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10.1371/journal.ppat.1003029 | The Mosquito Melanization Response Is Implicated in Defense against the Entomopathogenic Fungus Beauveria bassiana | Mosquito immunity studies have focused mainly on characterizing immune effector mechanisms elicited against parasites, bacteria and more recently, viruses. However, those elicited against entomopathogenic fungi remain poorly understood, despite the ubiquitous nature of these microorganisms and their unique invasion rou... | Melanization is an important immune response and wound healing mechanism in arthropods that leads to melanin formation and deposition on microbial and wound surfaces, respectively. In the Anopheles gambiae mosquito that transmits the malaria parasite Plasmodium, melanization is dispensable for parasite killing. Further... | Melanization is an immediate immune response in arthropods leading to the physical encapsulation of pathogens in a dense melanin coat, and to the generation of toxic metabolites that can harm certain pathogens. It is also a prominent wound healing process manifested by the blackening of the wound area in arthropods. Me... |
10.1371/journal.pntd.0003433 | Host-Seeking Behavior and Dispersal of Triatoma infestans, a Vector of Chagas Disease, under Semi-field Conditions | Chagas disease affects millions of people in Latin America. The control of this vector-borne disease focuses on halting transmission by reducing or eliminating insect vector populations. Most transmission of Trypanosoma cruzi, the causative agent of Chagas disease, involves insects living within or very close to househ... | Chagas disease is transmitted by triatomine bugs that actively disperse by walking and flying. The control of this vector-borne disease focuses on reducing or eliminating the insect vector populations. Most transmission of Trypanosoma cruzi, the causative agent of Chagas disease, involves insects living within or very ... | Chagas disease, a vector-borne disease caused by the parasite Trypanosoma cruzi, affects from 7 to 8 million people in the Americas [1]. The vast majority of people infected are not detected [2], [3], and when the disease manifests clinically it cannot be reversed and can be fatal [2]–[4]. In addition to the inability ... |
10.1371/journal.pntd.0002938 | Clinical Features and Course of Ocular Toxocariasis in Adults | To investigate the clinical features, clinical course of granuloma, serologic findings, treatment outcome, and probable infection sources in adult patients with ocular toxocariasis (OT).
In this retrospective cohort study, we examined 101 adult patients diagnosed clinically and serologically with OT. Serial fundus phot... | Toxocariasis is one of America's most common neglected infections of poverty and a helminthiasis of global importance. Little is known about the epidemiologic, demographic, and clinical features of ocular toxocariasis (OT) in adult patients, and the treatment regimen for OT has not been standardized. We conducted a ret... | Toxocariasis is a globally prevalent illness caused by infestation of the parasite Toxocara canis or Toxocara cati larvae, which is the most ubiquitous gastrointestinal helminth in dogs and cats [1], [2]. Human beings generally become infected through ingestion of embryonated eggs from contaminated sources such as soil... |
10.1371/journal.pgen.1007277 | Novel function of HATs and HDACs in homologous recombination through acetylation of human RAD52 at double-strand break sites | The p300 and CBP histone acetyltransferases are recruited to DNA double-strand break (DSB) sites where they induce histone acetylation, thereby influencing the chromatin structure and DNA repair process. Whether p300/CBP at DSB sites also acetylate non-histone proteins, and how their acetylation affects DSB repair, rem... | DNA double strand breaks (DSBs) are the most dangerous type of DNA damage in cells. Homologous recombination (HR) is a DSB repair system in which a central player, RAD51, functions with several proteins, including RAD52. DSBs activate the DNA damage response signaling network, in which the ataxia telangiectasia mutated... | Ionizing radiation (IR) induces deleterious DNA lesions, such as DNA double-strand breaks (DSB). In response to DSBs, DNA damage response (DDR) signaling is induced. Ataxia telangiectasia mutated (ATM) protein kinase is one of the central players for phosphorylation-mediated DDR signaling, which is activated at DSB sit... |
10.1371/journal.pgen.1006561 | Rapid turnover of DnaA at replication origin regions contributes to initiation control of DNA replication | DnaA is a conserved key regulator of replication initiation in bacteria, and is homologous to ORC proteins in archaea and in eukaryotic cells. The ATPase binds to several high affinity binding sites at the origin region and upon an unknown molecular trigger, spreads to several adjacent sites, inducing the formation of ... | Initiation of replication is a key event in the cell cycle of all living cells, and is mediated by the ATPase DnaA in bacteria, and by ORC proteins in eukaryotic cells. DnaA binds to several high affinity binding sites at the origin region of replication (oriC) on the bacterial chromosome, triggers the unwinding of the... | All cells must be able to integrate environmental and internal physiological cues into the decision when to commence the duplication of the genome in order to initiate the proliferation cycle. Nature appears to have invented the process of replication initiation only once, because the key players, called ORC in eukaryo... |
10.1371/journal.pmed.1002492 | Progression of the first stage of spontaneous labour: A prospective cohort study in two sub-Saharan African countries | Escalation in the global rates of labour interventions, particularly cesarean section and oxytocin augmentation, has renewed interest in a better understanding of natural labour progression. Methodological advancements in statistical and computational techniques addressing the limitations of pioneer studies have led to... | Dr Emmanuel Friedman’s studies on normal and abnormal labour progression have defined how labour should be managed since the mid-1950s until today. Although Friedman’s studies were conducted among pregnant women in the United States, the general belief that labour progression is the same in humans led to universal appl... | From the mid-1950s until the 1980s, Dr Emmanuel Friedman published a series of landmark studies describing the patterns of labour progression in nulliparous and multiparous women [1–9]. The classic sigmoidal labour curve derived from his work has defined the fundamental basis of labour management for more than six deca... |
10.1371/journal.pcbi.1002749 | The Role of Flexibility and Conformational Selection in the Binding Promiscuity of PDZ Domains | In molecular recognition, it is often the case that ligand binding is coupled to conformational change in one or both of the binding partners. Two hypotheses describe the limiting cases involved; the first is the induced fit and the second is the conformational selection model. The conformational selection model requir... | Proteins that are capable of binding to many different ligands are said to have broad specificity. This is sometimes also referred to as promiscuity. Whether a protein is promiscuous or not can sometimes be readily explained by the structure of the protein and the ligand in terms of electrostatic and steric effects. So... | A number of structural studies comparing holo and apo forms of proteins have demonstrated that ligand binding is often coupled to conformational changes of the interacting partners [1]–[3]. The real challenge is, however, to uncover the exact sequence of events resulting in the observed structural changes. Two main mod... |
10.1371/journal.pntd.0001874 | Cytokine Responses to Novel Antigens in an Indian Population Living in an Area Endemic for Visceral Leishmaniasis | There are no effective vaccines for visceral leishmaniasis (VL), a neglected parasitic disease second only to malaria in global mortality. We previously identified 14 protective candidates in a screen of 100 Leishmania antigens as DNA vaccines in mice. Here we employ whole blood assays to evaluate human cytokine respon... | Visceral leishmaniasis is a parasitic infection that results in death in susceptible people unless they are treated. Current drugs are expensive and toxic, and there are no vaccines in use in humans. We know that it is possible to become immune to infection with this parasite because people who have been cured using dr... | Visceral leishmaniasis (VL), also known as kala-azar, is a potentially fatal disease caused by obligate intracellular parasites of the Leishmania donovani species complex. VL is a serious public health problem in indigenous and rural populations in India, accounting for enormous morbidity and mortality, as well as majo... |
10.1371/journal.pcbi.1003315 | Prediction of Drug-Target Interactions for Drug Repositioning Only Based on Genomic Expression Similarity | Small drug molecules usually bind to multiple protein targets or even unintended off-targets. Such drug promiscuity has often led to unwanted or unexplained drug reactions, resulting in side effects or drug repositioning opportunities. So it is always an important issue in pharmacology to identify potential drug-target... | Small drug molecules usually bind to unintended off-targets, leading to unexpected drug responses such as side effects or drug repositioning opportunities. Thus, identifying unintended drug-target interactions (DTI) is particularly required for understanding complicated drug actions. It remains expensive nowadays to ex... | Drug promiscuity refers to the phenomenon that small molecule drug binds to multiple protein targets. In recent years, drug promiscuity has gained broad attention [1]–[3], because unintended drugs-target interactions (DTI) are often associated with drug repositioning [4] and side effects [5]–[8]. Although biotechnology... |
10.1371/journal.pcbi.1004663 | Discovery of Influenza A Virus Sequence Pairs and Their Combinations for Simultaneous Heterosubtypic Targeting that Hedge against Antiviral Resistance | The multiple circulating human influenza A virus subtypes coupled with the perpetual genomic mutations and segment reassortment events challenge the development of effective therapeutics. The capacity to drug most RNAs motivates the investigation on viral RNA targets. 123,060 segment sequences from 35,938 strains of th... | An average of three influenza pandemics occurred in each century over the last 300 years. As occurrence of the next influenza pandemic is definite, developing new antivirals is imperative since resistance to the remaining class of antivirals has been reported occasionally, and vaccines are ineffective in the initial wa... | An average of three influenza pandemics occurred in each century over the last 300 years [1]. The time interval between consecutive pandemics and their respective mortality are however irregular; while the 1918 H1N1 Spanish flu was estimated to kill 50 million people, the 2009 H1N1 Swine flu pandemic was probably respo... |
10.1371/journal.pcbi.1006075 | Spatial modeling of the membrane-cytosolic interface in protein kinase signal transduction | The spatial architecture of signaling pathways and the interaction with cell size and morphology are complex, but little understood. With the advances of single cell imaging and single cell biology, it becomes crucial to understand intracellular processes in time and space. Activation of cell surface receptors often tr... | Frequently, cells detect signals at their surface, which are transmitted to the nucleus. The influence of cell shape and size is often neglected and cells are regarded as well-mixed compartments. However, the advance of modern microscopy has unraveled heterogeneous distribution of signaling molecules in the cell and va... | Cells need to respond to a large variety of external stimuli such as environmental changes or extracellular communication signals. Signals transmitted from cell surface receptors to target genes in the nucleus are frequently transduced by cascades of covalent protein modifications. These modifications consist of inter-... |
10.1371/journal.ppat.1007209 | A fully-virulent retargeted oncolytic HSV armed with IL-12 elicits local immunity and vaccine therapy towards distant tumors | Oncolytic herpes simplex viruses (oHSVs) showed efficacy in clinical trials and practice. Most of them gain cancer-specificity from deletions/mutations in genes that counteract the host response, and grow selectively in cancer cells defective in anti-viral response. Because of the deletions/mutations, they are frequent... | There is increasing interest in oncolytic viruses (OVs), following the approval of OncovexGM-CSF, and the success of a number of them in clinical trials. Most OVs, particularly the oHSVs, are attenuated to varying degree. In contrast, the tropism-retargeted oHSVs are fully-virulent, highly effective oncolytic agents, a... | Oncolytic viruses (OVs) meet the need for novel anticancer agents characterized by low toxicity and low negative impact on the quality of life of patients [1–4]. Oncolytic herpes simplex viruses (oHSVs) stand for their efficacy in a number of clinical applications [5,6]. The most successful oHSV, OncovexGM-CSF, was app... |
10.1371/journal.pntd.0001839 | Molecular Diagnostics for Lassa Fever at Irrua Specialist Teaching Hospital, Nigeria: Lessons Learnt from Two Years of Laboratory Operation | Lassa fever is a viral hemorrhagic fever endemic in West Africa. However, none of the hospitals in the endemic areas of Nigeria has the capacity to perform Lassa virus diagnostics. Case identification and management solely relies on non-specific clinical criteria. The Irrua Specialist Teaching Hospital (ISTH) in the ce... | In the past, diagnostic testing for Lassa fever patients in Nigeria has been performed nearly exclusively outside of the country. Patients thus were managed on-site based on clinical suspicion alone, posing risks to patients and health care workers and exhausting resources. To tackle this problem, we established a diag... | Lassa fever is a viral hemorrhagic fever that was first described in 1969 in the town of Lassa in the North-East of Nigeria [1]. It is endemic in the West African countries of Sierra Leone, Guinea, Liberia, and Nigeria ([2], [3] and references therein). Cases imported to Europe indicate that Lassa fever also occurs in ... |
10.1371/journal.pgen.1003589 | H-NS Can Facilitate Specific DNA-binding by RNA Polymerase in AT-rich Gene Regulatory Regions | Extremely AT-rich DNA sequences present a challenging template for specific recognition by RNA polymerase. In bacteria, this is because the promoter −10 hexamer, the major DNA element recognised by RNA polymerase, is itself AT-rich. We show that Histone-like Nucleoid Structuring (H-NS) protein can facilitate correct re... | The information required to build and maintain a cell is written into an organism's DNA in the form of genes. When individual genes are “read,” the DNA code is transcribed into an mRNA molecule by RNA polymerase. Hence, the DNA sequence adjacent to the start of a gene must contain a signal to recruit RNA polymerase. In... | Transcription is initiated by binding of RNA polymerase to specific DNA sequences known as promoters [1]. Following promoter recognition the resulting complex undergoes a process of isomerisation. Hence, ∼14 base pairs (bp) of DNA, close to the transcription start site, are unwound [2]. RNA polymerase then engages in a... |
10.1371/journal.pgen.1006025 | Mapping Topoisomerase IV Binding and Activity Sites on the E. coli Genome | Catenation links between sister chromatids are formed progressively during DNA replication and are involved in the establishment of sister chromatid cohesion. Topo IV is a bacterial type II topoisomerase involved in the removal of catenation links both behind replication forks and after replication during the final sep... | DNA topoisomerases are ubiquitous enzymes that solve the topological problems associated with replication, transcription and recombination. Type II Topoisomerases play a major role in the management of newly replicated DNA. They contribute to the condensation and segregation of chromosomes to the future daughter cells ... | DNA replication of a circular bacterial chromosome involves strong DNA topology constraints that are modulated by the activity of DNA topoisomerases [1]. Our current understanding of these topological modifications comes from extensive studies on replicating plasmids [2, 3] These studies suggest that positive supercoil... |
10.1371/journal.ppat.1001211 | Glycosylation Focuses Sequence Variation in the Influenza A Virus H1 Hemagglutinin Globular Domain | Antigenic drift in the influenza A virus hemagglutinin (HA) is responsible for seasonal reformulation of influenza vaccines. Here, we address an important and largely overlooked issue in antigenic drift: how does the number and location of glycosylation sites affect HA evolution in man? We analyzed the glycosylation st... | Influenza A virus is highly susceptible to neutralizing antibodies specific for the viral hemagglutinin glycoprotein (HA), and is easily controlled by standard vaccines. Influenza A virus remains an important human pathogen, however, due to its ability to rapidly evade antibody responses. This process, termed antigenic... | The influenza A virus (IAV) hemagglutinin (HA) is a homotrimeric glycoprotein that initiates infection by attaching virus to host cell sialic acids and mediating fusion of viral and endosomal membranes [1]. HA consists of a fibrous stem inserted into the viral membrane supporting a globular domain containing three sial... |
10.1371/journal.pcbi.1002267 | Dynamical and Structural Analysis of a T Cell Survival Network Identifies Novel Candidate Therapeutic Targets for Large Granular Lymphocyte Leukemia | The blood cancer T cell large granular lymphocyte (T-LGL) leukemia is a chronic disease characterized by a clonal proliferation of cytotoxic T cells. As no curative therapy is yet known for this disease, identification of potential therapeutic targets is of immense importance. In this paper, we perform a comprehensive ... | T-LGL leukemia is a blood cancer characterized by an abnormal increase in the abundance of a type of white blood cell called T cell. Since there is no known curative therapy for this disease, identification of potential therapeutic targets is of utmost importance. Experimental identification of manipulations capable of... | Living cells perceive and respond to environmental perturbations in order to maintain their functional capabilities, such as growth, survival, and apoptosis. This process is carried out through a cascade of interactions forming complex signaling networks. Dysregulation (abnormal expression or activity) of some componen... |
10.1371/journal.ppat.1005703 | Chitosan Mediates Germling Adhesion in Magnaporthe oryzae and Is Required for Surface Sensing and Germling Morphogenesis | The fungal cell wall not only plays a critical role in maintaining cellular integrity, but also forms the interface between fungi and their environment. The composition of the cell wall can therefore influence the interactions of fungi with their physical and biological environments. Chitin, one of the main polysacchar... | Magnaporthe oryzae is a filamentous fungal pathogen which causes devastating crop losses in rice. Successful invasion of the host is dependent upon the ability of the fungus to remain undetected by the innate immune system of the plant, which recognizes conserved components of the fungal cell wall, such as chitin. Prev... | All fungal cells are encased within a cell wall. This complex and dynamic structural barrier is composed of interwoven polysaccharides and proteins. Indeed, the polysaccharide moiety makes up the majority of the fungal wall, being comprised of chitin (a polymer of β1,4-N-acetylglucosamine), β/α1,3-glucans and mannans [... |
10.1371/journal.pntd.0002815 | Trends in the Epidemiology of Pandemic and Non-pandemic Strains of Vibrio parahaemolyticus Isolated from Diarrheal Patients in Kolkata, India | A total of 178 strains of V. parahaemolyticus isolated from 13,607 acute diarrheal patients admitted in the Infectious Diseases Hospital, Kolkata has been examined for serovar prevalence, antimicrobial susceptibility and genetic traits with reference to virulence, and clonal lineages. Clinical symptoms and stool charac... | Vibrio parahaemolyticus has been associated with several epidemics of foodborne diarrheal infection. Recent observations in several counties have shown the emergence of pandemic strains of V. parahaemolyticus with unique genetic features and their role in diarrheal outbreaks. Unlike other enteric pathogens, the appeara... | Vibrio parahaemolyticus is a Gram-negative bacterium, which is normally found in several niches of the coastal environments. In humans, this pathogen causes three major clinical syndromes: gastroenteritis, wound infections and septicemia [1]. Intestinal infections caused by this pathogen are mainly associated with the ... |
10.1371/journal.pcbi.1005215 | Combined Changes in Chloride Regulation and Neuronal Excitability Enable Primary Afferent Depolarization to Elicit Spiking without Compromising its Inhibitory Effects | The central terminals of primary afferent fibers experience depolarization upon activation of GABAA receptors (GABAAR) because their intracellular chloride concentration is maintained above electrochemical equilibrium. Primary afferent depolarization (PAD) normally mediates inhibition via sodium channel inactivation an... | Postsynaptic GABAAR mediate inhibition by causing hyperpolarization or by preventing (shunting) the depolarization caused by concurrent excitatory input. Presynaptic GABAAR work differently, in the spinal cord at least. Because of their higher-than-equilibrium intracellular chloride concentration, the central terminals... | Synaptic inhibition regulates transmission of sensory signals through the spinal cord. Importantly, numerous chronic pain conditions are associated with diminished inhibition [1–5] and pharmacological blockade of inhibition at the spinal level has been shown to reproduce many features of those chronic pain conditions [... |
10.1371/journal.pgen.1006278 | Evolution of New cis-Regulatory Motifs Required for Cell-Specific Gene Expression in Caenorhabditis | Patterning of C. elegans vulval cell fates relies on inductive signaling. In this induction event, a single cell, the gonadal anchor cell, secretes LIN-3/EGF and induces three out of six competent precursor cells to acquire a vulval fate. We previously showed that this developmental system is robust to a four-fold vari... | Diversification of mechanisms regulating gene expression of key developmental factors is a major force in the evolution of development. However, in the past, comparisons of gene expression across different species have often been qualitative (i.e. ‘expression is on versus off’ in a certain cell) without precise quantif... | Developmental systems operate in the presence of stochastic, environmental and genetic perturbations. While the output of a developmental system may be under stabilizing selection and remain mostly invariant, many internal variables such as the expression of a key gene or the activity of signalling pathways can be sens... |
10.1371/journal.pgen.1000120 | Mechanisms of Cell Cycle Control Revealed by a Systematic and Quantitative Overexpression Screen in S. cerevisiae | Regulation of cell cycle progression is fundamental to cell health and reproduction, and failures in this process are associated with many human diseases. Much of our knowledge of cell cycle regulators derives from loss-of-function studies. To reveal new cell cycle regulatory genes that are difficult to identify in los... | All cells require proper cell cycle regulation; failure leads to numerous human diseases. Cell cycle mechanisms are broadly conserved across eukaryotes, with many key regulatory genes known. Nonetheless, our knowledge of regulators is incomplete. Many classic studies have analyzed yeast loss-of-function mutants to iden... | The budding yeast Saccharomyces cerevisiae undergoes a cell cycle similar to other eukaryotic organisms except for the lack of nuclear envelope dissolution during mitosis and the production of daughter cells via budding, and thus budding yeast has become a model system for studying eukaryotic cell cycle progression [1]... |
10.1371/journal.pcbi.1002378 | A Cell-based Computational Modeling Approach for Developing Site-Directed Molecular Probes | Modeling the local absorption and retention patterns of membrane-permeant small molecules in a cellular context could facilitate development of site-directed chemical agents for bioimaging or therapeutic applications. Here, we present an integrative approach to this problem, combining in silico computational models, in... | We have developed an integrative, cell-based modeling approach to facilitate the design and discovery of chemical agents directed to specific sites of action within a living organism. Here, a computational, multiscale transport model of the lung was adapted to enable virtual screening of small molecules targeting the e... | Local administration of therapeutic agents or bioimaging probes is commonly used to maximize concentrations at a desired site of action and to minimize side effects or background signals associated with distribution in off-target sites. However, in the specific case of inhaled, small molecule therapeutic agents or bioi... |
10.1371/journal.ppat.1007609 | Human IFIT proteins inhibit lytic replication of KSHV: A new feed-forward loop in the innate immune system | Kaposi’s sarcoma-associated herpesvirus (KSHV) is causally associated with Kaposi’s sarcoma, primary effusion lymphoma (PEL) and multicentric Castleman’s disease. The IFIT family of proteins inhibits replication of some viruses, but their effects on KSHV lytic replication was unknown. Here we show that KSHV lytic repli... | The innate immune response to infections is triggered by recognition of pathogens as foreign or non-self. Recognition of invading pathogens is carried out by various sensors or pattern recognition receptors (PRRs) that detect conserved features of pathogens including lipids, nucleic acids and proteins. PRR activation t... | Kaposi’s sarcoma-associated herpesvirus (KSHV, HHV8) is causally associated with Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman’s disease (for a review, see reference [1]). KSHV maintains a persistent latent infection in B lymphocytes, from which it occasionally reactivates, enters a ... |
10.1371/journal.pcbi.1005583 | Linking structure and activity in nonlinear spiking networks | Recent experimental advances are producing an avalanche of data on both neural connectivity and neural activity. To take full advantage of these two emerging datasets we need a framework that links them, revealing how collective neural activity arises from the structure of neural connectivity and intrinsic neural dynam... | Neuronal networks, like many biological systems, exhibit variable activity. This activity is shaped by both the underlying biology of the component neurons and the structure of their interactions. How can we combine knowledge of these two things—that is, models of individual neurons and of their interactions—to predict... | A fundamental goal in computational neuroscience is to understand how network connectivity and intrinsic neuronal dynamics relate to collective neural activity, and in turn drive neural computation. Experimental advances are vastly expanding both the scale and the resolution with which we can measure both neural connec... |
10.1371/journal.pbio.1000025 | Neuropilin-1/GIPC1 Signaling Regulates α5β1 Integrin Traffic and Function in Endothelial Cells | Neuropilin 1 (Nrp1) is a coreceptor for vascular endothelial growth factor A165 (VEGF-A165, VEGF-A164 in mice) and semaphorin 3A (SEMA3A). Nevertheless, Nrp1 null embryos display vascular defects that differ from those of mice lacking either VEGF-A164 or Sema3A proteins. Furthermore, it has been recently reported that ... | The vascular system is a hierarchical network of blood vessels lined by endothelial cells that, by means of the transmembrane integrin proteins, bind to the surrounding proteinaceous extracellular matrix (ECM). Integrins are required for proper cardiovascular development and exist in bent (inactive) and extended (activ... | In vertebrates, the development of a hierarchically organized and functional vascular tree relies on the dynamic interaction of endothelial cells (ECs) with the surrounding extracellular matrix (ECM), which is mediated by heterodimeric αβ integrin adhesive receptors [1]. During evolution, vertebrates have acquired an a... |
10.1371/journal.pntd.0004901 | Zika Virus, a New Threat for Europe? | Since its emergence in 2007 in Micronesia and Polynesia, the arthropod-borne flavivirus Zika virus (ZIKV) has spread in the Americas and the Caribbean, following first detection in Brazil in May 2015. The risk of ZIKV emergence in Europe increases as imported cases are repeatedly reported. Together with chikungunya vir... | In May 2015, local transmission of Zika virus (ZIKV) was reported in Brazil and since then, more than 1.5 million human cases have been reported in Latin America and the Caribbean. This arbovirus, primarily found in Africa and Asia, is mainly transmitted by Aedes mosquitoes, Aedes aegypti and Aedes albopictus. Viremic ... | Zika virus (ZIKV) (genus Flavivirus, family Flaviviridae) is an emerging arthropod-borne virus transmitted to humans by Aedes mosquitoes. ZIKV infection in humans was first observed in Africa in 1952 [1], and can cause a broad range of clinical symptoms presenting as a “dengue-like” syndrome: headache, rash, fever, and... |
10.1371/journal.pgen.1004918 | Combining Natural Sequence Variation with High Throughput Mutational Data to Reveal Protein Interaction Sites | Many protein interactions are conserved among organisms despite changes in the amino acid sequences that comprise their contact sites, a property that has been used to infer the location of these sites from protein homology. In an inter-species complementation experiment, a sequence present in a homologue is substitute... | The interactions of proteins with each other are essential for almost all biological processes. Many of the sites of protein contact have evolved to maintain these interactions, but use different sets of amino acid residues. As a result, the residues at a contact site in a protein from one species might not allow a pro... | Protein activity, folding and stability are regulated by the interactions of proteins with other macromolecules. Thus, the identification of sites on a protein where these interactions occur is a critical but difficult undertaking. In some cases, structural analyses provide these sites at high resolution. In other case... |
10.1371/journal.pntd.0005485 | Genetic diversity and population structure of the tsetse fly Glossina fuscipes fuscipes (Diptera: Glossinidae) in Northern Uganda: Implications for vector control | Uganda is the only country where the chronic and acute forms of human African Trypanosomiasis (HAT) or sleeping sickness both occur and are separated by < 100 km in areas north of Lake Kyoga. In Uganda, Glossina fuscipes fuscipes is the main vector of the Trypanosoma parasites responsible for these diseases as well for... | Northern Uganda is an epidemiologically important region affected by human African trypanosomiasis (HAT) because it harbors both forms of the HAT disease (T. b. gambiense and T. b. rhodesiense). The geographic location of this region creates the risk that these distinct foci could merge, which would complicate diagnosi... | The tsetse fly (genus Glossina) is the major vector of human African trypanosomiasis (HAT) and animal African trypanosomiasis (AAT). The diseases occur throughout sub-Saharan Africa, causing extensive morbidity and mortality in humans and livestock [1][2]. Human disease is caused by two different subspecies of the flag... |
10.1371/journal.pntd.0003262 | Evidence for Co-evolution of West Nile Virus and House Sparrows in North America | West Nile virus (WNV) has been maintained in North America in enzootic cycles between mosquitoes and birds since it was first described in North America in 1999. House sparrows (HOSPs; Passer domesticus) are a highly competent host for WNV that have contributed to the rapid spread of WNV across the U.S.; however, their... | West Nile virus (WNV) emerged in North America in 1999 and rapidly spread across the U.S. due to the presence of highly susceptible mosquito vectors and avian hosts. One of the major avian reservoirs for WNV in the U.S. is the house sparrow (HOSP), which has low mortality during WNV infection. Here, we investigate how ... | West Nile virus (WNV; Flaviviridae) is an arbovirus that was first reported in North America in 1999 in New York. By 2003, the virus had spread to the West Coast. WNV has remained endemic in the U.S. due to the high prevalence of competent Culex spp. mosquito vectors and avian hosts [1]–[4]. The birds considered to be ... |
10.1371/journal.pntd.0007068 | Very severe tungiasis in Amerindians in the Amazon lowland of Colombia: A case series | Tungiasis is a parasitic skin disease caused by penetrating female sand fleas. By nature, tungiasis is a self-limiting infection. However, in endemic settings re-infection is the rule and parasite load gradually accumulates over time. Intensity of infection and degree of morbidity are closely related.
This case series ... | Tungiasis (also called sand flea disease) is a neglected tropical disease (NTD) caused by the penetration of female sand fleas in the skin, typically at the toes, the sole or the heel. Once embedded in the upper strata of the skin, the parasite hypertrophies, enlarging its body size by a factor of 2000 within ten days.... | Tungiasis (sand flea disease), one of the most neglected tropical diseases (NTDs), is caused by female sand fleas (Tunga penetrans and more rarely T. trimamillata) penetrated into the skin. The disease is prevalent in resource-poor communities in South America, the Caribbean, sub-Saharan Africa and Madagascar [1–5]. Ch... |
10.1371/journal.pcbi.1004273 | Evolution of Self-Organized Task Specialization in Robot Swarms | Division of labor is ubiquitous in biological systems, as evidenced by various forms of complex task specialization observed in both animal societies and multicellular organisms. Although clearly adaptive, the way in which division of labor first evolved remains enigmatic, as it requires the simultaneous co-occurrence ... | Many biological systems execute tasks by dividing them into finer sub-tasks first. This is seen for example in the advanced division of labor of social insects like ants, bees or termites. One of the unsolved mysteries in biology is how a blind process of Darwinian selection could have led to such highly complex forms ... | The “major transitions in evolution”, whereby cells teamed up to form multicellular organisms or some animals went on to live in societies, are among the keys to the ecological success of much life on earth [1]. The efficiency of both organisms and animal societies frequently depends on the presence of an advanced divi... |
10.1371/journal.pgen.1000415 | Measures of Autozygosity in Decline: Globalization, Urbanization, and Its Implications for Medical Genetics | This research investigates the influence of demographic factors on human genetic sub-structure. In our discovery cohort, we show significant demographic trends for decreasing autozygosity associated with population variation in chronological age. Autozygosity, the genomic signature of consanguinity, is identifiable on ... | Population geneticists use genetic markers to quantify and compare levels of inbreeding in populations and identify disease-associated loci; epidemiologists utilize demographic factors to quantify disease risk modifiers. Our research group sought to investigate the intersection of these two disciplines and examine the ... | Rates of travel and migration within North America have increased substantially over the past century due to advancements in infrastructure and technology. It has been hypothesized that this ease of travel and globalization has shaped the demographic structure of both North American and world populations in recent gene... |
10.1371/journal.ppat.1000244 | Dissecting the Cell Entry Pathway of Dengue Virus by Single-Particle Tracking in Living Cells | Dengue virus (DENV) is an enveloped RNA virus that causes the most common arthropod-borne infection worldwide. The mechanism by which DENV infects the host cell remains unclear. In this work, we used live-cell imaging and single-virus tracking to investigate the cell entry, endocytic trafficking, and fusion behavior of... | Dengue virus (DENV) is the most common arthropod-borne infection worldwide with 50–100 million cases annually. Despite its high clinical impact, little is known about the infectious cell entry pathway of the virus. Previous studies have shown conflicting evidence about whether the virus fuses directly with the cell pla... | Dengue virus (DENV) is a mosquito-transmitted, enveloped RNA virus that belongs to the family Flaviviridae. This family also includes West-Nile virus (WNV) and tick-borne encephalitis virus (TBEV). DENV causes the most common arthropod-borne infection worldwide with 50–100 million cases annually [1]–[3]. Despite its th... |
10.1371/journal.pntd.0003844 | Diverse Genotypes of Yersinia pestis Caused Plague in Madagascar in 2007 | Yersinia pestis is the causative agent of human plague and is endemic in various African, Asian and American countries. In Madagascar, the disease represents a significant public health problem with hundreds of human cases a year. Unfortunately, poor infrastructure makes outbreak investigations challenging.
DNA was ext... | Yersinia pestis is a highly pathogenic bacterium and the causative agent of human plague. It has caused three recognized pandemics and is a current human health problem in many countries of Africa, Asia and the Americas, including Madagascar. The pathogen cannot be eradicated from natural plague foci as it persists in ... | Yersinia pestis, the causative agent of plague, is one of the most deadly zoonotic pathogens on record, with hundreds of millions of human deaths attributed to it over the course of three historical pandemics [1]. Human cases typically present in one of three forms, including bubonic, septicemic, and the contagious pne... |
10.1371/journal.ppat.1002706 | Plasticity of the β-Trefoil Protein Fold in the Recognition and Control of Invertebrate Predators and Parasites by a Fungal Defence System | Discrimination between self and non-self is a prerequisite for any defence mechanism; in innate defence, this discrimination is often mediated by lectins recognizing non-self carbohydrate structures and so relies on an arsenal of host lectins with different specificities towards target organism carbohydrate structures.... | All multicellular organisms have developed mechanisms to defend themselves against predators, parasites and pathogens. As a common mechanism, animals, plants and fungi use a large arsenal of carbohydrate-binding proteins (lectins) to protect themselves from predation and parasitism. The success of this type of innate d... | Adequate and efficient defence mechanisms to protect an organism's integrity and survival have been essential for the evolution of multicellularity since loss of individual cells may be detrimental for a multicellular organism. Any defence mechanism thereby critically relies on the ability to discriminate between self ... |
10.1371/journal.pgen.1005398 | The Relationship between Gene Network Structure and Expression Variation among Individuals and Species | Variation among individuals is a prerequisite of evolution by natural selection. As such, identifying the origins of variation is a fundamental goal of biology. We investigated the link between gene interactions and variation in gene expression among individuals and species using the mammalian limb as a model system. W... | The variation generating mechanisms of development interact with the variation sorting mechanism of natural selection to produce organismal diversity. While the impacts of natural selection on existing variation have received much study, those of development on the generation of this variation remain less understood. T... | Phenotypic variation within populations is a prerequisite of evolution by natural selection, and in theory has the potential to bias the trajectory and rate of evolutionary change [1–6]. As such, identifying the processes that shape phenotypic variation has long been a fundamental pursuit of evolutionary biologists. Hi... |
10.1371/journal.pcbi.1002154 | Change in Allosteric Network Affects Binding Affinities of PDZ Domains: Analysis through Perturbation Response Scanning | The allosteric mechanism plays a key role in cellular functions of several PDZ domain proteins (PDZs) and is directly linked to pharmaceutical applications; however, it is a challenge to elaborate the nature and extent of these allosteric interactions. One solution to this problem is to explore the dynamics of PDZs, wh... | PDZ domain proteins (PDZs) act as adapters in organizing functional protein complexes. Through dynamic interactions, PDZs play a key role in mediating key cellular functions in the cell, and they are linked to currently challenging diseases including Alzheimer's, Parkinson's and cancer. Moreover, they are associated wi... | Allosteric regulation orchestrates functional behaviors in biological networks through appropriate switches. From a biochemical perspective, allostery can be described as a perturbation at one place in a protein structure, such as the binding of a ligand that alters the binding affinity of a distant site or enzymatic a... |
10.1371/journal.pntd.0001505 | Association of Mast Cell-Derived VEGF and Proteases in Dengue Shock Syndrome | Recent in-vitro studies have suggested that mast cells are involved in Dengue virus infection. To clarify the role of mast cells in the development of clinical Dengue fever, we compared the plasma levels of several mast cell-derived mediators (vascular endothelial cell growth factor [VEGF], soluble VEGF receptors [sVEG... | To clarify the involvement of mast cells in the development of severe Dengue diseases, plasma levels of mast cell-derived mediators, namely vascular endothelial cell growth factor (VEGF), tryptase, and chymase, were estimated in Dengue patients and control subjects in Vietnam. The levels of the mediators were significa... | Dengue virus infection is associated with disease, ranging from Dengue fever (DF) to Dengue hemorrhagic fever (DHF) and/or Dengue shock syndrome (DSS). As severe diseases typically develop in individuals suffering secondary Dengue virus infection, host immunological factors appear to play a role in DHF and DSS [1]. DHF... |
10.1371/journal.pbio.0050332 | Indirect Effects of Ploidy Suggest X Chromosome Dose, Not the X:A Ratio, Signals Sex in Drosophila | In the textbook view, the ratio of X chromosomes to autosome sets, X:A, is the primary signal specifying sexual fate in Drosophila. An alternative idea is that X chromosome number signals sex through the direct actions of several X-encoded signal element (XSE) proteins. In this alternative, the influence of autosome do... | In the fruit fly, Drosophila, chromosomal signals determine sex. Diploid flies with two X chromosomes are female, whereas those with one X are male. Conventionally, it is thought that the ratio of the number of X chromosomes to autosomes (X:A) constitutes the signal, because triploid flies bearing two X chromosomes and... | Animals distinguish between numbers or kinds of sex chromosomes both to determine sex and to compensate for unequal gene expression between heterogametic (XY and ZW) and homogametic (XX and ZZ) sexes. In Drosophila and Caenorhabditis elegans, sex and dosage compensation are linked through genetic pathways that exploit ... |
10.1371/journal.pntd.0002413 | A Schistosoma haematobium-Specific Real-Time PCR for Diagnosis of Urogenital Schistosomiasis in Serum Samples of International Travelers and Migrants | Diagnosis of urogenital schistosomiasis by microscopy and serological tests may be elusive in travelers due to low egg load and the absence of seroconversion upon arrival. There is need for a more sensitive diagnostic test. Therefore, we developed a real-time PCR targeting the Schistosoma haematobium-specific Dra1 sequ... | Schistosomiasis is a disease caused by parasitic worms of the genus Schistosoma. About 200 million people are affected worldwide. Also travelers are at risk as even a brief contact with infested freshwater can cause infection. S. mansoni and S. haematobium are the two main species that are identified in travelers and m... | Urogenital schistosomiasis due to Schistosoma haematobium is a serious underestimated public health problem. It is endemic in 53 countries of the African continent and of the Middle East [1], [2]. Adult worms live in the capillary plexus of the bladder and other parts of the urino-genital system and eggs are excreted i... |
10.1371/journal.pgen.1003427 | Evolution after Introduction of a Novel Metabolic Pathway Consistently Leads to Restoration of Wild-Type Physiology | Organisms cope with physiological stressors through acclimatizing mechanisms in the short-term and adaptive mechanisms over evolutionary timescales. During adaptation to an environmental or genetic perturbation, beneficial mutations can generate numerous physiological changes: some will be novel with respect to prior p... | Acclimatizing and adaptive (evolutionary) processes allow organisms to thrive despite cellular and environmental perturbations. Our work examined whether adaptation restores stress responses towards wild-type (pre-stressed) versus novel physiological states during adaptation by studying a bacterium (Methylobacterium ex... | Physiological stressors affect organisms across individual and evolutionary timescales: they invoke in individuals processes that work to restore homeostasis, and become over evolutionary timescales the selective pressures that drive adaptation in populations. How organisms generate innate and evolved responses to stre... |
10.1371/journal.pntd.0004868 | Visceral Leishmaniasis on the Indian Subcontinent: Modelling the Dynamic Relationship between Vector Control Schemes and Vector Life Cycles | Visceral leishmaniasis (VL) is a disease caused by two known vector-borne parasite species (Leishmania donovani, L. infantum), transmitted to man by phlebotomine sand flies (species: Phlebotomus and Lutzomyia), resulting in ≈50,000 human fatalities annually, ≈67% occurring on the Indian subcontinent. Indoor residual sp... | Visceral leishmaniasis is a disease caused by a virulent vector-borne parasite transmitted to man by phlebotomine sand flies. Fipronil-based drugs, administered to cattle orally, provide a potential means of sand fly control by permeating in cattle blood and being excreted in cattle feces, targeting adult females feedi... | The deadliest form of leishmaniasis, visceral leishmaniasis (VL), is vector-transmitted through the bite of phlebotomine sand flies in the Phlebotomus and Lutzomyia genera. This protozoan parasite results in an estimated 500,000 human infections and 50,000 human fatalities annually, making it the second most prevalent ... |
10.1371/journal.ppat.1000430 | Atg5-Independent Sequestration of Ubiquitinated Mycobacteria | Like several other intracellular pathogens, Mycobacterium marinum (Mm) escapes from phagosomes into the host cytosol where it can polymerize actin, leading to motility that promotes spread to neighboring cells. However, only ∼25% of internalized Mm form actin tails, and the fate of the remaining bacteria has been unkno... | M. tuberculosis is one of the world's most prevalent pathogens, infecting one third of humans and contributing to 2 million deaths each year. M. marinum (Mm) has been increasingly studied as a model of M. tuberculosis due to its relative safety and its shared mechanisms of pathogenesis; for example, previous studies ha... | Mycobacterium marinum (Mm) is a close genetic relative of the important human pathogen M. tuberculosis, and shares with M. tuberculosis the ability to infect host macrophages, as well as to induce a similar pathologic response [1],[2]. As in mammalian models of infection with M. tuberculosis, loss of the ESX-1 secretio... |
10.1371/journal.pntd.0001922 | Differential Anti-Glycan Antibody Responses in Schistosoma mansoni-Infected Children and Adults Studied by Shotgun Glycan Microarray | Schistosomiasis (bilharzia) is a chronic and potentially deadly parasitic disease that affects millions of people in (sub)tropical areas. An important partial immunity to Schistosoma infections does develop in disease endemic areas, but this takes many years of exposure and maturation of the immune system. Therefore, c... | Schistosomes are parasitic worms that cause chronic and potentially deadly disease in millions of people in (sub)tropical areas. An important partial immunity to infection does develop but this takes many years of exposure and multiple infections. Therefore, children are far more susceptible to re-infection after treat... | Schistosomiasis (bilharzia) is a chronic and potentially deadly parasitic disease, and a major public health burden in (sub)tropical areas. An estimated 207 million people are affected and 779 million people are at risk of being infected with schistosomes [1], [2]. Schistosomiasis is caused by members of the helminth g... |
10.1371/journal.pcbi.1004502 | The Encoding of Decision Difficulty and Movement Time in the Primate Premotor Cortex | Estimating the difficulty of a decision is a fundamental process to elaborate complex and adaptive behaviour. In this paper, we show that the movement time of behaving monkeys performing a decision-making task is correlated with decision difficulty and that the activity of a population of neurons in ventral Premotor co... | Understanding how the brain produces complex cognitive functions has been a crucial question since ancient philosophical inquiries. The encoding of decision difficulty in the brain is fundamental for complex and adaptive behaviour, and can provide valuable information in uncertain environments where the future outcome ... | The information about the difficulty of a decision can be very valuable to properly allocate cognitive resources or to develop complex plans. Indeed, not only humans but even very simple form of life like honey bees are able to selectively avoid difficult decisions [1]. Moreover the degree of difficulty in a decision c... |
10.1371/journal.pgen.1000406 | The Distribution of Fitness Effects of Beneficial Mutations in Pseudomonas aeruginosa | Understanding how beneficial mutations affect fitness is crucial to our understanding of adaptation by natural selection. Here, using adaptation to the antibiotic rifampicin in the opportunistic pathogen Pseudomonas aeruginosa as a model system, we investigate the underlying distribution of fitness effects of beneficia... | Adaptation by natural selection depends on the spread of novel beneficial mutations, and one of the most important challenges in our understanding of adaptation is to be able to predict how beneficial mutations impact fitness. Here, we investigate the underlying distribution of fitness effects of beneficial mutations t... | Adaptation by natural selection ultimately depends on the spread of novel beneficial mutations that increase fitness. Can we predict the fitness effects of beneficial mutations? Gillespie[1],[2] argued that extreme value theory (EVT) provides a simple answer to this question: the tails of all-Gumbel type distributions ... |
10.1371/journal.pcbi.1006188 | Polymorphic sites preferentially avoid co-evolving residues in MHC class I proteins | Major histocompatibility complex class I (MHC-I) molecules are critical to adaptive immune defence mechanisms in vertebrate species and are encoded by highly polymorphic genes. Polymorphic sites are located close to the ligand-binding groove and entail MHC-I alleles with distinct binding specificities. Some efforts hav... | Amino acid co-evolution represents cases of simultaneous substitution of amino acids at distinct positions in protein sequences. In the MHC-I protein family, such co-evolution could result from either amino acid changes across species or changes within species due to the high polymorphism of MHC-I molecules. Here we sh... | Major Histocompatibility Complex class I proteins (MHC-I), also referred to as Human Leukocyte Antigen class I (HLA-I) in human, are expressed on the surface of cells. MHC-I proteins form a complex with either ‘self’ ligands derived from the endogenous proteins or ‘foreign’ ligands (non-self) derived from invading path... |
10.1371/journal.pntd.0001203 | The Effect of Egg Embryonation on Field-Use of a Hookworm Benzimidazole-Sensitivity Egg Hatch Assay in Yunnan Province, People's Republic of China | Current efforts to control human soil-transmitted helminths (STHs) involve the periodic mass administration of benzimidazole drugs to school aged children and other at- risk groups. Given that high levels of resistance to these drugs have developed in roundworms of livestock, there is a need to monitor drug efficacy in... | With the implementation of mass drug administration programmes for the control of human soil transmitted helminths there is a need to develop drug sensitivity monitoring tools to detect the emergence of resistance. The present study aimed to use an egg hatch assay to measure benzimidazole sensitivity in human hookworms... | Periodic mass administration of the benzimidazole drugs albendazole or mebendazole to school-aged children and other at-risk groups is the mainstay of all current programmes to control soil transmitted helminths (STHs) in humans [1]. The massive scale and increasing frequency of anthelmintic treatment mean that it is e... |
10.1371/journal.pgen.1000984 | Inactivation of hnRNP K by Expanded Intronic AUUCU Repeat Induces Apoptosis Via Translocation of PKCδ to Mitochondria in Spinocerebellar Ataxia 10 | We have identified a large expansion of an ATTCT repeat within intron 9 of ATXN10 on chromosome 22q13.31 as the genetic mutation of spinocerebellar ataxia type 10 (SCA10). Our subsequent studies indicated that neither a gain nor a loss of function of ataxin 10 is likely the major pathogenic mechanism of SCA10. Here, us... | In an earlier study, we showed that the mutation of spinocerebellar ataxia 10 (SCA10) is an enormous expansion of a gene segment, which contains a tandemly repeated 5-base (ATTCT) unit. Since SCA10 is the only known human disease that is proven to be caused by 5-base repeat expansion, it is important to learn how this ... | Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disease presented with progressive pancerebellar ataxia, leading to total disability [1]–[4]. Approximately 60% of the SCA10 patients also suffer from epilepsy with complex partial seizures and generalized tonic-clonic seizures, which bec... |
10.1371/journal.pcbi.1004467 | Genome-Wide Detection and Analysis of Multifunctional Genes | Many genes can play a role in multiple biological processes or molecular functions. Identifying multifunctional genes at the genome-wide level and studying their properties can shed light upon the complexity of molecular events that underpin cellular functioning, thereby leading to a better understanding of the functio... | Almost every aspect of cellular function depends on protein activity. In spite of being fine-tuned to carry out highly specific functions, proteins can also multitask. Experimental studies have identified genes and proteins endowed with more than one molecular function, or participating in very different biological pro... | Multifunctionality can be defined as the involvement of a gene in multiple cellular processes [1]. This can come about either because a protein coded by a gene is capable of performing distinct molecular functions [2–6], or as a result of a single molecular function being performed in different contexts [7, 8]. For exa... |
10.1371/journal.pntd.0004332 | Whole Genome Sequencing of Mycobacterium africanum Strains from Mali Provides Insights into the Mechanisms of Geographic Restriction | Mycobacterium africanum, made up of lineages 5 and 6 within the Mycobacterium tuberculosis complex (MTC), causes up to half of all tuberculosis cases in West Africa, but is rarely found outside of this region. The reasons for this geographical restriction remain unknown. Possible reasons include a geographically restri... | Mycobacterium africanum consists of two lineages, lineages 5 and 6, within the Mycobacterium tuberculosis complex (MTC) that cause human tuberculosis in West Africa, but are found rarely outside of this region. Our analysis of the whole genome sequences of 26 lineage 5 and 6 isolates, and 66 isolates from other lineage... | Mycobacterium africanum is a member of the Mycobacterium tuberculosis complex (MTC) that causes up to half of all tuberculosis cases in West Africa [1]. First identified by Castets in 1968, it was originally characterized as having biochemical characteristics intermediate between Mycobacterium tuberculosis, which consi... |
10.1371/journal.pntd.0007681 | Identification of anti-flaviviral drugs with mosquitocidal and anti-Zika virus activity in Aedes aegypti | Zika virus (ZIKV), an emerging arbovirus belonging to the genus Flavivirus, is transmitted by Aedes mosquitoes. ZIKV infection can cause microcephaly of newborn babies and Guillain–Barré syndrome in adults. Because no licensed vaccine or specific antiviral treatment is available for ZIKV infection, the most commonly us... | Zika virus (ZIKV) is a human threat with a global health burden. As many as 86 countries and territories have reported evidence of mosquito-transmitted Zika infection, and there is no effective means of control. Recently, several studies have identified FDA-approved drugs exerting anti-ZIKV activity in mammalian cells.... | Zika virus (ZIKV) belongs to the Flavivirus genus, which also includes dengue virus (DENV), West Nile (WNV), yellow fever virus (YFV) and Japanese encephalitis viruses (JEV) and is mainly transmitted by Aedes mosquitoes, including Ae. aegypti and Ae. albopictus, in an urban cycle [1]. The typical symptoms of Zika are v... |
10.1371/journal.pbio.3000189 | Ablating astrocyte insulin receptors leads to delayed puberty and hypogonadism in mice | Insulin resistance and obesity are associated with reduced gonadotropin-releasing hormone (GnRH) release and infertility. Mice that lack insulin receptors (IRs) throughout development in both neuronal and non-neuronal brain cells are known to exhibit subfertility due to hypogonadotropic hypogonadism. However, attempts ... | Astrocytes are a major cell type in the central nervous system, yet their impact on the neuroendocrine circuits that control fertility is under appreciated. Here, we show in mice that ablation of insulin signaling in astrocytes leads to delayed puberty, hypothalamic-pituitary-gonadotropin (HPG) axis dysfunction, and re... | Reproduction is essential for species survival. Because energy is required to locate a mate, maintain a pregnancy, and rear young, fertility is modulated by the status of energy stores [1–3]. Excessive energy expenditure or insufficient caloric intake in humans and rodents delays the pubertal transition and reduces fer... |
10.1371/journal.pntd.0006471 | Interruption of onchocerciasis transmission in Bioko Island: Accelerating the movement from control to elimination in Equatorial Guinea | Onchocerciasis, also known as river blindness, is a parasitic disease. More than 99 percent of all cases occur in Africa. Bioko Island (Equatorial Guinea) is the only island endemic for onchocerciasis in the world. Since 2005, when vector Simulium yahense was eliminated, there have not been any reported cases of infect... | Onchocerciasis, commonly called river blindness, is a chronic parasitic disease particularly prevalent in Africa. It is transmitted through the bites of infected Simulium blackflies. Onchocerciasis is endemic in Equatorial Guinea. Huge achievements have been made in human and vector control during the last two decades,... | Onchocerciasis is a parasitic disease caused by the filarial worm Onchocerca volvulus. It is transmitted through the bites of infected Simulium blackflies, which breed in fast-flowing streams and rivers. Symptoms include rashes, severe itching and various skin lesions, and blindness. The disease is endemic in 31 countr... |
10.1371/journal.pbio.1000085 | Coordinated Movement of Cytoplasmic and Transmembrane Domains of RyR1 upon Gating | Ryanodine receptor type 1 (RyR1) produces spatially and temporally defined Ca2+ signals in several cell types. How signals received in the cytoplasmic domain are transmitted to the ion gate and how the channel gates are unknown. We used EGTA or neuroactive PCB 95 to stabilize the full closed or open states of RyR1. Sin... | Maintaining a precise intracellular calcium concentration is key for cell survival. In skeletal muscle, ryanodine receptor type 1 (RyR1) is an intracellular calcium-release channel that is critical for contraction. Here, we used single-channel techniques to demonstrate the presence of functionally homogenous population... | Maintaining a precise intracellular Ca2+ concentration that is 10,000-fold lower than the surrounding environment of the cell, and the ability to dramatically increase intracellular calcium to trigger downstream events in response to specific stimulus are key for cell survival [1]. Ryanodine receptors (RyRs) are high-c... |
10.1371/journal.ppat.1003184 | Increased Functional Stability and Homogeneity of Viral Envelope Spikes through Directed Evolution | The functional HIV-1 envelope glycoprotein (Env) trimer, the target of anti-HIV-1 neutralizing antibodies (Abs), is innately labile and coexists with non-native forms of Env. This lability and heterogeneity in Env has been associated with its tendency to elicit non-neutralizing Abs. Here, we use directed evolution to o... | A vaccine is needed to prevent HIV/AIDS but eliciting potent neutralizing antibodies (Abs) against primary isolates has been a major stumbling block. The target of HIV-1 neutralizing antibodies is the native envelope glycoprotein (Env) trimer that is displayed on the surface of the virus. Virion associated Env typicall... | For an HIV/AIDS vaccine to be effective, it is widely thought that it should elicit high titers of broadly neutralizing antibody (Ab) [1], [2]. HIV-1 neutralizing Abs target the envelope glycoprotein (Env) spike, which is a trimer containing three copies each of the surface subunit, gp120, and the transmembrane subunit... |
10.1371/journal.pntd.0003784 | Free-Roaming Dog Population Estimation and Status of the Dog Population Management and Rabies Control Program in Dhaka City, Bangladesh | Beginning January 2012, a humane method of dog population management using a Catch-Neuter-Vaccinate-Release (CNVR) program was implemented in Dhaka City, Bangladesh as part of the national rabies control program. To enable this program, the size and distribution of the free-roaming dog population needed to be estimated... | Rabies is a public health problem in Bangladesh. A CNVR program was commenced in Dhaka City in January 2012 as part of the Bangladesh national rabies control program. We describe the findings of a dog population survey that was conducted to estimate the free-roaming dog population using a mark-resight framework and the... | Rabies kills an estimated 2,000–2,500 people every year in Bangladesh, ranking it third globally after India and China in terms of human impact [1–4]. In Bangladesh an estimated 166,590 (95% CI: 163,350–170,550) cases of animal bites in humans are reported each year, contributing to an estimated annual incidence of 1.4... |
10.1371/journal.pntd.0001890 | Filariasis Attenuates Anemia and Proinflammatory Responses Associated with Clinical Malaria: A Matched Prospective Study in Children and Young Adults | Wuchereria bancrofti (Wb) and Mansonella perstans (Mp) are blood-borne filarial parasites that are endemic in many countries of Africa, including Mali. The geographic distribution of Wb and Mp overlaps considerably with that of malaria, and coinfection is common. Although chronic filarial infection has been shown to al... | In many regions of the world, including sub-Saharan Africa, concomitant infection with multiple parasites is common. In order to examine the effects of filariasis, a chronic helminth infection, on immune responses and clinical manifestations of acute malaria infection, the authors followed 31 filaria-infected (FIL+) an... | Filarial infections and malaria are coendemic in many areas of the world, including sub-Saharan Africa, where human coinfection with malaria and filarial parasites is common [1], [2], [3]. Chronic filarial (helminth) infection is associated with skewing of parasite-specific immune responses towards a Th2/Treg cytokine ... |
10.1371/journal.pcbi.0030161 | Elucidating the Altered Transcriptional Programs in Breast Cancer using Independent Component Analysis | The quantity of mRNA transcripts in a cell is determined by a complex interplay of cooperative and counteracting biological processes. Independent Component Analysis (ICA) is one of a few number of unsupervised algorithms that have been applied to microarray gene expression data in an attempt to understand phenotype di... | The amount of a given transcript or protein in a cell is determined by a balance of expression and repression in a complex network of biological processes. This delicate balance is compromised in complex genetic diseases such as cancer by alterations in the activation patterns of functionally important biological proce... | Microarray technology is enabling genetic diseases like cancer to be studied in unprecedented detail, at both transcriptomic and genomic levels. A significant challenge that needs to be overcome to further our understanding of the relation between the quantitative transcriptome of a sample/cell and its phenotype is to ... |
10.1371/journal.pgen.1003231 | Delineating a Conserved Genetic Cassette Promoting Outgrowth of Body Appendages | The acquisition of the external genitalia allowed mammals to cope with terrestrial-specific reproductive needs for internal fertilization, and thus it represents one of the most fundamental steps in evolution towards a life on land. How genitalia evolved remains obscure, and the key to understanding this process may li... | Mammalian limbs and external genitalia are body appendages specialized for locomotion and internal fertilization, respectively. Despite their marked anatomical and functional differences, development of the limb and external genitalia appears to involve similar genetic controls, and some have suggested that regulatory ... | Development of the external genitalia is a crucial aspect of mammalian evolution that enables internal fertilization, a pivotal step towards land invasion. All therian mammals including metatherians develop external genitalia around their urogenital outlets. In mice, development of the embryonic anlage of external geni... |
10.1371/journal.pbio.0060310 | SUMO-Specific Protease 2 Is Essential for Modulating p53-Mdm2 in Development of Trophoblast Stem Cell Niches and Lineages | SUMO-specific protease 2 (SENP2) modifies proteins by removing SUMO from its substrates. Although SUMO-specific proteases are known to reverse sumoylation in many defined systems, their importance in mammalian development and pathogenesis remains largely elusive. Here we report that SENP2 is highly expressed in trophob... | Genome replication is essential for both expansion of stem cell numbers through mitosis and their maturation into certain specialized cell types through endoreduplication, a unique mechanism for multiplying chromosomes without dividing the cell. An important function of p53 as a guardian of the genome ensures that the ... | The first two distinct lineages to form in the mammalian embryos are the outer trophectoderm and the inner cell mass (ICM) of the blastocyst [1]. The trophectoderm initiates implantation and invasion of the uterus, processes that are essential for placental development [2]. This process depends on the differentiation o... |
10.1371/journal.pntd.0005912 | Use of a novel antigen expressing system to study the Salmonella enterica serovar Typhi protein recognition by T cells | Salmonella enterica serovar Typhi (S. Typhi), the causative agent of the typhoid fever, is a pathogen of great public health importance. Typhoid vaccines have the potential to be cost-effective measures towards combating this disease, yet the antigens triggering host protective immune responses are largely unknown. Giv... | Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of the life-threatening typhoid fever that affects 11.9–20.6 million individuals annually in low-income and middle-income countries. The T-cells, CD4+ and CD8+ T cells, play a significant role in protection against S. Typhi infection. Yet, the antigens... | Typhoid fever is caused by Salmonella enterica serovar Typhi (S. Typhi), a human-restricted pathogen that enters the host through the gut-associated lymphoid tissue. Recent calculations of the typhoid burden estimated that 11.9–20.6 million new cases of typhoid fever occur annually in low-income and middle-income count... |
10.1371/journal.pcbi.1003253 | Target Prediction for an Open Access Set of Compounds Active against Mycobacterium tuberculosis | Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), infects an estimated two billion people worldwide and is the leading cause of mortality due to infectious disease. The development of new anti-TB therapeutics is required, because of the emergence of multi-drug resistance strains as well as co-infect... | Mycobacterium tuberculosis is a major worldwide pathogen infecting millions individuals every year. Additionally, the number of antibiotic resistant strains has dramatically increased over the last decades. Trying to address this challenge, the pharmaceutical company GlaxoSmithKline has recently published the results o... | One third of the world's population is infected with Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis [1]. Approximately 95% of infected individuals are thought to have persistent, latent MTB infections that remain dormant until activated by specific environmental and host response events. Approxim... |
10.1371/journal.pgen.1006805 | Overexpression of the essential Sis1 chaperone reduces TDP-43 effects on toxicity and proteolysis | Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by selective loss of motor neurons with inclusions frequently containing the RNA/DNA binding protein TDP-43. Using a yeast model of ALS exhibiting TDP-43 dependent toxicity, we now show that TDP-43 overexpression dramatically a... | Many neurodegenerative diseases are associated with aggregation of specific proteins. Thus we are interested in factors that influence the aggregation and how the aggregated proteins are associated with pathology. Here, we study a protein called TDP-43 that is frequently aggregated in the neurons of patients with amyot... | Amyotrophic lateral sclerosis (ALS), often referred to as "Lou Gehrig's Disease", is a progressive neurodegenerative disorder characterized by degeneration and ultimately death of motor neurons in the brain and the spinal cord [1,2]. The most common pathologic characteristic of ALS is the formation of cytoplasmic inclu... |
10.1371/journal.pgen.1004534 | Accumulation of a Threonine Biosynthetic Intermediate Attenuates General Amino Acid Control by Accelerating Degradation of Gcn4 via Pho85 and Cdk8 | Gcn4 is a master transcriptional regulator of amino acid and vitamin biosynthetic enzymes subject to the general amino acid control (GAAC), whose expression is upregulated in response to amino acid starvation in Saccharomyces cerevisiae. We found that accumulation of the threonine pathway intermediate β-aspartate semia... | Transcriptional activator Gcn4 maintains amino acid homeostasis in budding yeast by inducing multiple amino acid biosynthetic pathways in response to starvation for any amino acid—the general amino acid control. Gcn4 abundance is tightly regulated by the interplay between an intricate translational control mechanism, w... | Cells undergo rapid transcriptional reprogramming in response to environmental changes by mobilizing transcriptional activators and repressors. Transcriptional activators function by binding to specific DNA sequences (UAS elements in yeast) and recruiting transcriptional cofactor proteins/complexes that remove repressi... |
10.1371/journal.pcbi.1004157 | Ligand-Target Prediction by Structural Network Biology Using nAnnoLyze | Target identification is essential for drug design, drug-drug interaction prediction, dosage adjustment and side effect anticipation. Specifically, the knowledge of structural details is essential for understanding the mode of action of a compound on a target protein. Here, we present nAnnoLyze, a method for target ide... | Description of the “mode-of-action” of a small chemical compound against a protein target is essential for the drug discovery process. Such description relies on three main steps: i) the identification of the target protein within the thousands of proteins in an organism, ii) the localization of the binding interaction... | The number of newly approved drugs has been significantly decreasing over the last two decades [1]. To make things worse, the therapeutic dogma that has prevailed over the years aimed at single target-specific ‘magic bullets’ against each disease. However, proteins act in complex interconnected networks, and thus, this... |
10.1371/journal.ppat.1007834 | ATP6V0d2 controls Leishmania parasitophorous vacuole biogenesis via cholesterol homeostasis | V-ATPases are part of the membrane components of pathogen-containing vacuoles, although their function in intracellular infection remains elusive. In addition to organelle acidification, V-ATPases are alternatively implicated in membrane fusion and anti-inflammatory functions controlled by ATP6V0d2, the d subunit varia... | V-ATPases control acidification and other processes at intracellular vesicles that bacteria and parasites exploit as compartments for replication and immune evasion. We report that the protozoan intracellular parasite Leishmania amazonensis resists inflammatory macrophage immune responses and upregulates an alternative... | Vacuolar H+-ATPases (V-ATPases) are membrane-associated ATP-dependent multimeric enzymes responsible for pumping protons from the cytosol into the lumen of intracellular organelles, thus controlling the acidification of lysosomes, endosomes, the trans-Golgi network and other intracellular vesicles [1, 2]. V-ATPases dis... |
10.1371/journal.pntd.0004562 | Cyclical Patterns of Hand, Foot and Mouth Disease Caused by Enterovirus A71 in Malaysia | Enterovirus A71 (EV-A71) is an important emerging pathogen causing large epidemics of hand, foot and mouth disease (HFMD) in children. In Malaysia, since the first EV-A71 epidemic in 1997, recurrent cyclical epidemics have occurred every 2–3 years for reasons that remain unclear. We hypothesize that this cyclical patte... | Enterovirus A71 (EV-A71) is a major cause of hand, foot, and mouth disease (HFMD) in children. Since the first outbreak in Malaysia in 1997, EV-A71 epidemics have occurred every 2–3 years, in 2000, 2003, 2006, 2008/2009, and 2012. As the reasons for this cyclical pattern are not known, we hypothesize that it is due to ... | Hand, foot and mouth disease (HFMD) is a common childhood disease, characterized by vesicles on the hands and feet, and ulcers in the mouth. Enterovirus A71 (EV-A71) is one of the main causative agents of HFMD apart from coxsackieviruses (CV) A6, A10, and A16 [1–3]. EV-A71, which belongs to the genus Enterovirus of the... |
10.1371/journal.pntd.0001674 | Sodium Stibogluconate (SSG) & Paromomycin Combination Compared to SSG for Visceral Leishmaniasis in East Africa: A Randomised Controlled Trial | Alternative treatments for visceral leishmaniasis (VL) are required in East Africa. Paromomycin sulphate (PM) has been shown to be efficacious for VL treatment in India.
A multi-centre randomized-controlled trial (RCT) to compare efficacy and safety of PM (20 mg/kg/day for 21 days) and PM plus sodium stibogluconate (SS... | Visceral leishmaniasis (VL) is a parasitic disease with about 500,000 new cases each year and is fatal if untreated. The current standard therapy involves long courses, has toxicity and there is evidence of increasing resistance. New and better treatment options are urgently needed. Recently, the antibiotic paromomycin... | The parasitic disease visceral leishmaniasis (VL) has an incidence of 500,000 new cases annually occurring primarily in India, Bangladesh, Nepal, Sudan, and Brazil and is fatal if untreated [1]. However, it is also an important disease in several other East African countries, with an incidence rate of 30,000 cases per ... |
10.1371/journal.pcbi.1002676 | Speeded Reaching Movements around Invisible Obstacles | We analyze the problem of obstacle avoidance from a Bayesian decision-theoretic perspective using an experimental task in which reaches around a virtual obstacle were made toward targets on an upright monitor. Subjects received monetary rewards for touching the target and incurred losses for accidentally touching the i... | In everyday, cluttered environments, moving to reach or grasp an object can result in unintended collisions with other objects along the path of movement. Depending on what we run into (a priceless Ming vase, a crotchety colleague) we can suffer serious monetary or social consequences. It makes sense to choose movement... | Imagine that you are sitting at your desk with a nice, hot cup of coffee in front of you and your laptop keyboard roughly behind it. In reaching out to hit the return key, you plan a trajectory that takes into account the possibility that you might jostle the cup and spill your coffee – that is, you plan a movement tra... |
10.1371/journal.pntd.0003399 | Functional Activity of Monocytes and Macrophages in HTLV-1 Infected Subjects | The Human T lymphotropic virus type-1 (HTLV-1) infects predominantly T cells, inducing proliferation and lymphocyte activation. Additionally, HTLV-1 infected subjects are more susceptible to other infections caused by other intracellular agents. Monocytes/macrophages are important cells in the defense against intracell... | HTLV-1 predominantly infects T cells, inducing cell proliferation and activation. While there is a larger amount of studies regarding T cells functions in HTLV-1 infected subjects, little is known about innate immunity. We evaluated monocyte and macrophage functions in HTLV-1 infected subjects. We observed that HAM/TSP... | Human T lymphotropic virus type 1 (HTLV-1) infects about 15 to 20 million people worldwide, with endemic foci in virtually all continents [1], [2]. A large proportion of individuals remain asymptomatic until the end of life, but a subgroup of infected individuals will develop a malignant lymphoproliferative disease cal... |
10.1371/journal.pgen.1002660 | The Probability of a Gene Tree Topology within a Phylogenetic Network with Applications to Hybridization Detection | Gene tree topologies have proven a powerful data source for various tasks, including species tree inference and species delimitation. Consequently, methods for computing probabilities of gene trees within species trees have been developed and widely used in probabilistic inference frameworks. All these methods assume a... | Species trees depict how species split and diverge. Within the branches of a species tree, gene trees, which depict the evolutionary histories of different genomic regions in the species, grow. Evolutionary analyses of the genomes of closely related organisms have highlighted the phenomenon that gene trees may disagree... | A molecular systematics paradigm that views molecular sequences as the characters of gene trees, and gene trees as characters of the species tree [1] is being increasingly adopted in the post-genomic era [2], [3]. Several models of evolution for the former type of characters have been devised [4], while the coalescent ... |
10.1371/journal.pntd.0007777 | Ultraviolet sensitivity of WASH (water, sanitation, and hygiene) -related helminths: A systematic review | Helminthiases are a group of disabling neglected tropical diseases that affect billions of people worldwide. Current control methods use preventative chemotherapy but reinfection is common and an inter-sectoral approach is required if elimination is to be achieved. Household and community scale water treatment can be u... | Helminth infections are currently controlled by mass administration of anthelmintic drugs which are effective at treating the diseases but cannot prevent reinfection. As we work to eliminate these diseases, complimentary control methods such as improving access to water, sanitation, and hygiene will be crucial to reduc... | In 2016, WASH-related helminth infections (e.g. schistosomiasis, soil-transmitted helminthiases, taeniasis) were responsible for over 9.5 million years lost due to ill-health, disability or early death [1]. They are transmitted through contact with (or consumption of) water, food, and soil that contain the human infect... |
10.1371/journal.pntd.0002989 | Presence of Antigen-Experienced T Cells with Low Grade of Differentiation and Proliferative Potential in Chronic Chagas Disease Myocarditis | The main consequence of chronic Trypanosoma cruzi infection is the development of myocarditis in approximately 20–30% of infected individuals but not until 10–20 years after the initial infection. We have previously shown that circulating interferon-γ-secreting T cells responsive to Trypanosoma cruzi antigens in chroni... | Chagas disease is a neglected tropical disease affecting approximately 10 million people in the world. It is caused by infection with the protozoan Trypanosoma cruzi. As a consequence of migration flows, the disease has been also become established in non-endemic countries. In this study, the functional and phenotypic ... | The main consequence of chronic Trypanosoma cruzi (T. cruzi) infection is the development of myocarditis in approximately 20–30% of infected individuals but not until 10–20 years after the initial infection [1]. Advanced chronic Chagas heart disease (cChHD) is characterized by dilated cavities with high degree of fibro... |
10.1371/journal.pgen.1002122 | Cooperative and Antagonistic Contributions of Two Heterochromatin Proteins to Transcriptional Regulation of the Drosophila Sex Determination Decision | Eukaryotic nuclei contain regions of differentially staining chromatin (heterochromatin), which remain condensed throughout the cell cycle and are largely transcriptionally silent. RNAi knockdown of the highly conserved heterochromatin protein HP1 in Drosophila was previously shown to preferentially reduce male viabili... | Eukaryotic genomes are organized into two distinct classes of chromatin, euchromatin and heterochromatin. The former is less condensed to enable transcription, whereas heterochromatin, which is marked by Heterochromatin Protein 1 (HP1), remains compact and mostly transcriptionally silent throughout the cell cycle. The ... | Eukaryotic genomes are organized into two distinct classes of chromatin [1]. The major class (euchromatin) can undergo decondensation to enable transcription during interphase, whereas a minor fraction (heterochromatin) remains compact and mostly transcriptionally silent throughout the cell cycle. Pericentric and telom... |
10.1371/journal.pntd.0003620 | Distribution of Lutzomyia longipalpis Chemotype Populations in São Paulo State, Brazil | American visceral leishmaniasis (AVL) is an emerging disease in the state of São Paulo, Brazil. Its geographical expansion and the increase in the number of human cases has been linked to dispersion of Lutzomyia longipalpis into urban areas. To produce more accurate risk maps we investigated the geographic distribution... | Information on the geographical distribution, dispersal mechanisms and dispersion route of insect-borne diseases can help to identify ongoing transmission areas, new risk areas and guide surveillance and control activities. Lutzomyia longipalpis, the principal vector of American visceral leishmaniasis disease in the Am... | Recording the geographic distribution and identifying the possible routes of expansion of both arthropod-borne diseases and their associated vectors is essential information for surveillance as well as the execution and elaboration of control strategies [1].
In Brazil, the expansion of the geographic range of Lutzomyi... |
10.1371/journal.pgen.1007262 | Zinc transporters belonging to the Cation Diffusion Facilitator (CDF) family have complementary roles in transporting zinc out of the cytosol | Zinc is an essential trace element that is required for the function of a large number of proteins. As these zinc-binding proteins are found within the cytosol and organelles, all eukaryotes require mechanisms to ensure that zinc is delivered to organelles, even under conditions of zinc deficiency. Although many zinc t... | All organisms require homeostasis mechanisms to maintain sufficient levels of zinc for normal cell metabolism and to avoid toxicity. As zinc-binding proteins are located in the cytosol and within intracellular compartments, all cells have to balance intracellular zinc ion distribution so that there are sufficient, but ... | Zinc is an essential trace metal that is required for the structure and activity of a large number of proteins. In eukaryotes these proteins include transcription factors containing structural domains stabilized by zinc ions, such as the C2H2-type and C4-type zinc fingers [1]. Zinc is also a cofactor for many enzymes t... |
10.1371/journal.pntd.0000690 | Secondary Syphilis in Cali, Colombia: New Concepts in Disease Pathogenesis | Venereal syphilis is a multi-stage, sexually transmitted disease caused by the spirochetal bacterium Treponema pallidum (Tp). Herein we describe a cohort of 57 patients (age 18–68 years) with secondary syphilis (SS) identified through a network of public sector primary health care providers in Cali, Colombia. To be eli... | Venereal syphilis is a sexually transmitted disease caused by the bacterium Treponema pallidum (Tp). We describe 57 patients (age 18–68 years) from Cali, Colombia diagnosed with secondary syphilis (SS). Most were women (64.9%); predominantly Afro-Colombian (38.6%) or mestizo (56.1%), and all of low socio-economic statu... | Syphilis is a sexually transmitted disease (STD) caused by the spirochetal bacterium Treponema pallidum (Tp) subspecies pallidum [1], [2]. Despite the existence of inexpensive and effective antibiotic treatment regimens, syphilis continues to be a major public health problem. According to the most recent World Health O... |
10.1371/journal.pgen.1000845 | Uncoupling of Satellite DNA and Centromeric Function in the Genus Equus | In a previous study, we showed that centromere repositioning, that is the shift along the chromosome of the centromeric function without DNA sequence rearrangement, has occurred frequently during the evolution of the genus Equus. In this work, the analysis of the chromosomal distribution of satellite tandem repeats in ... | Centromeres are the functional elements controlling chromosome segregation during cell division. Vertebrate centromeres, which typically contain large amounts of tandem repeats (satellite DNA), are highly conserved for function but not for DNA sequence, suggesting that centromeric function is mainly determined by epige... | Centromeres, cytologically appearing as visible primary constrictions in metaphase chromosomes, are essential for the proper segregation of sister chromatids during cell division. They are the sites of kinetochore assembly and spindle fiber attachment and consist of protein-DNA complexes, in which the DNA component is ... |
10.1371/journal.pmed.1002766 | Independent and combined effects of improved water, sanitation, and hygiene (WASH) and improved complementary feeding on early neurodevelopment among children born to HIV-negative mothers in rural Zimbabwe: Substudy of a cluster-randomized trial | Globally, nearly 250 million children (43% of all children under 5 years of age) are at risk of compromised neurodevelopment due to poverty, stunting, and lack of stimulation. We tested the independent and combined effects of improved water, sanitation, and hygiene (WASH) and improved infant and young child feeding (IY... | Some 43% of children globally fail to reach their full developmental potential due to stunting and poverty.
Current evidence shows that improved nutrition has a modest effect on early child development.
Improving water, sanitation, and hygiene (WASH) may plausibly benefit neurodevelopment through reduced illness and im... | Globally, nearly 250 million children (43% of all children under 5 years of age) are at risk of compromised neurodevelopment due to poverty, stunting, and lack of stimulation [1]. Stunting has now been inextricably linked to poor early child development (ECD) [2] and affects 150 million children globally [3,4]. Althoug... |
10.1371/journal.pbio.2003404 | Saccades are phase-locked to alpha oscillations in the occipital and medial temporal lobe during successful memory encoding | Efficient sampling of visual information requires a coordination of eye movements and ongoing brain oscillations. Using intracranial and magnetoencephalography (MEG) recordings, we show that saccades are locked to the phase of visual alpha oscillations and that this coordination is related to successful mnemonic encodi... | In everyday life, we constantly move our eyes to sample visual information. In order to make the sampling efficient, these eye movements need to be coordinated with the intrinsic brain dynamics that constrain visual computations. The present study provides novel evidence for how this coordination is achieved at the neu... | Sampling of visual information has been shown to be rhythmic rather than continuous [1–3]. In particular, brain rhythms clocked by oscillations in the alpha (7–14 Hz) range [4] constrain visual sampling: electroencephalography (EEG)/magnetoencephalography (MEG) studies in humans have shown that the trial-by-trial fluct... |
10.1371/journal.pgen.0030048 | Genome-Wide Linkage Analysis of Malaria Infection Intensity and Mild Disease | Although balancing selection with the sickle-cell trait and other red blood cell disorders has emphasized the interaction between malaria and human genetics, no systematic approach has so far been undertaken towards a comprehensive search for human genome variants influencing malaria. By screening 2,551 families in rur... | In tropical Africa, virtually all children become infected with malaria parasites. Most of them experience several malaria attacks per year, and over a million die from disease complications. Sickle-cell anemia, thalassemias, and other inherited red blood cell disorders indicate that malaria has selected for human gene... | Malaria caused by Plasmodium falciparum is one of the leading causes of human morbidity and mortality worldwide, predominantly affecting populations of resource-poor countries in the south [1]. Drawbacks in developing effective control measures have stressed the demand for research aiming at a better understanding of b... |
10.1371/journal.pbio.1002332 | A Latex Metabolite Benefits Plant Fitness under Root Herbivore Attack | Plants produce large amounts of secondary metabolites in their shoots and roots and store them in specialized secretory structures. Although secondary metabolites and their secretory structures are commonly assumed to have a defensive function, evidence that they benefit plant fitness under herbivore attack is scarce, ... | Plant roots produce diverse and abundant blends of bioactive metabolites. One potential function of these compounds is to protect roots against the devastating effects of below ground herbivore attack. However, examples demonstrating such a protective function in native plant-herbivore systems are lacking. Here, we inv... | Plants produce over 200,000 different metabolites that are not directly needed for their growth and development [1]. Many of these so-called secondary metabolites have a negative impact on insect herbivores [2–6], leading to the hypothesis that they evolved as defenses against the latter [7]. Indeed, recent studies dem... |
10.1371/journal.pntd.0005861 | Host regulation of liver fibroproliferative pathology during experimental schistosomiasis via interleukin-4 receptor alpha | Interleukin-4 receptor (IL-4Rα) is critical for the initiation of type-2 immune responses and implicated in the pathogenesis of experimental schistosomiasis. IL-4Rα mediated type-2 responses are critical for the control of pathology during acute schistosomiasis. However, type-2 responses tightly associate with fibrogra... | Liver fibroproliferative diseases drive a considerable fraction of the overall human mortality. This is closely linked to the absence of efficient control measures against such diseases. Schistosomiasis, a chronic disease that affects humans, preferentially causes liver fibrosis and is responsible for devastating econo... | Schistosomiasis is a parasitic disease caused by blood-dwelling parasitic flatworms of the genus Schistosoma, mainly, Schistosoma mansoni (S. mansoni), S. japonicum and S. haematobium that are infective to humans and the most clinically relevant [1]. Schistosomiasis is estimated to affect more than 200 million people w... |
10.1371/journal.pbio.1000609 | Retinoic Acid Functions as a Key GABAergic Differentiation Signal in the Basal Ganglia | Although retinoic acid (RA) has been implicated as an extrinsic signal regulating forebrain neurogenesis, the processes regulated by RA signaling remain unclear. Here, analysis of retinaldehyde dehydrogenase mutant mouse embryos lacking RA synthesis demonstrates that RA generated by Raldh3 in the subventricular zone of... | The vitamin A metabolite retinoic acid is an important signaling molecule needed for development of the central nervous system. Previous studies have shown a role for retinoic acid in regulating genes involved in the generation of motor neurons both in the hindbrain and spinal cord, but the role of retinoic acid in the... | The embryonic forebrain, deriving from the most anterior part of the neural tube, comprises a complex set of structures in the developing brain. This complexity arises mainly due to the heterogeneity of the neurons comprising it in terms of morphology, structure, function, and genetic specification. During forebrain de... |
10.1371/journal.pcbi.1004680 | Topological Phenotypes Constitute a New Dimension in the Phenotypic Space of Leaf Venation Networks | The leaves of angiosperms contain highly complex venation networks consisting of recursively nested, hierarchically organized loops. We describe a new phenotypic trait of reticulate vascular networks based on the topology of the nested loops. This phenotypic trait encodes information orthogonal to widely used geometric... | Planar reticular networks are ubiquitous in nature and engineering, formed for instance by the arterial vasculature in the mammalian neocortex, urban street grids or the vascular network of plant leaves. We use a topological metric to characterize the way loops are nested in such networks and analyze a large database o... | The angiosperm leaf vein network fulfills the combined requirements of efficient liquid transport within the leaf and high robustness against load fluctuations and damage, while at the same time providing structural reinforcement [1–4].
Modern leaf vein networks evolved gradually from simple dendritic branching patter... |
10.1371/journal.pbio.1000505 | Polarized Secretion of Drosophila EGFR Ligand from Photoreceptor Neurons Is Controlled by ER Localization of the Ligand-Processing Machinery | The release of signaling molecules from neurons must be regulated, to accommodate their highly polarized structure. In the developing Drosophila visual system, photoreceptor neurons secrete the epidermal growth factor receptor ligand Spitz (Spi) from their cell bodies, as well as from their axonal termini. Here we show... | Cells secrete signaling molecules that trigger a variety of responses in neighboring cells by activating their respective cell-surface receptors. Because many cells in an organism are polarized, regulating the precise location of ligand secretion is important for controlling the position and nature of the response. Dur... | Communication between cells and their environment entails the release and reception of signaling molecules. In polarized cells, such as epithelia or neurons, the unique cellular architecture imposes constraints on the precise sites where signal release and reception occur. For example, the distribution of axonal guidan... |
10.1371/journal.pntd.0001642 | Characterisation of the Native Lipid Moiety of Echinococcus granulosus Antigen B | Antigen B (EgAgB) is the most abundant and immunogenic antigen produced by the larval stage (metacestode) of Echinococcus granulosus. It is a lipoprotein, the structure and function of which have not been completely elucidated. EgAgB apolipoprotein components have been well characterised; they share homology with a gro... | The larva of the cestode parasite Echinococcus granulosus affects a wide range of livestock mammals and humans, causing cystic echinococcosis (hydatid disease), a zoonosis with significant economic and public health impact. The disease is characterised by the growth of a fluid-filled cyst in the host's viscera (mainly ... | The larval stage of the cestode parasite Echinococcus granulosus is the causative agent of cystic echinococcosis (hydatid disease) in a range of mammalian species (mainly domestic ungulates) as well as in humans. It is a unilocular fluid-filled cyst, which steadily grows inside host visceras (mostly liver and lung). On... |
10.1371/journal.pgen.1007059 | A subset of sweet-sensing neurons identified by IR56d are necessary and sufficient for fatty acid taste | Fat represents a calorically potent food source that yields approximately twice the amount of energy as carbohydrates or proteins per unit of mass. The highly palatable taste of free fatty acids (FAs), one of the building blocks of fat, promotes food consumption, activates reward circuitry, and is thought to contribute... | Fat represents a calorically potent food source that yields approximately twice the amount of energy as carbohydrates or proteins per unit of mass. Dietary lipids are comprised of both triacylglycerides and FAs, and growing evidence suggests that it is the free FAs that are detected by the gustatory system. The highly ... | Fat represents a calorically potent food source that yields approximately twice the amount of energy as carbohydrates or proteins per unit of mass. In mammals, dietary lipids are detected by taste cells, mechanosensory and olfactory neurons, as well as by post-ingestive feedback [1–4]. Dietary lipids are comprised of t... |
10.1371/journal.pgen.0040026 | Genome-Wide Expression of Azoospermia Testes Demonstrates a Specific Profile and Implicates ART3 in Genetic Susceptibility | Infertility affects about one in six couples attempting pregnancy, with the man responsible in approximately half of the cases. Because the pathophysiology underlying azoospermia is not elucidated, most male infertility is diagnosed as idiopathic. Genome-wide gene expression analyses with microarray on testis specimens... | Worldwide, approximately 15% of couples attempting pregnancy meet with failure. Male factors are thought to be responsible in 20%–50% of all infertility cases. Azoospermia, the absence of sperm in the ejaculate due to defects in its production or delivery is common in male infertility. In this study, we focused on non-... | Spermatogenesis, a major function of mammalian testes, is complex and strictly regulated. While spermatogenesis is a maturation of germ cells, other cells including Sertoli, Leydig, and peritubular myoid cells also play important roles, and defects at any differentiation stage might result in infertility. Male infertil... |
10.1371/journal.pcbi.1004756 | Oligomers of Heat-Shock Proteins: Structures That Don’t Imply Function | Most proteins must remain soluble in the cytosol in order to perform their biological functions. To protect against undesired protein aggregation, living cells maintain a population of molecular chaperones that ensure the solubility of the proteome. Here we report simulations of a lattice model of interacting proteins ... | The vast majority of living cells express molecular chaperones that suppress protein aggregation by inhibiting illicit protein–protein interactions. We refer to this class of chaperones as ‘passive molecular chaperones,’ since they do not require an external energy source in order to function. We use simulations of a m... | Passive molecular chaperones inhibit the aggregation of cytosolic proteins and are thus a nearly ubiquitous component of living cells [1–3]. This class of chaperones comprises clusterin, α-crystallins and many other small heat-shock proteins (sHSPs), which promote tolerance to a wide range of cellular stressors such as... |
10.1371/journal.pcbi.1000142 | Evolutionarily Conserved Substrate Substructures for Automated Annotation of Enzyme Superfamilies | The evolution of enzymes affects how well a species can adapt to new environmental conditions. During enzyme evolution, certain aspects of molecular function are conserved while other aspects can vary. Aspects of function that are more difficult to change or that need to be reused in multiple contexts are often conserv... | Enzymes are biological molecules essential for catalyzing the chemical reactions in living systems, allowing organisms to convert nutrients into usable forms and convert harmful or unneeded molecules into forms that can be reused or excreted. During enzyme evolution, enzymes maintain the ability to perform some aspects... | The molecular functions of enzymes result from a complex evolutionary interplay between environmental constraints, requirements for organismal fitness, and the functional malleability of a particular enzyme scaffold. Within these constraints, existing enzymes are recruited during evolution to perform new or modified fu... |
10.1371/journal.pcbi.1004923 | Stochastic Simulation of Biomolecular Networks in Dynamic Environments | Simulation of biomolecular networks is now indispensable for studying biological systems, from small reaction networks to large ensembles of cells. Here we present a novel approach for stochastic simulation of networks embedded in the dynamic environment of the cell and its surroundings. We thus sample trajectories of ... | Simulation algorithms have become indispensable tools in modern quantitative biology, providing deep insight into many biochemical systems, including gene regulatory networks. However, current stochastic simulation approaches handle the effects of fluctuating extracellular signals and upstream processes poorly, either ... | Dynamic simulation is an essential and widespread approach for studying biomolecular networks in cell biology [1]. However, the computational resources required can quickly become limiting for several reasons. Cellular networks are complex, containing many biomolecular species and reactions. The effects of biochemical ... |
10.1371/journal.pcbi.1000008 | Diminished Self-Chaperoning Activity of the ΔF508 Mutant of CFTR Results in Protein Misfolding | The absence of a functional ATP Binding Cassette (ABC) protein called the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) from apical membranes of epithelial cells is responsible for cystic fibrosis (CF). Over 90% of CF patients carry at least one mutant allele with deletion of phenylalanine at position 508 ... | Deletion of a single residue, phenylalanine at position 508, in the first nucleotide binding domain (NBD1) of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is present in approximately 90% of cystic fibrosis (CF) patients. Experiments show that this mutant protein exhibits inefficient biosynthetic matur... | CF is the most common autosomal inherited disease with high morbidity among Caucasians. CF patients have altered epithelial ion transport that leads to decreased hydration of epithelial surfaces in the gut, kidney, pancreas, and airways [1]. Decreased surface liquid volume impairs mucociliary clearance which in turn le... |
10.1371/journal.pcbi.1004732 | PSAMM: A Portable System for the Analysis of Metabolic Models | The genome-scale models of metabolic networks have been broadly applied in phenotype prediction, evolutionary reconstruction, community functional analysis, and metabolic engineering. Despite the development of tools that support individual steps along the modeling procedure, it is still difficult to associate mathemat... | The broad application of genome-scale metabolic modeling has made it a useful technique for tackling fundamental questions in biological research and engineering. Today over 100 models have been constructed for organisms that carry out a diverse array of metabolic activities spanning all three kingdoms of life. These m... | The GEnome-scale Models (GEMs) of metabolic networks have broad applications in biological research and engineering [1]. Models have been developed for organisms of all three kingdoms of life [2–5] and have been used to simulate a wide variety of metabolic processes, such as photo- and chemo-autotrophic carbon fixation... |
10.1371/journal.pbio.2003663 | A novel unsupervised analysis of electrophysiological signals reveals new sleep substages in mice | Sleep science is entering a new era, thanks to new data-driven analysis approaches that, combined with mouse gene–editing technologies, show a promise in functional genomics and translational research. However, the investigation of sleep is time consuming and not suitable for large-scale phenotypic datasets, mainly due... | Sleep is a heterogeneous process determined by a number of genetic and epigenetic factors. To investigate the biology of sleep, animal models, such as mice, are extensively used in sleep studies, and large-scale phenotypic datasets are required to reach meaningful conclusions. Currently, manual annotations of electroph... | Sleep is a physiological, metabolic, and behavioral state of the organism that plays an important role in many biological functions. It is described by 2 different states—namely, non-rapid-eye-movement (NREM) sleep and rapid-eye-movement (REM) sleep. In laboratory settings, sleep is conventionally defined by properties... |
10.1371/journal.pntd.0001608 | Increased Birth Weight Associated with Regular Pre-Pregnancy Deworming and Weekly Iron-Folic Acid Supplementation for Vietnamese Women | Hookworm infections are significant public health issues in South-East Asia. In women of reproductive age, chronic hookworm infections cause iron deficiency anaemia, which, upon pregnancy, can lead to intrauterine growth restriction and low birth weight. Low birth weight is an important risk factor for neonatal and inf... | Low birth weight is an important risk factor for neonatal and infant morbidity and mortality and may impact on growth and development. Maternal iron deficiency anaemia contributes to intrauterine growth restriction and low birth weight. Hookworm infections and an iron-depleted diet may lead to iron deficiency anaemia, ... | Low birth weight is widely recognised as a risk factor for neonatal mortality and morbidity, as well as reduced cognitive function and the development of chronic diseases in later life [1]–[3]. Iron deficiency anaemia during pregnancy is an important cause of restricted foetal growth leading to low birth weight and pre... |
10.1371/journal.pntd.0001516 | Excretory/Secretory-Products of Echinococcus multilocularis Larvae Induce Apoptosis and Tolerogenic Properties in Dendritic Cells In Vitro | Alveolar echinococcosis, caused by Echinococcus multilocularis larvae, is a chronic disease associated with considerable modulation of the host immune response. Dendritic cells (DC) are key effectors in shaping the immune response and among the first cells encountered by the parasite during an infection. Although it is... | Parasitic helminths are inducers of chronic diseases and have evolved mechanisms to suppress the host immune response. Mostly from studies on roundworms, a picture is currently emerging that helminths secrete factors (E/S-products) that directly act on sentinels of the immune system, dendritic cells, in order to achiev... | The metacestode larval stage of the fox-tapeworm E. multilocularis is the causative agent of alveolar echinococcosis, one of the most dangerous zoonoses world-wide [1]. Apart from the strobilar adult stage that resides within the intestine of the definitive host (e.g. foxes, dogs), the life cycle of this cestode compri... |
10.1371/journal.pcbi.1002025 | Cell-Sorting at the A/P Boundary in the Drosophila
Wing Primordium: A Computational Model to Consolidate Observed Non-Local Effects
of Hh Signaling | Non-intermingling, adjacent populations of cells define compartment boundaries;
such boundaries are often essential for the positioning and the maintenance of
tissue-organizers during growth. In the developing wing primordium of
Drosophila melanogaster, si... | In developing animal tissues, cells can often re-arrange locally and mix
relatively freely. However, in some stereotypic and crucially important
instances during body development, cells will strictly not intermingle, and
instead form sharp boundaries along whi... | During embryonic development of complex multicellular organisms, spatial reference
points need to be established within tissues. These are often formed by specialized
groups of cells that are capable of signaling to neighboring cells. Such signaling
centers define coordin... |
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