. Active DNA demethylation in animals requires the DNA glycosylase TDG or MBD4, which functions after oxidation or deamination of 5-methylcy... | DNA cytosine methylation (5-methylcytosine, 5-meC) is an important epigenetic mark, and methylation patterns are coordinately controlled by methylation and demethylation reactions during development and reproduction. In plants, REPRESSOR OF SILENCING (ROS1) is one of the well characterized 5-meC DNA glycosylases that i... | DNA methylation is a stable epigenetic mark that regulates numerous aspects of the genome, including transposon silencing and gene expression [1]–[7]. In plants, DNA methylation can occur within CG, CHG, and CHH motifs (H represents A, T, or C). Genome-wide mapping of DNA methylation in Arabidopsis has revealed that me... |
10.1371/journal.pgen.1006597 | Bovine and murine models highlight novel roles for SLC25A46 in mitochondrial dynamics and metabolism, with implications for human and animal health | Neuropathies are neurodegenerative diseases affecting humans and other mammals. Many genetic causes have been identified so far, including mutations of genes encoding proteins involved in mitochondrial dynamics. Recently, the “Turning calves syndrome”, a novel sensorimotor polyneuropathy was described in the French Rou... | Mitochondria are essential organelles, the site of numerous biochemical reactions, with a critical role in delivering energy to cells, particularly in the nervous system. Consequently, disrupted mitochondrial function often results in neurodegenerative diseases, in humans and in other mammals. Herein, we determined tha... | Mitochondria are eukaryotic organelles with a wide range of functions. In addition to delivery of energy to cells via oxidative phosphorylation (OXPHOS), they are involved in various other bioenergetic reactions, including Krebs cycle, β-oxidation of fatty acids and heme biosynthesis. Furthermore, they have roles in ca... |
10.1371/journal.ppat.1000754 | TgMORN1 Is a Key Organizer for the Basal Complex of Toxoplasma gondii | Toxoplasma gondii is a leading cause of congenital birth defects, as well as a cause for ocular and neurological diseases in humans. Its cytoskeleton is essential for parasite replication and invasion and contains many unique structures that are potential drug targets. Therefore, the biogenesis of the cytoskeletal stru... | The disease toxoplasmosis is the result of uncontrolled growth and proliferation of the intracellular parasite Toxoplasma gondii, which is pathogenic for most warm-blooded animals. If growth of the parasite is blocked, then it does not cause disease, even though it may persist in the host as a chronic infection. Proper... | Toxoplasma gondii is one of the most successful human parasites, infecting ∼30% of the total world population. It is the most common cause of congenital neurological defects in humans, and an agent for devastating opportunistic infections in immunocompromised patients. T. gondii is also a member of the phylum Apicomple... |
10.1371/journal.pcbi.1003395 | Utilizing a Dynamical Description of IspH to Aid in the Development of Novel Antimicrobial Drugs | The nonmevalonate pathway is responsible for isoprenoid production in microbes, including H. pylori, M. tuberculosis and P. falciparum, but is nonexistent in humans, thus providing a desirable route for antibacterial and antimalarial drug discovery. We coordinate a structural study of IspH, a [4Fe-4S] protein responsib... | Drug resistance has recently entered into media conversations through the lens of MRSA (methicillin-resistant Staphylococcus aureus) infections, but conventional therapies are also failing to address resistance in cases of malaria and other bacterial infections, such as tuberculosis. To address these problems, we must ... | In the past couple decades, antimicrobial drug resistance has risen dramatically and greatly hampered the efficacy of currently available therapies for bacterial and malarial infections [1]–[9]. Whereas (multiple-)drug-resistant bacterial infections are a ubiquitous problem, affecting both the Western world and develop... |
10.1371/journal.pgen.1007409 | TGFβ signaling limits lineage plasticity in prostate cancer | Although treatment options for localized prostate cancer (CaP) are initially effective, the five-year survival for metastatic CaP is below 30%. Mutation or deletion of the PTEN tumor suppressor is a frequent event in metastatic CaP, and inactivation of the transforming growth factor (TGF) ß signaling pathway is associa... | Prostate cancer is among the leading causes of cancer deaths in men. While treatments for localized disease are quite effective, once the cancer metastasizes five-year survival rates drop to below 30%. The transforming growth factor (TGF) ß pathway is frequently inactivated in prostate cancer, and reduced expression of... | Prostate cancer (CaP) is the second-leading cause of cancer deaths in men [1], with more than 161,000 cases and nearly 27,000 deaths predicted in the US in 2017 (http://seer.cancer.gov/statfacts/html/prost.html). Although five-year survival rates for patients with localized disease are high, for patients with distant m... |
10.1371/journal.pbio.1001900 | Calcineurin Mediates Synaptic Scaling Via Synaptic Trafficking of Ca2+-Permeable AMPA Receptors | Homeostatic synaptic plasticity is a negative-feedback mechanism for compensating excessive excitation or inhibition of neuronal activity. When neuronal activity is chronically suppressed, neurons increase synaptic strength across all affected synapses via synaptic scaling. One mechanism for this change is alteration o... | Synaptic scaling is a form of homeostatic plasticity that normalizes the strength of synapses (the structure that allows nerve cells to communicate) and is triggered by chronic inhibition of neuronal activity. Although extensive studies have been conducted, the molecular mechanism of this synaptic adaptation is not und... | Synaptic scaling, a form of homeostatic synaptic plasticity, is a negative feedback process that stabilizes neuronal activity in response to changes in synaptic strength by altering various aspects of neuronal function [1]. It has been implicated in neurodevelopment and in neurological disorders [2]–[5]. One of the mec... |
10.1371/journal.ppat.1002503 | Immune Subversion and Quorum-Sensing Shape the Variation in Infectious Dose among Bacterial Pathogens | Many studies have been devoted to understand the mechanisms used by pathogenic bacteria to exploit human hosts. These mechanisms are very diverse in the detail, but share commonalities whose quantification should enlighten the evolution of virulence from both a molecular and an ecological perspective. We mined the lite... | Every pathogen is unique and uses distinctive combinations of specific mechanisms to exploit the human host. Yet, several common themes in the ways pathogens use these mechanisms can be found among distantly related bacteria. The understanding of these common themes provides useful concepts and uncovers important princ... | Bacteria are a significant part of the human body, often establishing commensal or mutualistic interactions with it [1]. Yet, some species, or some strains within species, have a significant negative impact on the host while exploiting its resources. Such antagonistic associations lead to co-evolution between the two s... |
10.1371/journal.pntd.0005484 | An integrated overview of the midgut bacterial flora composition of Phlebotomus perniciosus, a vector of zoonotic visceral leishmaniasis in the Western Mediterranean Basin | The Leishmania developmental life cycle within its sand fly vector occurs exclusively in the lumen of the insect’s digestive tract in the presence of symbiotic bacteria. The composition of the gut microbiota and the factors that influence its composition are currently poorly understood. A set of factors, including the ... | The use of conventional microbiological methods gave us the opportunity to investigate the richness of symbiotic bacteria that inhabit the gut of P. perniciosus during its main period of activity. Our results were subsequently analyzed in the framework of what has been done on sand flies microbiota in order to validate... | Sand flies are vectors of various pathogens, including arboviruses and bacteria, but are best known as the principal vectors of Leishmania, the etiological agent of leishmaniasis, a neglected tropical disease with clinical symptoms varying in form from cutaneous to visceral [1,2]. According to the most recent reports, ... |
10.1371/journal.pgen.1007901 | Functional divergence of a global regulatory complex governing fungal filamentation | Morphogenetic transitions are prevalent in the fungal kingdom. For a leading human fungal pathogen, Candida albicans, the capacity to transition between yeast and filaments is key for virulence. For the model yeast Saccharomyces cerevisiae, filamentation enables nutrient acquisition. A recent functional genomic screen ... | Fungal infections pose a severe burden to human health worldwide. Candida albicans is a leading cause of systemic fungal infections, with mortality rates approaching 40%. One of the key virulence traits of this fungus is its ability to transition between yeast and filamentous forms in response to diverse host-relevant ... | The fungal kingdom is recognized for its vast morphological plasticity, with many species capable of undergoing morphogenetic transformations in response to diverse environmental cues. For instance, filamentous fungi such as Aspergillus fumigatus undergo spore germination and branching throughout their life cycle, derm... |
10.1371/journal.pgen.1000145 | Antagonism between DNA and H3K27 Methylation at the Imprinted Rasgrf1 Locus | At the imprinted Rasgrf1 locus in mouse, a cis-acting sequence controls DNA methylation at a differentially methylated domain (DMD). While characterizing epigenetic marks over the DMD, we observed that DNA and H3K27 trimethylation are mutually exclusive, with DNA and H3K27 methylation limited to the paternal and matern... | Methylation of DNA and histones exert profound and inherited effects on gene expression. These occur without changes to the underlying DNA sequence and are considered epigenetic effects. Disrupting epigenetic states can cause developmental abnormalities and cancer. Very little is known about how locations in the mammal... | In mammals, imprinted loci are expressed from only one allele. Accompanying and controlling monoallelic expression are allele-specific epigenetic modifications influenced by an imprinting control region (ICR). Within this region, there is a differentially methylated domain (DMD) that is subject to acquisition of epigen... |
10.1371/journal.pbio.0060105 | Biogenesis of the Trypanosome Endo-Exocytotic Organelle Is Cytoskeleton Mediated | Trypanosoma brucei is a protozoan parasite that is used as a model organism to study such biological phenomena as gene expression, protein trafficking, and cytoskeletal biogenesis. In T. brucei, endocytosis and exocytosis occur exclusively through a sequestered organelle called the flagellar pocket (FP), an invaginatio... | Trypanosomes are ubiquitous unicellular parasites that infect humans, animals, insects, and plants. African, Asian, and some South American trypanosomes have evolved the amazing ability to change their surface coat proteins, an essential strategy for their survival. The surface coat proteins are recycled and targeted t... | Endocytosis and exocytosis in trypanosomes is performed by the flagellar pocket (FP), an important organelle that is sequestered within the cytoplasm of the posterior region of the cell. On the basis of its protein composition, the FP membrane is biochemically distinct from the flagellar or pellicular membranes [1–3] a... |
10.1371/journal.ppat.1005983 | Potent and Broad Inhibition of HIV-1 by a Peptide from the gp41 Heptad Repeat-2 Domain Conjugated to the CXCR4 Amino Terminus | HIV-1 entry can be inhibited by soluble peptides from the gp41 heptad repeat-2 (HR2) domain that interfere with formation of the 6-helix bundle during fusion. Inhibition has also been seen when these peptides are conjugated to anchoring molecules and over-expressed on the cell surface. We hypothesized that potent anti-... | HIV-1 infection persists and requires life-long therapy. Approaches to prevent viral replication in the absence of treatment will likely require effective antiviral immune responses, but this goal has been confounded by HIV-1’s ability to target CD4 T cells that coordinate adaptive immunity. We describe a novel approac... | HIV-1 infection persists in the face of suppressive anti-retroviral therapy, and following cessation of treatment, typically rebounds rapidly, generating new rounds of infection [1–4]. Viral persistence results from long-lived reservoirs that include memory CD4 T cells [5–7] and perhaps other cell types [8] that are es... |
10.1371/journal.pcbi.1007054 | Mathematical modelling reveals unexpected inheritance and variability patterns of cell cycle parameters in mammalian cells | The cell cycle is the fundamental process of cell populations, it is regulated by environmental cues and by intracellular checkpoints. Cell cycle variability in clonal cell population is caused by stochastic processes such as random partitioning of cellular components to progeny cells at division and random interaction... | All cells in multicellular organisms obey orchestrated sequences of signals to ensure developmental and homeostatic fitness under a variety of external stimuli. However, there also exist self-perpetuating stem-cell populations, the function of which is to provide a steady supply of differentiated progenitors that in tu... | The cell cycle is a process leading to cell division. It plays a critical role in tissue growth, development and regeneration of multicellular organisms. It consists of two critical phases: the S phase, in which the cell replicates its DNA, and the M phase where it divides in two progeny cells (mitosis). These phases f... |
10.1371/journal.pntd.0002824 | Reproductive Status of Onchocerca volvulus after Ivermectin Treatment in an Ivermectin-Naïve and a Frequently Treated Population from Cameroon | For two decades, onchocerciasis control has been based on mass treatment with ivermectin (IVM), repeated annually or six-monthly. This drug kills Onchocerca volvulus microfilariae (mf) present in the skin and the eyes (microfilaricidal effect) and prevents for 3–4 months the release of new mf by adult female worms (emb... | Onchocerciasis, also known as river blindness, is a parasitic disease due to the filarial nematode Onchocerca volvulus. It affects more than 37 million people worldwide, most of them (99%) living in Africa. The control of river blindness is, up to now, based on annual or six-monthly mass treatment with ivermectin. This... | The macrocyclic lactone drug ivermectin (IVM) has a broad spectrum of applications against arthropods and nematodes. In human medicine, one of the major indications for IVM is the treatment of onchocerciasis or river blindness [1]. IVM targets both the microfilariae (mf) and adult stages of Onchocerca volvulus, the fil... |
10.1371/journal.pgen.1008370 | Environmental and epigenetic regulation of Rider retrotransposons in tomato | Transposable elements in crop plants are the powerful drivers of phenotypic variation that has been selected during domestication and breeding programs. In tomato, transpositions of the LTR (long terminal repeat) retrotransposon family Rider have contributed to various phenotypes of agronomical interest, such as fruit ... | Transposons are major constituents of plant genomes and represent a powerful source of internal genetic and epigenetic variation. For example, domestication of maize has been facilitated by a dramatic change in plant architecture, the consequence of a transposition event. Insertion of transposons near genes often confe... | Transposable elements (TEs) replicate and move within host genomes. Based on their mechanisms of transposition, TEs are either DNA transposons that use a cut-and-paste mechanism or retrotransposons that transpose through an RNA intermediate via a copy-and-paste mechanism [1]. TEs make up a significant part of eukaryoti... |
10.1371/journal.pcbi.1003604 | Mechanistic, Mathematical Model to Predict the Dynamics of Tissue Genesis in Bone Defects via Mechanical Feedback and Mediation of Biochemical Factors | The link between mechanics and biology in the generation and the adaptation of bone has been well studied in context of skeletal development and fracture healing. Yet, the prediction of tissue genesis within - and the spatiotemporal healing of - postnatal defects, necessitates a quantitative evaluation of mechano-biolo... | Arising as a consequence of trauma, tumor resection, removal of necrotic or infected tissue, and congenital abnormalities, critical-sized defects are too large to heal spontaneously and therefore require surgical intervention. New surgical approaches harness the regenerative power of the periosteum, a tissue membrane c... | Critical-sized long bone defects pose a currently intractable challenge in orthopaedics as they do not heal spontaneously without surgical intervention and they are associated with significant disability and health care costs. Drawbacks of currently available treatment options, such as distraction osteogenesis, include... |
10.1371/journal.pntd.0003616 | Prevalence and Determinants of the Gender Differentials Risk Factors of Child Deaths in Bangladesh: Evidence from the Bangladesh Demographic and Health Survey, 2011 | The number of child deaths is a potential indicator to assess the health condition of a country, and represents a major health challenge in Bangladesh. Although the country has performed exceptionally well in decreasing the mortality rate among children under five over the last few decades, mortality still remains rela... | Children are a significant asset of a country. Child deaths are an important way to determine the health sector development. The effectiveness of the interventions is required to prevent child deaths. The purpose of this study is to identify the prevalence and risk factors of child deaths in Bangladesh. Data were colle... | Child deaths, which are one of the most important health indicators for a country, represent the socio-economic development of a population and have received considerable attention from national and international agencies in the last few decades because of their inclusion in the Millennium Development Goals (MDGs) [1, ... |
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