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10.1371/journal.pcbi.1006550 | Comprehensive computational modelling of the development of mammalian cortical connectivity underlying an architectonic type principle | The architectonic type principle relates patterns of cortico-cortical connectivity to the relative architectonic differentiation of cortical regions. One mechanism through which the observed close relation between cortical architecture and connectivity may be established is the joint development of cortical areas and t... | The mechanisms that govern the establishment of cortico-cortical connections during the development of the mammalian brain are poorly understood. In computational simulation experiments reported here, we explored the foundations of an architectonic type principle, which attributes adult cortical connectivity to the dif... | Axonal connections among brain areas are the structural substrate of information transfer throughout the brain. Cortico-cortical connections form networks that are neither regular nor random, but characteristically link specific brain regions, and exhibit large-scale topological features, such as modules and hubs [1, 2... |
10.1371/journal.ppat.1003292 | Illumination of Murine Gammaherpesvirus-68 Cycle Reveals a Sexual Transmission Route from Females to Males in Laboratory Mice | Transmission is a matter of life or death for pathogen lineages and can therefore be considered as the main motor of their evolution. Gammaherpesviruses are archetypal pathogenic persistent viruses which have evolved to be transmitted in presence of specific immune response. Identifying their mode of transmission and t... | Epstein-Barr virus and the Kaposi's Sarcoma-associated Herpesvirus are two human gammaherpesviruses which are linked to the development of several cancers. Efficient control of these infections is therefore of major interest, particularly in some epidemiological circumstances. These viruses are however host-specific an... | Herpesviruses are important pathogens which are ubiquitous in both human and animal populations. They establish persistent, productive infections, with virus carriers both making anti-viral immune responses that protect against disease and excreting infectious virions. Among herpesviruses, gammaherpesviruses establish ... |
10.1371/journal.ppat.1003838 | Cell Tropism Predicts Long-term Nucleotide Substitution Rates of Mammalian RNA Viruses | The high rates of RNA virus evolution are generally attributed to replication with error-prone RNA-dependent RNA polymerases. However, these long-term nucleotide substitution rates span three orders of magnitude and do not correlate well with mutation rates or selection pressures. This substitution rate variation may b... | RNA viruses are the fastest evolving human pathogens, making their treatment and control difficult. Compared to DNA viruses, RNA viruses replicate with much lower fidelity, which can explain why RNA viruses evolve significantly faster than most DNA viruses. However, there is tremendous variation among the evolutionary ... | RNA viruses are responsible for a disproportionate number of emerging human diseases, including influenza, ebola hemorrhagic fever, hantavirus pulmonary syndrome, and Middle East respiratory syndrome, which place tremendous health and economic burdens on both the developing and developed world [1], [2]. In 2008, rotavi... |
10.1371/journal.pntd.0004151 | Impact of an Ivermectin Mass Drug Administration on Scabies Prevalence in a Remote Australian Aboriginal Community | Scabies is endemic in many Aboriginal and Torres Strait Islander communities, with 69% of infants infected in the first year of life. We report the outcomes against scabies of two oral ivermectin mass drug administrations (MDAs) delivered 12 months apart in a remote Australian Aboriginal community.
Utilizing a before a... | Scabies is endemic in many Australian Aboriginal and Torres Strait Islander communities, with 69% of infants infected in the first year of life. Previous mass drug administration (MDA) programs using topical acaricides to decrease scabies prevalence have had varying degrees of success in Australia. We were invited by o... | Scabies mites infect up to 300 million people worldwide, most of whom are children living in poverty and overcrowded conditions.[1–3] In remote Australian Aboriginal communities, scabies has been near universal during the first year of life (69%).[4] Secondary infections with highly pathogenic bacterial pathogens Strep... |
10.1371/journal.pntd.0004875 | Spatiotemporal Dynamics of Scrub Typhus Transmission in Mainland China, 2006-2014 | Scrub typhus is endemic in the Asia-Pacific region including China, and the number of reported cases has increased dramatically in the past decade. However, the spatial-temporal dynamics and the potential risk factors in transmission of scrub typhus in mainland China have yet to be characterized.
This study aims to exp... | Scrub typhus is a vector-borne disease carried by the chigger mite and is endemic in the Asia-Pacific region. Now scrub typhus causes a considerable burden on public health and the economy in China. We explored the spatiotemporal dynamics of scrub typhus cases in China between January 2006 and December 2014, and explor... | Scrub typhus, also known as tsutsugamushi disease, is endemic in the so-called “tsutsugamushi triangle” area that includes Pakistan and Afghanistan in the west, far-eastern Russia and Japan in the north, and northern Australia in the south [1]. The causative bacterium of this disease, Orientia tsutsugamushi (O. tsutsug... |
10.1371/journal.ppat.1002539 | Novel Transmembrane Receptor Involved in Phagosome Transport of Lysozymes and β-Hexosaminidase in the Enteric Protozoan Entamoeba histolytica | Lysozymes and hexosaminidases are ubiquitous hydrolases in bacteria and eukaryotes. In phagocytic lower eukaryotes and professional phagocytes from higher eukaryotes, they are involved in the degradation of ingested bacteria in phagosomes. In Entamoeba histolytica, which is the intestinal protozoan parasite that causes... | Phagocytosis is the cellular process of engulfing solid particles to form an internal phagosome in protozoa, algae, and professional phagocytes of multicellular eukaryotic organisms. In phagocytic protozoa, phagocytosis is involved in the acquisition of nutrients, and the evasion from the host immune system and inflamm... | Lysozymes (EC 3.2.1.17) are the antibacterial protein that has an ability to damage the cell wall of bacteria [1]. The enzyme acts by catalyzing the hydrolysis of 1,4-beta-linkages between N-acetylmuramic acid and N-acetyl-D-glucosamine in peptidoglycans and between the N-acetyl-D-glucosamine residues in chitodextrins.... |
10.1371/journal.pntd.0001187 | Health Services for Buruli Ulcer Control: Lessons from a Field Study in Ghana | Buruli ulcer (BU), caused by Mycobacterium ulcerans infection, is a debilitating disease of the skin and underlying tissue. The first phase of a BU prevention and treatment programme (BUPaT) was initiated from 2005–2008, in the Ga-West and Ga-South municipalities in Ghana to increase access to BU treatment and to impro... | Buruli ulcer (BU), caused by Mycobacterium ulcerans infection, is a debilitating disease of the skin and underlying tissue which starts as a painless nodule, oedema or plaque and could develop into painful and massive ulcers if left untreated. Using a combination of quantitative and qualitative methods, the study asses... | In the absence of a proven strategy for preventing infection, control of Buruli Ulcer (BU) relies on efficient health services to prevent progression of pre-ulcerative conditions and treat ulcers. According to the World Health Organisation (WHO), service delivery is the primary function of any health system and entails... |
10.1371/journal.ppat.1005591 | Neutrophil and Alveolar Macrophage-Mediated Innate Immune Control of Legionella pneumophila Lung Infection via TNF and ROS | Legionella pneumophila is a facultative intracellular bacterium that lives in aquatic environments where it parasitizes amoeba. However, upon inhalation of contaminated aerosols it can infect and replicate in human alveolar macrophages, which can result in Legionnaires’ disease, a severe form of pneumonia. Upon experim... | Legionella pneumophila is a motile gram-negative bacterium found mainly in fresh water environments where it replicates in amoeba. It uses a molecular syringe to inject effector molecules into these predatory host cells, reprograming them to support L. pneumophila growth. Upon inhalation of contaminated aerosols, L. pn... | L. pneumophila is a Gram-negative bacterium with global distribution in freshwater environments, where it replicates intracellularly mainly in amoebae [1–3]. L. pneumophila commonly causes community acquired and nosocomial pneumonia. Although it is normally controlled by the innate immune response, L. pneumophila has t... |
10.1371/journal.pcbi.1000425 | Dynamic Modeling of Vaccinating Behavior as a Function of Individual Beliefs | Individual perception of vaccine safety is an important factor in determining a person's adherence to a vaccination program and its consequences for disease control. This perception, or belief, about the safety of a given vaccine is not a static parameter but a variable subject to environmental influence. To complicate... | A frequently made assumption in population models is that individuals make decisions in a standard way, which tends to be fixed and set according to the modeler's view on what is the most likely way individuals should behave. In this paper we acknowledge the importance of modeling behavioral changes (in the form of bel... | Since early vaccination campaigns against smallpox, vaccination policies have been a matter of debate [1]: mass vaccination versus blocking strategies; compulsory versus voluntary, are some highly debated issues. Despite these early controversies - and consequent alternative policies implemented in different countries ... |
10.1371/journal.ppat.1004200 | Ubiquitin-Mediated Response to Microsporidia and Virus Infection in C. elegans | Microsporidia comprise a phylum of over 1400 species of obligate intracellular pathogens that can infect almost all animals, but little is known about the host response to these parasites. Here we use the whole-animal host C. elegans to show an in vivo role for ubiquitin-mediated response to the microsporidian species ... | Microbial pathogens have two distinct lifestyles: some pathogens live outside of host cells, and others live inside of host cells and are called intracellular pathogens. Microsporidia are fungal-related intracellular pathogens that can infect all animals, but are poorly understood. We used the roundworm C. elegans as a... | The Microsporidia phylum contains over 1400 species of obligate intracellular pathogens most closely related to fungi [1]. These pathogens can infect a wide variety of animal hosts including humans, where they can cause significant disease. Infections in humans can cause lethal diarrhea in immunocompromised people such... |
10.1371/journal.pntd.0001135 | Chagas Disease among the Latin American Adult Population Attending in
a Primary Care Center in Barcelona, Spain | The epidemiology of Chagas disease, until recently confined to areas of
continental Latin America, has undergone considerable changes in recent
decades due to migration to other parts of the world, including Spain. We
studied the prevalence of Chag... | Chagas disease is a parasitic infection caused by the protozoan
Trypanosoma cruzi, and is becoming an emerging health
problem in non-endemic areas because of growing population movements. The
clinical manifestations of chronic T. cruzi infection include
... | Trypanosoma cruzi (T. cruzi) is a flagellate
protozoan that causes Chagas disease (CD). It is traditionally linked to rural areas
of continental Latin America, where it is transmitted by a variety of bug vectors.
In recent decades, the epidemiological pattern of this dise... |
10.1371/journal.pntd.0006679 | Comparative proteomics of the two T. brucei PABPs suggests that PABP2 controls bulk mRNA | Poly(A)-binding proteins (PABPs) regulate mRNA fate by controlling stability and translation through interactions with both the poly(A) tail and eIF4F complex. Many organisms have several paralogs of PABPs and eIF4F complex components and it is likely that different eIF4F/PABP complex combinations regulate distinct set... | Poly(A)-binding proteins (PABPs) bind to the poly(A) tails of eukaryotic mRNAs and function in regulating mRNA fate. Many eukaryotes have several PABP paralogs and the current view is that each PABP binds a specific subset of mRNAs. Trypanosoma brucei has two PABPs, and to understand the differential functionality of t... | Gene expression is regulated by multiple transcriptional and post-transcriptional mechanisms. At the post-transcriptional level, regulation of protein synthesis by modulation of translation initiation is a major contributor. The first step in mRNA cap-dependent translation initiation is assembly of the eIF4F complex at... |
10.1371/journal.ppat.1003561 | Replication Vesicles are Load- and Choke-Points in the Hepatitis C Virus Lifecycle | Hepatitis C virus (HCV) infection develops into chronicity in 80% of all patients, characterized by persistent low-level replication. To understand how the virus establishes its tightly controlled intracellular RNA replication cycle, we developed the first detailed mathematical model of the initial dynamic phase of the... | Hepatitis C is a severe disease and a prime cause for liver transplantation. Up to 3% of the world's population are chronically infected with its causative agent, the Hepatitis C virus (HCV). This capacity to establish long (decades) lasting persistent infection sets HCV apart from other plus-strand RNA viruses typical... | Hepatitis C virus (HCV) infection is a major global health problem, with approximately 170 million chronically infected individuals worldwide and 3 to 4 million new infections occurring each year [1]. Acute infection is mostly asymptomatic, however, it develops into a chronic infection in about 80% of patients, and the... |
10.1371/journal.pntd.0007548 | The effect of amantadine on an ion channel protein from Chikungunya virus | Viroporins like influenza A virus M2, hepatitis C virus p7, HIV-1 Vpu and picornavirus 2B associate with host membranes, and create hydrophilic corridors, which are critical for viral entry, replication and egress. The 6K proteins from alphaviruses are conjectured to be viroporins, essential during egress of progeny vi... | Chikungunya fever is a severe crippling illness caused by the arthropod-borne virus CHIKV. Originally from the African subcontinent, the virus has now spread worldwide and is responsible for substantial morbidity and economic loss. The existing treatment against CHIKV is primarily symptomatic, and it is imperative that... | Chikungunya fever is a severe and debilitating illness caused by the mosquito-borne arbovirus, Chikungunya Virus (CHIKV) [1–4]. Infections are generally non-fatal, but this virus has been much in the limelight lately, due to its rapid spread and outbreaks worldwide [2–4]. Although, India is endemic for CHIKV; outbreaks... |
10.1371/journal.pgen.1003416 | Differential Association of the Conserved SUMO Ligase Zip3 with Meiotic Double-Strand Break Sites Reveals Regional Variations in the Outcome of Meiotic Recombination | During the first meiotic prophase, programmed DNA double-strand breaks (DSBs) are distributed non randomly at hotspots along chromosomes, to initiate recombination. In all organisms, more DSBs are formed than crossovers (CO), the repair product that creates a physical link between homologs and allows their correct segr... | For sexual reproduction, meiosis is an essential step ensuring the formation of haploid gametes from diploid precursors of the germline. This reduction in the genome's content is achieved through a specialized type of division, where a single round of DNA replication is followed by two successive rounds of chromosome s... | During meiosis, the programmed formation of DNA double-strand breaks (DSBs) and their repair by homologous recombination ensures that crossovers (CO) occur between homologous chromosomes. COs promote the accurate segregation of homologs at the first meiotic division, thus avoiding aneuploidy, which is a common cause of... |
10.1371/journal.pntd.0006277 | Validation of rK39 immunochromatographic test and direct agglutination test for the diagnosis of Mediterranean visceral leishmaniasis in Spain | Visceral leishmaniasis (VL), the most severe form of leishmaniasis, is endemic in Europe with Mediterranean countries reporting endemic status alongside a worrying northward spread. Serological diagnosis, including immunochromatographic test based on the recombinant antigen rK39 (rK39-ICT) and a direct agglutination te... | Visceral leishmaniasis is the most severe form of leishmaniasis, a disease transmitted through the bite of an infected sandfly. Although the biggest burden of leishmaniasis is in eastern Africa and the Indian subcontinent, the disease is also endemic in parts of Europe. Previous studies have looked at performance of di... | Visceral leishmaniasis (VL) is a life-threatening disease caused by protozoan parasites of the Leishmania donovani complex. It is widely endemic in South America, eastern Africa and Asia as well as in the Mediterranean basin [1]. More than 500 million people are at risk of acquiring leishmaniasis worldwide, with approx... |
10.1371/journal.pntd.0007250 | A polyvalent coral snake antivenom with broad neutralization capacity | Coral snakes of the genus Micrurus have a high diversity and wide distribution in the Americas. Despite envenomings by these animals being uncommon, accidents are often severe and may result in death. Producing an antivenom to treat these envenomings has been challenging since coral snakes are difficult to catch, produ... | Coral snakes are distributed in the Americas form Southern United States to Argentina. These snakes cause envenomings that, despite not being common, often lead to death. The antivenoms currently produced to treat accidents caused by these snakes have limitations regarding the number of species venoms they could neutra... | Coral snakes of the genus Micrurus and Micruroides represent a highly diverse neotropical monophyletic assembly of about 80 species distributed from the southern United States to northern Argentina [1].
Although uncommon (1–2% of the snake bites in the Americas) [2–4], Micrurus envenomation can be lethal due to the pr... |
10.1371/journal.ppat.1003500 | The Footprint of Genome Architecture in the Largest Genome Expansion in RNA Viruses | The small size of RNA virus genomes (2-to-32 kb) has been attributed to high mutation rates during replication, which is thought to lack proof-reading. This paradigm is being revisited owing to the discovery of a 3′-to-5′ exoribonuclease (ExoN) in nidoviruses, a monophyletic group of positive-stranded RNA viruses with ... | RNA viruses include many major pathogens. The adaptation of viruses to their hosts is facilitated by fast mutation and constrained by small genome sizes, which are both due to the extremely high error rate of viral polymerases. Using an innovative computational approach, we now provide evidence for additional forces th... | Genome size is the net result of evolution driven by the environment, mutation, and the genetics of a given organism [1], [2]. Particularly mutation rate is a powerful evolutionary factor [3]. The relation between mutation rate and genome size is inversely proportional for a range of life forms from viroids to viruses ... |
10.1371/journal.pntd.0007103 | Reprogramming of Trypanosoma cruzi metabolism triggered by parasite interaction with the host cell extracellular matrix | Trypanosoma cruzi, the etiological agent of Chagas’ disease, affects 8 million people predominantly living in socioeconomic underdeveloped areas. T. cruzi trypomastigotes (Ty), the classical infective stage, interact with the extracellular matrix (ECM), an obligatory step before invasion of almost all mammalian cells i... | Adhesion of Trypanosoma cruzi to distinct elements of ECM involving different surface proteins from the infective stage of the parasite has been described. Despite the relevance of ECM for T. cruzi infection, the signaling pathways triggered in trypomastigotes upon interactions with ECM are less well understood. In pre... | The protozoan T. cruzi, the etiological agent of Chagas’ disease, affects a wide range of mammalian hosts, including humans. It is estimated that 8 million people are infected and 25 million are at risk, most of them living in areas of poor socioeconomic development [1]. The cell cycle of T. cruzi involves an invertebr... |
10.1371/journal.pgen.1004914 | Structured Observations Reveal Slow HIV-1 CTL Escape | The existence of viral variants that escape from the selection pressures imposed by cytotoxic T-lymphocytes (CTLs) in HIV-1 infection is well documented, but it is unclear when they arise, with reported measures of the time to escape in individuals ranging from days to years. A study of participants enrolled in the SPA... | The cytotoxic T-lymphocyte (CTL) arm of the immune response is thought to play a significant role in the control of HIV-1 infection. Mutations within the HIV-1 genome allow the virus to escape recognition by CTLs and so evade the immune response. These escape mutations have been well documented but observed waiting tim... | The HIV-1-specific cytotoxic T-lymphocyte (CTL) response begins as early as 2 to 3 weeks after infection [1], and there is evidence to suggest it may play an important role in the early control of viraemia [2, 3]. The onset of the response coincides with the decline of viral load. Certain host HLA genotypes (and theref... |
10.1371/journal.ppat.1004695 | Spatiotemporal Regulation of a Legionella pneumophila T4SS Substrate by the Metaeffector SidJ | Modulation of host cell function is vital for intracellular pathogens to survive and replicate within host cells. Most commonly, these pathogens utilize specialized secretion systems to inject substrates (also called effector proteins) that function as toxins within host cells. Since it would be detrimental for an intr... | A key attribute of many pathogens is their ability to survive and replicate within eukaryotic host cells. One such pathogen, Legionella pneumophila, is able to grow within macrophages in the lungs, thereby causing a form of pneumonia called Legionnaires’ Disease. L. pneumophila causes disease by translocating several h... | Legionella pneumophila, the causative agent of Legionnaires' disease, is a facultative intracellular bacterial pathogen that can replicate within fresh water amoeba and mammalian alveolar macrophages [1–3]. L. pneumophila survives and replicates within host cells by inhibiting the host endocytic pathway and creating a ... |
10.1371/journal.pcbi.1003457 | Bayesian Reconstruction of Disease Outbreaks by Combining Epidemiologic and Genomic Data | Recent years have seen progress in the development of statistically rigorous frameworks to infer outbreak transmission trees (“who infected whom”) from epidemiological and genetic data. Making use of pathogen genome sequences in such analyses remains a challenge, however, with a variety of heuristic approaches having b... | Understanding how infectious diseases are transmitted from one individual to another is essential for designing containment strategies and epidemic prevention. Recently, the reconstruction of transmission trees (“who infected whom”) has been revolutionized by the availability of pathogen genome sequences. Exploiting th... | Statistical methods for analyzing detailed epidemiological data collected during infectious disease outbreaks have seen rapid development in recent years [1], [2], [3], [4], [5], [6], [7], [8]. These methods probabilistically reconstruct likely transmission links between cases using data on the timing of symptoms and, ... |
10.1371/journal.pcbi.1006134 | Nonmechanistic forecasts of seasonal influenza with iterative one-week-ahead distributions | Accurate and reliable forecasts of seasonal epidemics of infectious disease can assist in the design of countermeasures and increase public awareness and preparedness. This article describes two main contributions we made recently toward this goal: a novel approach to probabilistic modeling of surveillance time series ... | Seasonal influenza is associated with 250 000 to 500 000 deaths worldwide each year (WHO estimates). In the United States and other temperate regions, seasonal influenza epidemics occur annually, but their timing and intensity varies significantly; accurate and reliable forecasts that quantify their uncertainty can ass... | Seasonal influenza epidemics cause widespread illness which is associated each year with an estimated 250 000 to 500 000 deaths worldwide [1] and 3000 to 56 000 deaths in the United States alone [2–4]. In contrast to influenza “pandemics”, which are rare global outbreaks of especially novel influenza A viruses [5, 6], ... |
10.1371/journal.pcbi.1003402 | A Latent Markov Modelling Approach to the Evaluation of Circulating Cathodic Antigen Strips for Schistosomiasis Diagnosis Pre- and Post-Praziquantel Treatment in Uganda | Regular treatment with praziquantel (PZQ) is the strategy for human schistosomiasis control aiming to prevent morbidity in later life. With the recent resolution on schistosomiasis elimination by the 65th World Health Assembly, appropriate diagnostic tools to inform interventions are keys to their success. We present a... | Schistosomiasis remains one of the most prevalent parasitic diseases in developing countries, with Schistosoma mansoni being the most widespread of the human-infecting schistosomes. For the routine surveillance of human S. mansoni infection more “field-applicable,” sensitive, and cost-effective diagnostics that replica... | Schistosomiasis is a debilitating parasitic disease in tropical and sub-tropical areas which has recently attracted increased focus and funding for control through large scale mass drug administration (MDA) of praziquantel (PZQ) [1]. However the ability of current control initiatives to operate cost effectively is redu... |
10.1371/journal.ppat.1004499 | Restriction of Francisella novicida Genetic Diversity during Infection of the Vector Midgut | The genetic diversity of pathogens, and interactions between genotypes, can strongly influence pathogen phenotypes such as transmissibility and virulence. For vector-borne pathogens, both mammalian hosts and arthropod vectors may limit pathogen genotypic diversity (number of unique genotypes circulating in an area) by ... | Co-infection, the presence of multiple genotypes of the same pathogen species within an infected individual, is common. Genotype diversity, defined as the number of unique genotypes, and the interaction between genotypes, can strongly influence virulence and pathogen transmission. Understanding how genotypic diversity ... | Genetic diversity within a single microbial species can lead to infection of hosts with mixtures of pathogen genotypes. Remarkably, studies across numerous systems have demonstrated that mixed-genotype infections are more common than infections with a single clonal variant [1]–[5]. The degree of genotypic diversity, de... |
10.1371/journal.ppat.1005357 | Characterization of RyDEN (C19orf66) as an Interferon-Stimulated Cellular Inhibitor against Dengue Virus Replication | Dengue virus (DENV) is one of the most important arthropod-borne pathogens that cause life-threatening diseases in humans. However, no vaccine or specific antiviral is available for dengue. As seen in other RNA viruses, the innate immune system plays a key role in controlling DENV infection and disease outcome. Althoug... | Dengue is the most common arthropod-borne viral infection and is spreading to new areas every year. Its causative agent, dengue virus (DENV), has immunologically distinct serotypes that increase the risk of life-threatening diseases such as dengue hemorrhagic fever. However, an effective medication for dengue has not y... | Dengue virus (DENV) is a mosquito-borne virus belonging to the genus Flavivirus, which is a large family of enveloped, positive-stranded RNA viruses. DENV has four antigenically distinct serotypes (DENV-1 to -4); all serotypes are able to cause dengue fever (DF) and dengue hemorrhagic fever (DHF) in humans. While prima... |
10.1371/journal.pgen.1007877 | Separate Polycomb Response Elements control chromatin state and activation of the vestigial gene | Patterned expression of many developmental genes is specified by transcription factor gene expression, but is thought to be refined by chromatin-mediated repression. Regulatory DNA sequences called Polycomb Response Elements (PREs) are required to repress some developmental target genes, and are widespread in genomes, ... | Eukaryotic genes are packaged in chromatin, and their transcription relies on activators that recruit RNA polymerases and on repressive factors. In multicellular organisms, cell types have distinct patterns of gene expression, and these patterns are controlled by by the expression of cell-type-specific transcription fa... | The patterns of chromatin histone modifications differ between cell types, reflecting the activity of genes for developmental programs. Tri-methylation of the lysine-27 residue of histone H3 (H3K27me3) typically marks extended chromatin domains, leading to chromatin compaction and epigenetic gene silencing that is main... |
10.1371/journal.pntd.0002743 | Identification of Carboxylesterase Genes Implicated in Temephos Resistance in the Dengue Vector Aedes aegypti | Thailand is currently experiencing one of its worst dengue outbreaks in decades. As in most countries where this disease is endemic, dengue control in Thailand is largely reliant on the use of insecticides targeting both immature and adult stages of the Aedes mosquito, with the organophosphate insecticide, temephos, be... | Temephos is the most important insecticide used in larviciding campaigns to reduce the risk of dengue transmission. This organophosphate insecticide has been in use for over 50 years and resistance to this chemical has been reported in Aedes aegypti populations from Latin America, the Caribbean and from Asia. In other ... | Aedes aegypti is a major vector of dengue fever and yellow fever viruses. Despite an effective vaccine, there are over 200,000 cases of yellow fever each year (WHO source, 2012). With no vaccine currently available for dengue, and no specific drug treatment, approximately 40% of the world's population is at risk of den... |
10.1371/journal.ppat.1006871 | Liver macrophage-associated inflammation correlates with SIV burden and is substantially reduced following cART | Liver disease is a leading contributor to morbidity and mortality during HIV infection, despite the use of combination antiretroviral therapy (cART). The precise mechanisms of liver disease during HIV infection are poorly understood partially due to the difficulty in obtaining human liver samples as well as the presenc... | Liver disease is common in HIV-infected individuals and is one of the leading causes of death in this population. Currently, the factors that contribute to liver disease during HIV infection are not known, as human studies are difficult to conduct. Therefore, pathogenic SIV infection of macaques is a valuable model sys... | Liver disease has become a leading contributor to morbidity and mortality in HIV-infected people with the occurrence of nonalcoholic fatty liver disease (NAFLD) being one of the most predominant complications [1–5]. Within the setting of HIV infection, not only is NAFLD more common than in the general population, but a... |
10.1371/journal.pcbi.1006182 | Assessment of ab initio models of protein complexes by molecular dynamics | Determining how proteins interact to form stable complexes is of crucial importance, for example in the development of novel therapeutics. Computational methods to determine the thermodynamically stable conformation of complexes from the structure of the binding partners, such as RosettaDock, might potentially emerge t... | Determining how proteins fold and form complexes is of crucial importance, for example in the development of novel therapeutics. Experimental determination of structures is costly and lengthy. Computational methods to determine the thermodynamically stable conformation of complexes from the structure of the binding par... | Most biological processes are mediated by interactions between proteins. The high-resolution structure of protein complexes may help understand those processes at the molecular level and possibly interfere with them by rational design.
Predicting structures of complexes from known protein structures is, at first sight... |
10.1371/journal.pcbi.1002065 | Extracting Message Inter-Departure Time Distributions from the Human Electroencephalogram | The complex connectivity of the cerebral cortex is a topic of much study, yet the link between structure and function is still unclear. The processing capacity and throughput of information at individual brain regions remains an open question and one that could potentially bridge these two aspects of neural organizatio... | The brain may be thought of as a network of regions that communicate with each other to produce emergent phenomena such as perception and cognition. Many potentially interesting aspects of brain networks, such as how information is emitted at different nodes, also tend to be of interest in various types of telecommunic... | Recent years have witnessed a remarkable drive to characterize the large-scale structural topology of the brain. The graph model of cortical connectivity – whereby space is discretized and the brain is delineated as a set of regional nodes interconnected by white matter edges – has enabled the application of a whole ho... |
10.1371/journal.pgen.1005410 | The Shelterin TIN2 Subunit Mediates Recruitment of Telomerase to Telomeres | Dyskeratosis Congenita (DC) is a heritable multi-system disorder caused by abnormally short telomeres. Clinically diagnosed by the mucocutaneous symptoms, DC patients are at high risk for bone marrow failure, pulmonary fibrosis, and multiple types of cancers. We have recapitulated the most common DC-causing mutation in... | The shelterin complex protects telomeres from being processed by the DNA damage repair machinery, and also regulates telomerase access and activity at telomeres. The only shelterin subunit known to promote telomerase function is TPP1, which mediates telomerase recruitment to telomeres and stimulates telomerase processi... | The multi-subunit shelterin complexes bind along mammalian telomeres, shielding the natural chromosome ends from engaging the DNA damage signaling and repair machinery [1]. Among the shelterin components, TRF1 and TRF2 bind directly to duplex telomeric repeats [2], while POT1 binds to the single-stranded regions of tel... |
10.1371/journal.pbio.2003067 | Spliced integrated retrotransposed element (SpIRE) formation in the human genome | Human Long interspersed element-1 (L1) retrotransposons contain an internal RNA polymerase II promoter within their 5′ untranslated region (UTR) and encode two proteins, (ORF1p and ORF2p) required for their mobilization (i.e., retrotransposition). The evolutionary success of L1 relies on the continuous retrotranspositi... | Long interspersed element-1 (L1) sequences comprise about 17% of the human genome reference sequence. The average human genome contains about 100 active L1s that mobilize throughout the genome by a “copy and paste” process termed retrotransposition. Active L1s encode two proteins (ORF1p and ORF2p). ORF1p and ORF2p pref... | Long interspersed element-1 (L1) is a non-long terminal repeat (non-LTR) retrotransposon that comprises approximately 17% of human genomic DNA [1]. Over 99.9% of human L1s cannot retrotranspose due to 5′ truncations, internal DNA rearrangements, or point mutations that inactivate the L1-encoded proteins [1–4]. However,... |
10.1371/journal.pgen.1002698 | An Essential Role for Katanin p80 and Microtubule Severing in Male Gamete Production | Katanin is an evolutionarily conserved microtubule-severing complex implicated in multiple aspects of microtubule dynamics. Katanin consists of a p60 severing enzyme and a p80 regulatory subunit. The p80 subunit is thought to regulate complex targeting and severing activity, but its precise role remains elusive. In low... | Microtubules are critical components of cells, acting as a “scaffold” for the movement of organelles and proteins within the cytoplasm. The control of microtubule length, number, and movement is essential for many cellular processes, including division, architecture, and migration. We have defined the role of the micro... | The regulation of microtubule dynamics is an essential requirement for all cells and in many aspects of their daily function. The ability to precisely regulate microtubule number, the assembly of networks, and the rate of microtubule assembly and disassembly underpins cellular processes including division, differentiat... |
10.1371/journal.pcbi.1003221 | Potential Role of a Bistable Histidine Kinase Switch in the Asymmetric Division Cycle of Caulobacter crescentus | The free-living aquatic bacterium, Caulobacter crescentus, exhibits two different morphologies during its life cycle. The morphological change from swarmer cell to stalked cell is a result of changes of function of two bi-functional histidine kinases, PleC and CckA. Here, we describe a detailed molecular mechanism by w... | Recent evidence suggests that the transition of PleC from phosphatase to kinase is induced by its own substrate, DivK. Based on experimental clues, we propose a molecular mechanism to explain this substrate-induced conformational change in PleC. The general principles of thermodynamics, enzyme-substrate reactions and t... | The function of the cell division cycle of both prokaryotes and eukaryotes is to produce two nearly identical copies of a progenitor cell. The two progeny cells have identical genomes (modulo unavoidable mutations in the DNA replication process), and they are usually quite similar in all other aspects (called “symmetri... |
10.1371/journal.pgen.1004928 | Functional Interplay between the 53BP1-Ortholog Rad9 and the Mre11 Complex Regulates Resection, End-Tethering and Repair of a Double-Strand Break | The Mre11-Rad50-Xrs2 nuclease complex, together with Sae2, initiates the 5′-to-3′ resection of Double-Strand DNA Breaks (DSBs). Extended 3′ single stranded DNA filaments can be exposed from a DSB through the redundant activities of the Exo1 nuclease and the Dna2 nuclease with the Sgs1 helicase. In the absence of Sae2, ... | DNA double strand breaks (DSBs) are among the most deleterious types of damage occurring in the genome, as failure to repair these lesions through either non-homologous-end-joining (NHEJ) or homologous recombination (HR) leads to genetic instability. The 5′ strand of a DSB can be nucleolytically degraded by several nuc... | Similarly to what is seen in higher eukaryotes, in S. cerevisiae the ends of a double-strand DNA break (DSB) are recognized and bound by the Mre11-Rad50-Xrs2 (MRX) complex and the Ku70-Ku80 heterodimer, which compete for end binding. Once the MRX complex, together with CDK1-phosphorylated Sae2 (CtIP in human), initiate... |
10.1371/journal.ppat.1002739 | HIV-Specific Antibodies Capable of ADCC Are Common in Breastmilk and Are Associated with Reduced Risk of Transmission in Women with High Viral Loads | There are limited data describing the functional characteristics of HIV-1 specific antibodies in breast milk (BM) and their role in breastfeeding transmission. The ability of BM antibodies to bind HIV-1 envelope, neutralize heterologous and autologous viruses and direct antibody-dependent cell cytotoxicity (ADCC) were ... | In the absence of intervention, only about one third of infants born to HIV-1 infected mothers who are continuously exposed to maternal breast milk over prolonged periods get infected. This observation raises the possibility that immune factors in infected women play a role in limiting HIV-1 transmission. Identifying f... | Breast milk (BM) can be a vehicle for transmission of various pathogens, but the risk of infant infection is balanced by the potential clinical benefit of BM, which provides significant passive immunity and protection against many infectious agents [1]–[4]. In the case of HIV-1, exposure to virus through breastfeeding ... |
10.1371/journal.pntd.0007442 | Linear growth in preschool children treated with mass azithromycin distributions for trachoma: A cluster-randomized trial | Mass azithromycin distributions have been shown to reduce mortality among pre-school children in sub-Saharan Africa. It is unclear what mediates this mortality reduction, but one possibility is that antibiotics function as growth promoters for young children.
24 rural Ethiopian communities that had received biannual ma... | Mass distribution of a single dose of the broad-spectrum antibiotic azithromycin twice per year to pre-school children in Sub-Saharan Africa has been shown to reduce childhood mortality. The mechanism by which azithromycin reduces mortality is currently not clear, especially since the antibiotic is not targeted to sick... | Undernutrition is thought to contribute more to the global burden of disease than any other risk factor.[1] Poor nutrition potentiates the effects of infections such as diarrhea, respiratory infections, and malaria, leading to worse outcomes and higher mortality.[2, 3] Infectious diseases in turn lead to poor growth.[4... |
10.1371/journal.pgen.1007043 | Combinatorial action of Grainyhead, Extradenticle and Notch in regulating Hox mediated apoptosis in Drosophila larval CNS | Hox mediated neuroblast apoptosis is a prevalent way to pattern larval central nervous system (CNS) by different Hox genes, but the mechanism of this apoptosis is not understood. Our studies with Abdominal-A (Abd-A) mediated larval neuroblast (pNB) apoptosis suggests that AbdA, its cofactor Extradenticle (Exd), a helix... | Specification of the head to tail axis of the developing central nervous system is carried out by Hox genes. Hox mediated programmed cell death of the neural progenitor cells plays an important role in specification of this axis, but the molecular mechanism of this phenomenon is not well understood. We have studied thi... | Apoptosis is used to eliminate defective and/or dispensable cell types during development of an organism. Removal of excess cells from the developing tissue is critical for its final size, shape and functionality in the whole organismal context [1–3]. The central nervous system (CNS) also relies heavily on apoptosis fo... |
10.1371/journal.pntd.0004133 | Nodular Worm Infections in Wild Non-human Primates and Humans Living in the Sebitoli Area (Kibale National Park, Uganda): Do High Spatial Proximity Favor Zoonotic Transmission? | Nodular Oesophagostomum genus nematodes are a major public health concern in some African regions because they can be lethal to humans. Their relatively high prevalence in people has been described in Uganda recently. While non-human primates also harbor Oesophagostomum spp., the epidemiology of this oesophagostomosis ... | Nodular worms frequently infect primates, pigs and ruminants. These intestinal nematodes induce inflammatory masses in the colon wall that cause severe abdominal pain, diarrhea, weight loss, and potential death. Through microscopic and molecular analyses, we studied the presence of nodular worms in three non-human prim... | Emerging zoonotic diseases are a serious threat to public health and animal conservation. This is especially true for apes, whose close phylogenetic relationship with humans increases the risk of zoonotic transmission between them. Although humans have always shared habitats with non-human primates, the dynamics of the... |
10.1371/journal.pcbi.1004058 | Heterogeneous CD8+ T Cell Migration in the Lymph Node in the Absence of Inflammation Revealed by Quantitative Migration Analysis | The three-dimensional positions of immune cells can be tracked in live tissues precisely as a function of time using two-photon microscopy. However, standard methods of analysis used in the field and experimental artifacts can bias interpretations and obscure important aspects of cell migration such as directional migr... | Migration is fundamental to immune cell function, and accurate quantitative methods are crucial for analyzing and interpreting migration statistics. However, existing methods of analysis cannot uniquely describe cell behavior and suffer from various limitations. This complicates efforts to address questions such as to ... | A primary challenge of immunological imaging experimentation is to understand the nature of cell migration statistics, and the role that these statistics play in immune function. Over the last decade, two-photon microscopy has transformed the understanding of the role of cell migration in the immune response [1–3]. How... |
10.1371/journal.pntd.0006583 | Identifying residual transmission of lymphatic filariasis after mass drug administration: Comparing school-based versus community-based surveillance - American Samoa, 2016 | Under the Global Programme to Eliminate Lymphatic Filariasis (LF), American Samoa conducted seven rounds of mass drug administration (MDA) from 2000–2006. The World Health Organization recommends systematic post-MDA surveillance using Transmission Assessment Surveys (TAS) for epidemiological assessment of recent LF tra... | Lymphatic filariasis (LF) is caused by infection with filarial worms that are transmitted by mosquito bites. Globally, 68 million are infected, with ~36 million people disfigured and disabled by complications such as severe swelling of the legs (elephantiasis) or scrotum (hydrocele). The Global Programme to Eliminate L... | Lymphatic filariasis (LF) is a neglected tropical disease caused by Wuchereria bancrofti and Brugia species of helminth worms. The disease is transmitted by mosquito vectors including Aedes, Anopheles, Culex and Mansonia species. Globally, an estimated 68 million people are infected; with 36 million microfilaemic peopl... |
10.1371/journal.ppat.1006936 | Nubbin isoform antagonism governs Drosophila intestinal immune homeostasis | Gut immunity is regulated by intricate and dynamic mechanisms to ensure homeostasis despite a constantly changing microbial environment. Several regulatory factors have been described to participate in feedback responses to prevent aberrant immune activity. Little is, however, known about how transcriptional programs a... | The numerous human diseases caused by aberrations in intestinal immunity and integrity urge a better understanding of the regulatory interactions that balance the output of host-microbe interactions. In this study, we discovered a novel phenomenon of transcriptional antagonism exerted via two isoforms encoded from the ... | The innate immune system of mammals and insects is regulated by intracellular signaling pathways and transcriptional programs that show remarkable signs of evolutionary conservation. Well-known examples are the Toll/Toll-like receptor (TLR), immune deficiency (IMD)/tumor necrosis factor-α (TNF-α), JAK/STAT and JNK sign... |
10.1371/journal.ppat.1005987 | Swimming Motility Mediates the Formation of Neutrophil Extracellular Traps Induced by Flagellated Pseudomonas aeruginosa | Pseudomonas aeruginosa is an opportunistic pathogen causing severe infections often characterized by robust neutrophilic infiltration. Neutrophils provide the first line of defense against P. aeruginosa. Aside from their defense conferred by phagocytic activity, neutrophils also release neutrophil extracellular traps (... | Pseudomonas aeruginosa leaves a large footprint in human disease because it causes infections in immunocompromised patients. Its ability to quickly adapt to diverse environments and to form biofilms poses a significant challenge to the medical community. Neutrophil granulocytes, professional phagocytes found cruising t... | Pseudomonas aeruginosa is a ubiquitous opportunistic Gram-negative pathogen found in the environment. P. aeruginosa rarely infects healthy individuals and mainly causes lung infections in patients with compromised immune defenses [cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), HIV, non-CF bronchiec... |
10.1371/journal.ppat.1003074 | Transcription of a cis-acting, Noncoding, Small RNA Is Required for Pilin Antigenic Variation in Neisseria gonorrhoeae | The strict human pathogen Neisseria gonorrhoeae can utilize homologous recombination to generate antigenic variability in targets of immune surveillance. To evade the host immune response, N. gonorrhoeae promotes high frequency gene conversion events between many silent pilin copies and the expressed pilin locus (pilE)... | To evade the host immune response, pathogens have evolved mechanisms to provide genetic diversity in targets of immune surveillance. Organisms that express these diversification systems are under strong evolutionary pressure to provide subpopulations of preexisting variants and often rely on cellular recombination mach... | Neisseria gonorrhoeae is an obligate human pathogen and the causative agent of the sexually transmitted infection gonorrhea. Gonococci generally infect the urogenital tract and the infection typically presents as urethritis in men and cervicitis in women, but many women can be asymptomatic carriers [1]. The N. gonorrho... |
10.1371/journal.pcbi.1003883 | Stochastic Modeling of Mouse Motor Activity under Deep Brain Stimulation: The Extraction of Arousal Information | In the present paper, we quantify, with a rigorous approach, the nature of motor activity in response to Deep Brain Stimulation (DBS), in the mouse. DBS is currently being used in the treatment of a broad range of diseases, but its underlying principles are still unclear. Because mouse movement involves rapidly repeate... | Brainstem and thalamic regulation of arousal has been studied experimentally since the mid 20-th century. Today, Deep Brain Stimulation (DBS) is used in the treatment of movement disorders, chronic pain, clinical depression, amongst others. At present, the proper choice of DBS parameters (frequency and strength of the ... | Deep Brain Stimulation is currently being used in the treatment of Parkinson’s Disease, Disorders of Consciousness (DoC) and clinical depression [1–3]. The possibility that Deep Brain Stimulation (DBS) could be used to enhance brain arousal is a subject of immense interest, e.g., in traumatic brain injury (TBI). For ex... |
10.1371/journal.ppat.1003523 | Clostridium difficile 027/BI/NAP1 Encodes a Hypertoxic and Antigenically Variable Form of TcdB | The Clostridium difficile exotoxin, TcdB, which is a major virulence factor, varies between strains of this pathogen. Herein, we show that TcdB from the epidemic BI/NAP1/027 strain of C. difficile is more lethal, causes more extensive brain hemorrhage, and is antigenically variable from TcdB produced by previously stud... | During the past decade, the C. difficile BI/NAP1/027 strain has emerged and in some settings predominated as the cause of C. difficile infection. Moreover, in some reports C. difficile BI/NAP1/027 has been associated with more severe disease. The reasons for association of this strain with more severe disease and relap... | Clostridium difficile is the leading cause of hospital-acquired diarrhea in developed countries [1], [2], [3], [4]. This spore-forming anaerobic bacterium contaminates hospital environments and infects patients undergoing antibiotic therapy within health care facilities [2], [5], [6]. Despite these problems, historical... |
10.1371/journal.pcbi.1002528 | Fine-Tuning Tomato Agronomic Properties by Computational Genome Redesign | Considering cells as biofactories, we aimed to optimize its internal processes by using the same engineering principles that large industries are implementing nowadays: lean manufacturing. We have applied reverse engineering computational methods to transcriptomic, metabolomic and phenomic data obtained from a collecti... | Considering cells as biofactories, we aimed to optimize their internal processes by using existing design principles acquired from engineering. Herein, we present a synthetic biology approach based on experimental and computational methodology that integrates genomic, transcriptomic, metabolomic and phenomic data to fo... | Considering a cell as a DNA-based molecular factory [1] and applying principles drawn from industrial engineering provides new approaches to optimize cellular performance (Figure S1). This approach adopts the new philosophy implemented nowadays by large industries that is known as Lean Manufacturing (LM). LM consists i... |
10.1371/journal.pgen.1007502 | Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy | Left ventricular non-compaction (LVNC) is a rare cardiomyopathy associated with a hypertrabeculated phenotype and a large spectrum of symptoms. It is still unclear whether LVNC results from a defect of ventricular trabeculae development and the mechanistic basis that underlies the varying severity of this pathology is ... | During fetal heart morphogenesis, formation of the mature ventricular wall requires coordinated compaction of the inner trabecular layer and growth of the outer layer of myocardium. Arrested trabecular development has been implicated in the pathogenesis of hypertrabeculation associated with ventricular non-compaction c... | Left ventricular non-compaction (LVNC) or hypertrabeculation is a cardiac anomaly characterized by a thickened sub-endocardial layer of ventricular myocardium with prominent trabeculations and deep recesses that communicate with the left ventricular (LV) cavity [1]. The recent classification of LVNC as the third most c... |
10.1371/journal.pntd.0004057 | Assessment of Efficacy and Quality of Two Albendazole Brands Commonly Used against Soil-Transmitted Helminth Infections in School Children in Jimma Town, Ethiopia | There is a worldwide upscale in mass drug administration (MDA) programs to control the morbidity caused by soil-transmitted helminths (STHs): Ascaris lumbricoides, Trichuris trichiura and hookworm. Although anthelminthic drugs which are used for MDA are supplied by two pharmaceutical companies through donation, there i... | Soil-transmitted helminths (STHs) infect millions of children worldwide. To fight STH, large-scale de-worming programs are implemented in which anthelmintic drugs (either albendazole (ABZ) or mebendazole (MEB)) are administered. However, there is a wide range of other brands, which are even more accessible, but for whi... | Currently, there is a worldwide upscale in the implementation of programs to control and to eliminate a selection of 10 neglected tropical diseases [1, 2]. Among these, soil-transmitted helminthiasis causes the highest burden on public health. It is estimated that more than 1.4 billion people were infected with at leas... |
10.1371/journal.pntd.0000698 | Human Complement Regulators C4b-Binding Protein and C1 Esterase Inhibitor Interact with a Novel Outer Surface Protein of Borrelia recurrentis | The spirochete Borrelia recurrentis is the causal agent of louse-borne relapsing fever and is transmitted to humans by the infected body louse Pediculus humanus. We have recently demonstrated that the B. recurrentis surface receptor, HcpA, specifically binds factor H, the regulator of the alternative pathway of complem... | Borrelia recurrentis, the causal agent of louse-borne relapsing fever is transmitted to humans via infected body lice. Infection with B. recurrentis has been achieved only in humans and is accompanied by a systemic inflammatory disease, multiple relapses of fever and massive spirochetemia. A key virulence factor of B. ... | B. recurrentis, the causative agent of louse-borne relapsing fever is transmitted to humans by contamination of abraded skin with either hemolymph from crushed, infected lice (Pediculus humanus humanus) or excreted feces thereof [1], [2]. The last century has seen multiple epidemics of louse-borne relapsing fever in Eu... |
10.1371/journal.pntd.0001658 | Methodology for Definition of Yellow Fever Priority Areas, Based on Environmental Variables and Multiple Correspondence Analyses | Yellow fever (YF) is endemic in much of Brazil, where cases of the disease are reported every year. Since 2008, outbreaks of the disease have occurred in regions of the country where no reports had been registered for decades, which has obligated public health authorities to redefine risk areas for the disease. The aim... | Yellow fever (YF) is an infectious disease, transmitted by mosquitoes, and very common in North and Middle East region of Brazil, where cases of the disease are reported every year. Since 2008, outbreaks of the disease have occurred in regions of the country where no reports had been registered for decades, which has o... | Brazil has an extended enzootic or endemic area for sylvatic yellow fever (YF), where cases of the disease are annually reported. The highest frequency of the disease occurs between January and April, when high levels of rainfall and an increase in the vector population coincide with greater agricultural activity [1]–[... |
10.1371/journal.pgen.1007520 | Hypodermal responses to protein synthesis inhibition induce systemic developmental arrest and AMPK-dependent survival in Caenorhabditis elegans | Across organisms, manipulation of biosynthetic capacity arrests development early in life, but can increase health- and lifespan post-developmentally. Here we demonstrate that this developmental arrest is not sickness but rather a regulated survival program responding to reduced cellular performance. We inhibited prote... | Protein synthesis is an essential cellular process, but post-developmental reduction of protein synthesis across multiple species leads to improved health- and lifespan. To better understand the physiological responses to impaired protein synthesis, we characterize a novel developmental arrest state that occurs when re... | The differing phenotypes stemming from the loss of essential cellular functions, such as protein synthesis, are specific to the time in life (development or adulthood) when the deficit occurs. Under such deficits, arresting development is an established strategy at the disposal of animals to ensure future reproductive ... |
10.1371/journal.pntd.0004126 | Animal Reservoirs of Zoonotic Tungiasis in Endemic Rural Villages of Uganda | Animal tungiasis is believed to increase the prevalence and parasite burden in humans. Animal reservoirs of Tunga penetrans differ among endemic areas and their role in the epidemiology of tungiasis had never been investigated in Uganda.
To identify the major animal reservoirs of Tunga penetrans and their relative impo... | Tungiasis is a neglected skin disease, frequent in resource-poor communities in the tropics. It is caused by sand fleas (also called jigger fleas) which burrow in the skin of humans and animals. Tungiasis can cause physical disabilities and the associated wounds facilitate entry of pathogens including those causing tet... | Tungiasis is an ectoparasitosis that accrues from the penetration of female sand fleas into the skin. Tunga penetrans [1] and Tunga trimamillata [2] are the only species known to cause tungiasis in both humans and animals. Currently, zoonotic tungiasis is endemic in southern America, the Caribbean and sub-Saharan Afric... |
10.1371/journal.pntd.0004120 | Carbohydrate Recognition Specificity of Trans-sialidase Lectin Domain from Trypanosoma congolense | Fourteen different active Trypanosoma congolense trans-sialidases (TconTS), 11 variants of TconTS1 besides TconTS2, TconTS3 and TconTS4, have been described. Notably, the specific transfer and sialidase activities of these TconTS differ by orders of magnitude. Surprisingly, phylogenetic analysis of the catalytic domain... | In this study we demonstrated the binding of TconTS lectin domains (TconTS-LD) to high-mannose N-glycans and provide evidence for a biological function for this interaction. TconTS1 and TconTS2 lectin domain bind to galactosyl as well as mannosyl glycans with different affinities as shown by glycan array analysis. Alon... | The protozoan parasite Trypanosoma congolense is the most prevalent cause of animal African Trypanosomiasis (AAT), also called Nagana in cattle and other livestock, causing death to millions of animals resulting in huge economic losses [1–3]. During the parasite’s life cycle in the mammalian host and the tsetse fly vec... |
10.1371/journal.pntd.0000928 | A DNA Vaccine against Chikungunya Virus Is Protective in Mice and Induces Neutralizing Antibodies in Mice and Nonhuman Primates | Chikungunya virus (CHIKV) is an emerging mosquito-borne alphavirus indigenous to tropical Africa and Asia. Acute illness is characterized by fever, arthralgias, conjunctivitis, rash, and sometimes arthritis. Relatively little is known about the antigenic targets for immunity, and no licensed vaccines or therapeutics ar... | Chikungunya fever epidemics are sustained by a cycle of human-mosquito-human transmission, with the epidemic cycle being similar to those of dengue and urban yellow fever. While the threat of a pandemic continues to engage the public's attention, the peculiar problems associated with the more immediate and very real se... | Chikungunya virus (CHIKV) is an enveloped, single-stranded, positive-sense RNA virus that belongs to the family Togaviridae, genus Alphavirus, and is part of the Semliki Forest virus antigenic complex [1], [2], [3], [4]. CHIKV has been responsible for unprecedented, explosive outbreaks during 2004 and 2007 in India and... |
10.1371/journal.ppat.1002219 | Genomic Insights into the Origin of Parasitism in the Emerging Plant Pathogen Bursaphelenchus xylophilus | Bursaphelenchus xylophilus is the nematode responsible for a devastating epidemic of pine wilt disease in Asia and Europe, and represents a recent, independent origin of plant parasitism in nematodes, ecologically and taxonomically distinct from other nematodes for which genomic data is available. As well as being an i... | Bursaphelenchus xylophilus is an important plant pathogen, responsible for an epidemic of pine wilt disease in Asia and Europe. B. xylophilus has acquired the ability to parasitise plants independently from other economically important nematodes and has a complex life cycle that includes fungal feeding and a stage asso... | The nematode Caenorhabditis elegans was the first multicellular organism for which a complete genome sequence was available, and subsequent genomics research on a wider range of nematodes has provided information on many important biological processes and is underpinned by the information developed for C. elegans [1]. ... |
10.1371/journal.ppat.1002275 | Strain Specific Resistance to Murine Scrapie Associated with a Naturally Occurring Human Prion Protein Polymorphism at Residue 171 | Transmissible spongiform encephalopathies (TSE) or prion diseases are neurodegenerative disorders associated with conversion of normal host prion protein (PrP) to a misfolded, protease-resistant form (PrPres). Genetic variations of prion protein in humans and animals can alter susceptibility to both familial and infect... | Transmissible spongiform encephalopathies (TSE) or prion diseases are infectious fatal neurological diseases that affect many mammals, including humans. In these diseases a misfolded form of host prion protein (PrP) leads to brain degeneration and death. The genetic code of PrP in individual animals or humans has minor... | TSE or prion diseases are transmissible neurodegenerative diseases occurring in a variety of mammalian species including domestic and wild animals as well as humans [1]. Examples include scrapie in sheep, chronic wasting disease (CWD) in cervids and bovine spongiform encephalopathy (BSE) in cattle. Human diseases inclu... |
10.1371/journal.ppat.1003067 | Influenza Human Monoclonal Antibody 1F1 Interacts with Three Major Antigenic Sites and Residues Mediating Human Receptor Specificity in H1N1 Viruses | Most monoclonal antibodies (mAbs) to the influenza A virus hemagglutinin (HA) head domain exhibit very limited breadth of inhibitory activity due to antigenic drift in field strains. However, mAb 1F1, isolated from a 1918 influenza pandemic survivor, inhibits select human H1 viruses (1918, 1943, 1947, and 1977 isolates... | Influenza infection kills thousands of people every year and causes major pandemics every few decades. The most lethal outbreak of influenza known was the 1918 H1N1 influenza pandemic that killed an estimated 20 to 100 million people. The 1918 virus was likely introduced into the human population from birds. We previou... | The hemagglutinin (HA) protein of influenza viruses binds to sialic acid receptors on host cells and is the major target of neutralizing antibodies. Amino-acid changes in the immunodominant HA antigenic sites that arise in response to immune selective pressure (antigenic drift) enable seasonal influenza A viruses to ca... |
10.1371/journal.pbio.1000154 | The Neuropeptide PDF Acts Directly on Evening Pacemaker Neurons to Regulate Multiple Features of Circadian Behavior | Discrete clusters of circadian clock neurons temporally organize daily behaviors such as sleep and wake. In Drosophila, a network of just 150 neurons drives two peaks of timed activity in the morning and evening. A subset of these neurons expresses the neuropeptide pigment dispersing factor (PDF), which is important fo... | Animals depend on being awake at the right time of day to find food and mates and fend off predators. Circadian pacemaker neurons in the brain play a crucial role in timing of specific behaviors to the appropriate times of day. These neurons are further specialized to those primarily responsible for morning and evening... | Circadian clocks act in many organisms to promote daily rhythms of behavior and physiology. In Drosophila, clock function under conditions of light-dark entrainment (12-h light∶12-h dark; LD) is evident as increases in locomotor activity in advance of lights-on (morning anticipation) and lights-off (evening anticipatio... |
10.1371/journal.pmed.1002620 | Reducing the burden of dizziness in middle-aged and older people: A multifactorial, tailored, single-blind randomized controlled trial | Dizziness is common among older people and is associated with a cascade of debilitating symptoms, such as reduced quality of life, depression, and falls. The multifactorial aetiology of dizziness is a major barrier to establishing a clear diagnosis and offering effective therapeutic interventions. Only a few multidisci... | Dizziness is a frequent complaint amongst middle-aged and older people.
Dizziness can lead to poor health outcomes, including reduced quality of life, depression, and falls.
The increasingly multifactorial nature of dizziness with advancing age makes it difficult to objectively establish a diagnosis and offer effective... | Dizziness is common in older people: prevalence rates in the community range between 10% and 30% [1–4] and increase with age [1,2,5]. Dizziness is often associated with a marked increase in self-reported functional disability [1,6], depressive symptoms [3,4], decreased participation in social activities, poor self-repo... |
10.1371/journal.pgen.1000329 | Why Is the Correlation between Gene Importance and Gene Evolutionary Rate So Weak? | One of the few commonly believed principles of molecular evolution is that functionally more important genes (or DNA sequences) evolve more slowly than less important ones. This principle is widely used by molecular biologists in daily practice. However, recent genomic analysis of a diverse array of organisms found onl... | The fact that functionally more important genes or DNA sequences evolve more slowly than less important ones is commonly believed and frequently used by molecular biologists. However, previous genome-wide studies of a diverse array of organisms found only weak, negative correlations between the importance of a gene and... | When referring to any DNA sequence, a popular textbook of cell and molecular biology [1] states that “if it's conserved, it must be important” and calls this “one of the foremost principles of molecular evolution” (p. 416). Here, the word “conserved” means that the sequence has a low rate of evolution such that its ort... |
10.1371/journal.ppat.1005024 | Vpu Exploits the Cross-Talk between BST2 and the ILT7 Receptor to Suppress Anti-HIV-1 Responses by Plasmacytoid Dendritic Cells | Plasmacytoid dendritic cells (pDCs) constitute a major source of type-I interferon (IFN-I) production during acute HIV infection. Their activation results primarily from TLR7-mediated sensing of HIV-infected cells. However, the interactions between HIV-infected T cells and pDCs that modulate this sensing process remain... | Plasmacytoid dendritic cells (pDCs) produce large quantities of type I interferon (IFN-I) upon stimulation by many viruses, including HIV. Their activation is very effective following cell contacts with HIV-1-infected CD4+ T cells. We investigated whether HIV-1 could regulate the antiviral responses of pDCs triggered u... | Plasmacytoid dendritic cells (pDCs) are a distinct subset of DCs that exhibit a unique ability to secrete high amounts of interferons and other cytokines in response to viruses. Even though they constitute less than 1% of the total cell content of peripheral blood in humans, they are considered a primary source of type... |
10.1371/journal.ppat.1004932 | Vaccine-Elicited Tier 2 HIV-1 Neutralizing Antibodies Bind to Quaternary Epitopes Involving Glycan-Deficient Patches Proximal to the CD4 Binding Site | Eliciting broad tier 2 neutralizing antibodies (nAbs) is a major goal of HIV-1 vaccine research. Here we investigated the ability of native, membrane-expressed JR-FL Env trimers to elicit nAbs. Unusually potent nAb titers developed in 2 of 8 rabbits immunized with virus-like particles (VLPs) expressing trimers (trimer ... | Here we show that native HIV-1 Env spikes expressed in a natural membrane context can induce potent tier 2 nAbs in rabbits. These antibodies reacted exclusively with epitopes present on these trimers and not with isolated Env subunits. Intriguingly, the neutralizing sera were found to take advantage of natural gaps in ... | Eliciting broadly neutralizing antibodies (bnAbs) is a major goal of HIV-1 vaccine development [1,2]. NAbs block infection by binding to native Env spikes, consisting of trimers of gp120/gp41 heterodimers [2,3]. However, the compact, sequence-diverse, and heavily glycosylated nature of these trimers allows the virus to... |
10.1371/journal.pgen.1007658 | Whole exome sequencing of ENU-induced thrombosis modifier mutations in the mouse | Although the Factor V Leiden (FVL) gene variant is the most prevalent genetic risk factor for venous thrombosis, only 10% of FVL carriers will experience such an event in their lifetime. To identify potential FVL modifier genes contributing to this incomplete penetrance, we took advantage of a perinatal synthetic letha... | Abnormal blood clotting in veins (venous thrombosis) or arteries (arterial thrombosis) are major health problems, with venous thrombosis affecting approximately 1 in every thousand individuals annually in the United States. Susceptibility to venous thrombosis is governed by both genes and environment, with approximatel... | Venous thromboembolism (VTE) affects 1:1000 individuals in the US each year and is highly heritable [1, 2]. A single nucleotide variant (SNV) in the F5 gene, referred to as Factor V Leiden (FVL, p.R506G) is present in 5–10% of Europeans, conferring a 2–4 fold increased risk for VTE [3]. Although ~25% of VTE patients ca... |
10.1371/journal.ppat.1004149 | Dusp3 and Psme3 Are Associated with Murine Susceptibility to Staphylococcus aureus Infection and Human Sepsis | Using A/J mice, which are susceptible to Staphylococcus aureus, we sought to identify genetic determinants of susceptibility to S. aureus, and evaluate their function with regard to S. aureus infection. One QTL region on chromosome 11 containing 422 genes was found to be significantly associated with susceptibility to ... | Staphylococcus aureus causes life-threatening infections in humans. Host genetic determinants influence the outcome of S. aureus infection, yet are poorly understood. Susceptible A/J and resistant C57BL/6J mice provide a unique platform to study the genetic difference responsible for variable host response to S. aureus... | Staphylococcus aureus is an important cause of potentially lethal human infections [1]–[3]. It is generally accepted that host genetic variation influences susceptibility to S. aureus colonization and infection [4], [5].
A significant body of evidence supports the importance of human genetic variation on host suscepti... |
10.1371/journal.ppat.1000683 | The T3SS Effector EspT Defines a New Category of Invasive Enteropathogenic E. coli (EPEC) Which Form Intracellular Actin Pedestals | Enteropathogenic Escherichia coli (EPEC) strains are defined as extracellular pathogens which nucleate actin rich pedestal-like membrane extensions on intestinal enterocytes to which they intimately adhere. EPEC infection is mediated by type III secretion system effectors, which modulate host cell signaling. Recently w... | Enteropathogenic E. coli (EPEC) is an important diarrheal pathogen responsible for significant infant mortality in the developing world and is increasingly associated with sporadic outbreaks in the developed world. The virulence strategy of EPEC revolves around a conserved Type 3 secretion system (T3SS) which transloca... | The human pathogens enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) [1] and the mouse pathogen Citrobacter rodentium [2] are closely related extra-cellular diarrhoeal agents characterized by their ability to colonize the gut epithelium via attaching and effacing (A/E) lesion formation (rev... |
10.1371/journal.pbio.1002135 | Extracellular Adenosine Mediates a Systemic Metabolic Switch during Immune Response | Immune defense is energetically costly, and thus an effective response requires metabolic adaptation of the organism to reallocate energy from storage, growth, and development towards the immune system. We employ the natural infection of Drosophila with a parasitoid wasp to study energy regulation during immune respons... | The immune response is energetically costly and often requires adaption of the whole organism to ensure it receives enough energy. It is not well understood how distribution of energy resources within the organism is regulated during an immune response. To understand this better, we used parasitoid wasp infection of fr... | Immune response is energetically costly [1,2]. Immune cells, upon activation, favor glycolysis over oxidative phosphorylation for fast, albeit inefficient, energy generation and macromolecule synthesis [3,4]. This metabolic shift requires extra glucose as glycolysis produces much less ATP than does oxidative phosphoryl... |
10.1371/journal.pgen.1000969 | Affecting Rhomboid-3 Function Causes a Dilated Heart in Adult Drosophila | Drosophila is a well recognized model of several human diseases, and recent investigations have demonstrated that Drosophila can be used as a model of human heart failure. Previously, we described that optical coherence tomography (OCT) can be used to rapidly examine the cardiac function in adult, awake flies. This tec... | Heart failure is a common cardiovascular disease that is characterized by problems with the ability of the heart muscle to contract, called impaired systolic function, and an enlarged heart chamber. Model systems of human heart failure are necessary to facilitate the screening and identification of genes and genetic va... | The identification of genes that cause or modify cardiac dysfunction is required to understand the complex biology that is responsible for cardiomyopathies and heart failure in humans. The screening and identification of genetic mutants that affect cardiac function are facilitated by model systems of human heart failur... |
10.1371/journal.ppat.1002184 | Activation of HIV Transcription by the Viral Tat Protein Requires a Demethylation Step Mediated by Lysine-specific Demethylase 1 (LSD1/KDM1) | The essential transactivator function of the HIV Tat protein is regulated by multiple posttranslational modifications. Although individual modifications are well characterized, their crosstalk and dynamics of occurrence during the HIV transcription cycle remain unclear.
We examine interactions between two critical modi... | One of the remaining questions in HIV research is how the virus establishes a dormant (latent) stage and thereby escapes eradication by current antiretroviral therapy. Latently infected T cells do not produce significant amounts of viral genomes or viral proteins due to the silencing of a specific step in the viral lif... | Epigenetic processes are critical in the regulation of gene expression from the integrated HIV provirus and have become a focal point of research in therapeutics for HIV latency. Latently infected T cells persist in HIV-infected individuals despite highly active antiretroviral therapy (HAART) and rekindle the infection... |
10.1371/journal.pgen.1002572 | Nos2 Inactivation Promotes the Development of Medulloblastoma in Ptch1+/− Mice by Deregulation of Gap43–Dependent Granule Cell Precursor Migration | Medulloblastoma is the most common malignant brain tumor in children. A subset of medulloblastoma originates from granule cell precursors (GCPs) of the developing cerebellum and demonstrates aberrant hedgehog signaling, typically due to inactivating mutations in the receptor PTCH1, a pathomechanism recapitulated in Ptc... | Medulloblastoma is a common pediatric brain tumor, a subtype of which is driven by aberrant hedgehog pathway activation in cerebellar granule cell precursors. Although this tumor etiology has been intensively investigated in the well-established Ptch1+/− mouse model, knowledge is still lacking about the molecular inter... | Medulloblastoma (MB) is a highly malignant tumor of the cerebellum that preferentially develops in children and adolescents. Although the survival rate for standard risk MB is around 70% [1] surviving patients often suffer from neurodevelopmental and cognitive side effects of the aggressive therapy [2]. Therefore, impr... |
10.1371/journal.ppat.1002696 | Analysis of Functional Differences between Hepatitis C Virus NS5A of Genotypes 1–7 in Infectious Cell Culture Systems | Hepatitis C virus (HCV) is an important cause of chronic liver disease. Several highly diverse HCV genotypes exist with potential key functional differences. The HCV NS5A protein was associated with response to interferon (IFN)-α based therapy, and is a primary target of currently developed directly-acting antiviral co... | Hepatitis C virus (HCV) is a major public health burden and leads to chronic liver disease, including liver cirrhosis and liver cancer. Understanding the biological functions of the virus is crucial to the development of a vaccine and to improve current therapy through development of directly-acting antiviral compounds... | Hepatitis C virus (HCV) chronically infects 130–170 million people and leads to increased risk of severe liver disease. HCV belongs to the Flaviviridae family and has a positive-strand RNA genome containing one long open reading frame (ORF). The ORF encodes a polyprotein that is co- and post-translationally cleaved int... |
10.1371/journal.pcbi.1004659 | Structural and Energetic Characterization of the Ankyrin Repeat Protein Family | Ankyrin repeat containing proteins are one of the most abundant solenoid folds. Usually implicated in specific protein-protein interactions, these proteins are readily amenable for design, with promising biotechnological and biomedical applications. Studying repeat protein families presents technical challenges due to ... | Some natural proteins are formed with repetitions of similar amino acid stretches. Ankyrin-repeat proteins constitute one of the most abundant families of this class of proteins that serve as model systems to analyze how variations in sequences exert effects in structures and biological functions. We present an in-dept... | Ankyrin Repeat Proteins (ANKs) are usually described as composed of linear arrays of tandem copies of a ∼33 residues length motif with a canonical helix-loop-helix-β-hairpin/loop fold. Being one of the most common protein motifs in nature [1], these molecules are known to function as specific protein-protein interactor... |
10.1371/journal.pcbi.1000769 | Energy-Information Trade-Offs between Movement and Sensing | While there is accumulating evidence for the importance of the metabolic cost of information in sensory systems, how these costs are traded-off with movement when sensing is closely linked to movement is poorly understood. For example, if an animal needs to search a given amount of space beyond the range of its vision ... | Animals thrive by sensing their environment and using the information they've gathered to guide their movement. But collecting better information can result in less efficient movement: Bicycling while standing up on the pedals may help you see over obstacles ahead of you, but it causes more air drag, forcing your legs ... | Animals must constantly negotiate trade-offs in sensory and motor performance. The most well known of these trade-offs occur within either movement or sensory systems, rather than between them. As an example within motor systems, fish body shapes and styles of movement that maximize cruising efficiency may suffer from ... |
10.1371/journal.pntd.0003342 | Rapid and Sensitive Detection of Bartonella bacilliformis in Experimentally Infected Sand Flies by Loop-Mediated Isothermal Amplification (LAMP) of the Pap31 Gene | Carrion' disease, caused by Bartonella bacilliformis, remains truly neglected due to its focal geographical nature. A wide spectrum of clinical manifestations, including asymptomatic bacteremia, and lack of a sensitive diagnostic test can potentially lead to a spread of the disease into non-endemic regions where compet... | Carrion's disease, caused by Bartonella bacilliformis remains truly neglected due to its focal geographical nature. A wide spectrum of clinical manifestations, including asymptomatic bacteremia can potentially lead to a spread of the disease into non-endemic regions. The PCR-based approach is sensitive for detection of... | Carrion's disease, caused by Bartonella bacilliformis remains truly neglected due to its focal geographical nature, occurring in small rural communities of inter-Andean valleys between altitudes of 500–200 meters above sea level in Peru, Columbia and Ecuador [1]. The disease typically presents with acute fever and deva... |
10.1371/journal.pgen.1007665 | Hrg1 promotes heme-iron recycling during hemolysis in the zebrafish kidney | Heme-iron recycling from senescent red blood cells (erythrophagocytosis) accounts for the majority of total body iron in humans. Studies in cultured cells have ascribed a role for HRG1/SLC48A1 in heme-iron transport but the in vivo function of this heme transporter is unclear. Here we present genetic evidence in a zebr... | Total body iron stores in mammals is a composite of iron absorption from diet and iron recycled by macrophages from dying red blood cells (RBCs). Upon erythrophagocytosis of RBCs, the hemoglobin is degraded and heme is imported from the phagosomal compartment into the cytoplasm so that the iron can be released from hem... | Heme is an iron-containing porphyrin that acts as an essential cofactor in numerous biological processes such as oxygen transport, miRNA processing, electron transfer, and circadian clock control [1]. In humans, total body iron store is a composite of dietary iron absorption, which accounts for around 10% of the daily ... |
10.1371/journal.pgen.1003677 | Mediator Directs Co-transcriptional Heterochromatin Assembly by RNA Interference-Dependent and -Independent Pathways | Heterochromatin at the pericentromeric repeats in fission yeast is assembled and spread by an RNAi-dependent mechanism, which is coupled with the transcription of non-coding RNA from the repeats by RNA polymerase II. In addition, Rrp6, a component of the nuclear exosome, also contributes to heterochromatin assembly and... | DNA is packaged into chromatin structure, which is important for various genome functions such as gene expression and maintenance of genetic information. Heterochromatin is a condensed chromatin structure and involved in epigenetic regulation of gene expression through repression of transcription. Heterochromatin at th... | Heterochromatin is a silent higher-order chromatin structure that is associated with various genome functions such as transcriptional regulation, chromosomal segregation, suppression of recombination and repression of selfish elements. The fission yeast Schizosaccharomyces pombe provides a good model system for investi... |
10.1371/journal.ppat.1003153 | Plasmodium falciparum Malaria Elicits Inflammatory Responses that Dysregulate Placental Amino Acid Transport | Placental malaria (PM) can lead to poor neonatal outcomes, including low birthweight due to fetal growth restriction (FGR), especially when associated with local inflammation (intervillositis or IV). The pathogenesis of PM-associated FGR is largely unknown, but in idiopathic FGR, impaired transplacental amino acid tran... | Malaria infection during pregnancy can cause fetal growth restriction and low birthweight associated with high infant mortality and morbidity rates. The pathogenesis of fetal growth restriction in placental malaria is largely unknown, but in other pathological pregnancies, impaired transplacental amino acid transport h... | Pregnant women living in malaria endemic regions are highly susceptible to malaria, especially in first pregnancies [1], [2]. Malaria in pregnancy is characterized by placental malaria (PM), the selective accumulation of Plasmodium-falciparum infected erythrocytes (IE) in the maternal intervillous blood space of the pl... |
10.1371/journal.pbio.1000196 | Loss of Mitogen-Activated Protein Kinase Kinase Kinase 4 (MAP3K4) Reveals a Requirement for MAPK Signalling in Mouse Sex Determination | Sex determination in mammals is controlled by the presence or absence of the Y-linked gene SRY. In the developing male (XY) gonad, sex-determining region of the Y (SRY) protein acts to up-regulate expression of the related gene, SOX9, a transcriptional regulator that in turn initiates a downstream pathway of testis dev... | In mammals, whether an individual develops as a male or female depends on its sex chromosome constitution: those with a Y chromosome become males because of the development of the embryonic gonad into a testis. The Y-linked sex determining gene SRY regulates this process by initiating a pathway of gene and protein expr... | Sex determination is the process by which an embryo develops into a male or female, namely, the formation of testes in an XY embryo and ovaries in an XX embryo. In the mouse, this process begins with commitment of cells of the bipotential genital ridge to either the testicular or ovarian fate at 11.5 d post coitum (dpc... |
10.1371/journal.pgen.1002050 | Loss-of-Function Mutations in PTPN11 Cause Metachondromatosis, but Not Ollier Disease or Maffucci Syndrome | Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple ost... | Children with cartilage tumor syndromes form multiple tumors of cartilage next to joints. These tumors can occur inside the bones, as with Ollier disease and Maffuci syndrome, or on the surface of bones, as in the Multiple Osteochondroma syndrome (MO). In a hybrid syndrome, called metachondromatosis (MC), patients deve... | Cartilage tumor syndromes are characterized by multiple cartilaginous bone tumors that develop in childhood, often causing significant morbidity and predisposing to chondrosarcoma. Tumors can form as exostoses (on the surface of bone), as in the autosomal dominant, multiple osteochondroma (hereditary multiple exostoses... |
10.1371/journal.ppat.1000797 | Fine-Tuning Translation Kinetics Selection as the Driving Force of Codon Usage Bias in the Hepatitis A Virus Capsid | Hepatitis A virus (HAV), the prototype of genus Hepatovirus, has several unique biological characteristics that distinguish it from other members of the Picornaviridae family. Among these, the need for an intact eIF4G factor for the initiation of translation results in an inability to shut down host protein synthesis b... | Each organism has a specific codon usage signature. Translational selection i.e., selection for the codon adaptation to the tRNA pools, is one of the driving forces of codon bias. In the virus world, this implies an adjustment of the virus codon usage to that of the host cell. Hepatitis A virus appears as an exception ... | Non-random usage of synonymous codons is a widespread phenomenon observed in genomes from many species in all domains of life and it has been proposed that each genome has a specific codon usage signature that reflects particular evolutionary forces acting within that genome [1],[2]. Such codon usage biases may result ... |
10.1371/journal.pcbi.1005464 | Functional asymmetry and plasticity of electrical synapses interconnecting neurons through a 36-state model of gap junction channel gating | We combined the Hodgkin–Huxley equations and a 36-state model of gap junction channel gating to simulate electrical signal transfer through electrical synapses. Differently from most previous studies, our model can account for dynamic modulation of junctional conductance during the spread of electrical signal between c... | In most computational models of neuronal networks, it is assumed that electrical synapses have a constant and ohmic conductance. However, numerous experimental studies demonstrate that connexin-based channels expressed in neuronal gap junctions can change their conductance in response to a transjunctional voltage or va... | In most models of neuronal networks, it is assumed that electrical synapses exhibit constant conductance, and that electric synaptic transmission is bidirectional and symmetric. However, experimental studies show that these assumptions are not always satisfied. For instance, some synapses formed of gap junction channel... |
10.1371/journal.ppat.1003802 | The Genetic Basis of Escherichia coli Pathoadaptation to Macrophages | Antagonistic interactions are likely important driving forces of the evolutionary process underlying bacterial genome complexity and diversity. We hypothesized that the ability of evolved bacteria to escape specific components of host innate immunity, such as phagocytosis and killing by macrophages (MΦ), is a critical ... | The selective pressure imposed by the host immune system is an important component of microbial adaptation from commensalism to pathogenicity. We used experimental evolution to study the initial steps of the adaptation of Escherichia coli to cells of the innate immune system, i.e., macrophages. Our results demonstrate ... | Bacteria can be used to study evolution in real time in controlled environments, i.e. experimental evolution [1]. Different studies have demonstrated that bacterial populations have an enormous potential to adapt to relatively simple abiotic challenges under laboratory environments [2], [3]. On the other hand, far less... |
10.1371/journal.pntd.0001720 | Administration of Triclabendazole Is Safe and Effective in Controlling Fascioliasis in an Endemic Community of the Bolivian Altiplano | The Bolivian northern Altiplano is characterized by a high prevalence of Fasciola hepatica infection. In order to assess the feasibility, safety and efficacy of large-scale administration of triclabendazole as an appropriate public health measure to control morbidity associated with fascioliasis, a pilot intervention w... | Fascioliasis is highly prevalent in the northern Altiplano of Bolivia. We wanted to ascertain whether a preventive chemotherapy approach, involving the large-scale distribution of triclabendazole within endemic communities, would be feasible for controlling morbidity associated with this disease. Consequently, we imple... | Preventive chemotherapy, the large-scale administration of anthelminthic drugs to population groups at risk, is recommended by WHO for control and elimination of lymphatic filariasis, onchocerciasis, schistosomiasis and soil-transmitted helminth infections [1]. The aim of preventive chemotherapy is to regularly reduce ... |
10.1371/journal.pgen.1007062 | A trehalose biosynthetic enzyme doubles as an osmotic stress sensor to regulate bacterial morphogenesis | The dissacharide trehalose is an important intracellular osmoprotectant and the OtsA/B pathway is the principal pathway for trehalose biosynthesis in a wide range of bacterial species. Scaffolding proteins and other cytoskeletal elements play an essential role in morphogenetic processes in bacteria. Here we describe ho... | For free living bacteria, little is known about how environmental cues are perceived and translated into changes in cell morphology. Here we describe how a biosynthetic enzyme involved in synthesis of an important intracellular osmoprotectant doubles as an osmotic stress sensing morphogenetic protein. This protein is i... | Trehalose (a-D-glucopyranosyl(1,1)-a-D-glucopyranoside) is a non-reducing disaccharide that functions as an important intracellular protectant against a variety of stress conditions including desiccation, dehydration, heat, cold, and oxidation [1]. At least four different pathways for trehalose biosynthesis have been r... |
10.1371/journal.pcbi.1003781 | Logarithmic and Power Law Input-Output Relations in Sensory Systems with Fold-Change Detection | Two central biophysical laws describe sensory responses to input signals. One is a logarithmic relationship between input and output, and the other is a power law relationship. These laws are sometimes called the Weber-Fechner law and the Stevens power law, respectively. The two laws are found in a wide variety of huma... | One of the first measurements an experimentalist makes to understand a sensory system is to explore the relation between input signal and the systems response amplitude. Here, we show using mathematical models that this measurement can give important clues about the possible mechanism of sensing. We use models that inc... | Biological sensory systems have been quantitatively studied for over 150 years. In many sensory systems, the response to a step increase in signal rises, reaches a peak response, and then falls, adapting back to a baseline level, (Fig. 1a upper panel). Consider a step increase in input signal from to , such that the ... |
10.1371/journal.pgen.1004511 | Knock-In Reporter Mice Demonstrate that DNA Repair by Non-homologous End Joining Declines with Age | Accumulation of genome rearrangements is a characteristic of aged tissues. Since genome rearrangements result from faulty repair of DNA double strand breaks (DSBs), we hypothesized that DNA DSB repair becomes less efficient with age. The Non-Homologous End Joining (NHEJ) pathway repairs a majority of DSBs in vertebrate... | DNA damage disrupting both DNA strands, termed double strand breaks (DSBs), poses a threat to cell survival. If repaired inappropriately, such DNA breaks lead to genomic rearrangements, mutations, and ultimately cancer. Nonhomologous end joining (NHEJ) is the major pathway for repairing double-stranded breaks in mammal... | The somatic mutation theory of aging posits that the accumulation of unrepaired somatic mutations over time leads to the ‘functional failure’ frequently observed during the course of aging [1]. Cellular DNA is a target of various endogenous and environmental insults, leading to DNA damage, of which double-stranded DNA ... |
10.1371/journal.pntd.0007058 | Maternal Leishmania infantum infection status has significant impact on leishmaniasis in offspring | Visceral Leishmaniasis is a deadly disease caused by Leishmania infantum, endemic in more than 98 countries across the globe. Although the most common means of transmission is via a sand fly vector, there is growing evidence that vertical transmission may be critical for maintaining L. infantum infection within the res... | Canine leishmaniosis (CanL) is a deadly disease caused by Leishmania infantum parasite, it is found in animal populations, including people, in more than 98 countries across the globe. CanL was first identified within the US in hunting dogs 1980 and then again in 1999 when a large outbreak in a kennel in New York occur... | Leishmaniosis is a disease caused by the obligate intracellular protozoan parasite Leishmania infantum [1–3]. Visceral Leishmaniasis (VL) can also be caused by Leishmania donovani which causes anthroponotic human visceral leishmaniasis in many countries including areas of Asia and Africa [4, 5]. Zoonotic visceral leish... |
10.1371/journal.pgen.1005509 | Synergistic and Dose-Controlled Regulation of Cellulase Gene Expression in Penicillium oxalicum | Filamentous fungus Penicillium oxalicum produces diverse lignocellulolytic enzymes, which are regulated by the combinations of many transcription factors. Here, a single-gene disruptant library for 470 transcription factors was constructed and systematically screened for cellulase production. Twenty transcription facto... | Cellulolytic fungi have evolved into sophisticated lignocellulolytic systems to adapt to their natural habitat. This trait is important for filamentous fungi, which are the main source of cellulases utilized to degrade lignocellulose to fermentable sugars. Penicillium oxalicum, which produces lignocellulolytic enzymes ... | Cellulolytic fungi have an inherent characteristic of cellulose deconstruction and can be used for bioconversion of insoluble plant cell wall polysaccharides into fermentable sugars [1–3]. The highly efficient production of their extracellular hydrolytic enzymes and other synergistic proteins [2,4], such as swollenin [... |
10.1371/journal.ppat.1000777 | Kaposi's Sarcoma Associated Herpes Virus (KSHV) Induced COX-2: A Key Factor in Latency, Inflammation, Angiogenesis, Cell Survival and Invasion | Kaposi's sarcoma (KS), an enigmatic endothelial cell vascular neoplasm, is characterized by the proliferation of spindle shaped endothelial cells, inflammatory cytokines (ICs), growth factors (GFs) and angiogenic factors. KSHV is etiologically linked to KS and expresses its latent genes in KS lesion endothelial cells. ... | Kaposi's sarcoma associated herpes virus (KSHV), with a 160 kb DNA genome, has evolved with two distinct life cycle phases, namely latency and lytic replication. KS, a complex angioproliferative disease, is regulated by a balance between pro-angiogenic and anti-angiogenic factors. In our previous study, we showed that ... | KSHV, the most recently discovered human tumor virus, is etiologically associated with Kaposi sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD) [1],[2]. KS, an AIDS defining condition, is a highly disseminated unusual angiogenic tumor of proliferative endothelial cells and display... |
10.1371/journal.pcbi.1006141 | Ten quick tips for getting the most scientific value out of numerical data | Most studies in the life sciences and other disciplines involve generating and analyzing numerical data of some type as the foundation for scientific findings. Working with numerical data involves multiple challenges. These include reproducible data acquisition, appropriate data storage, computationally correct data an... | Data expressed as numbers are ubiquitous in research in the life sciences and other fields. The typical scientific workflow using such numerical data consists of analyzing the raw data to obtain numerical results, followed by interpreting the results and presenting derived findings.
In this article, we present some tip... | In many studies in the life sciences and other fields, findings are derived from some type of experiment via the analysis of numerical data in one form or another. The typical workflow, cf. Fig 1, involves multiple steps where good scientific practice needs to be followed so that sound results are obtained.
Experiment... |
10.1371/journal.pntd.0002644 | Characterization of a Gene Family Encoding SEA (Sea-urchin Sperm Protein, Enterokinase and Agrin)-Domain Proteins with Lectin-Like and Heme-Binding Properties from Schistosoma japonicum | We previously identified a novel gene family dispersed in the genome of Schistosoma japonicum by retrotransposon-mediated gene duplication mechanism. Although many transcripts were identified, no homolog was readily identifiable from sequence information.
Here, we utilized structural homology modeling and biochemical m... | While isolating membrane-bound and secreted proteins as targets for Schistosoma japonicum vaccine, we identified a novel potentially functional gene family which had originated by a gene duplication mechanism. Here, we integrated structural homology modeling and biochemical methods to show that this gene family encodes... | Schistosomiasis still ranks as the most important helminthic infection; second only to malaria in its socioeconomic burden in the resource constrained tropics and subtropics. It affects over 200 million people worldwide with more than 700 million people at risk of getting infected [1]. Although an effective treatment i... |
10.1371/journal.ppat.1006901 | Picornavirus 2A protease regulates stress granule formation to facilitate viral translation | Stress granules (SGs) contain stalled messenger ribonucleoprotein complexes and are related to the regulation of mRNA translation. Picornavirus infection can interfere with the formation of SGs. However, the detailed molecular mechanisms and functions of picornavirus-mediated regulation of SG formation are not clear. H... | When cellular translation initiation is stalled, translation initiation complexes aggregate in cytoplasm. We call these aggregations stress granules (SGs), and they can be marked by components such as TIA-1. SGs are always considered to be antiviral structures during viral infection, but viruses also regulate SG format... | Stress granules (SGs) form in response to a variety of stresses such as oxidative stress, heat shock (HS), hypoxia, nutrient deprivation, and viral infection [1]. During SG formation, messenger RNA (mRNA) translation initiation is inhibited, and polysomes are disassembled. Thus, SGs contain stalled pre-initiation compl... |
10.1371/journal.pcbi.1005268 | Could a Neuroscientist Understand a Microprocessor? | There is a popular belief in neuroscience that we are primarily data limited, and that producing large, multimodal, and complex datasets will, with the help of advanced data analysis algorithms, lead to fundamental insights into the way the brain processes information. These datasets do not yet exist, and if they did w... | Neuroscience is held back by the fact that it is hard to evaluate if a conclusion is correct; the complexity of the systems under study and their experimental inaccessability make the assessment of algorithmic and data analytic technqiues challenging at best. We thus argue for testing approaches using known artifacts, ... | The development of high-throughput techniques for studying neural systems is bringing about an era of big-data neuroscience [1, 2]. Scientists are beginning to reconstruct connectivity [3], record activity [4], and simulate computation [5] at unprecedented scales. However, even state-of-the-art neuroscientific studies ... |
10.1371/journal.pgen.1000452 | Positive Feedback between Transcriptional and Kinase Suppression in Nematodes with Extraordinary Longevity and Stress Resistance | Insulin/IGF-1 signaling (IIS) regulates development and metabolism, and modulates aging, of Caenorhabditis elegans. In nematodes, as in mammals, IIS is understood to operate through a kinase-phosphorylation cascade that inactivates the DAF-16/FOXO transcription factor. Situated at the center of this pathway, phosphatid... | Insulin/IGF-1 signaling (IIS) impacts development, metabolism, and longevity in Caenorhabditis elegans. It has been viewed as a cascade of kinase reactions, chiefly phosphorylation of other kinases, leading to inactivation of the DAF-16/FOXO transcription factor. PI3K, a phosphatidylinositol kinase at the center of thi... | The IIS pathway, governing developmental arrest, metabolism and life span in Caenorhabditis elegans [1]–[3], is highly conserved from invertebrates to mammals. The single IIS pathway of nematodes corresponds in structure and function to two distinct pathways of mammals that signal metabolic responses to insulin, and gr... |
10.1371/journal.pgen.1006829 | Amino acid metabolites that regulate G protein signaling during osmotic stress | All cells respond to osmotic stress by implementing molecular signaling events to protect the organism. Failure to properly adapt can lead to pathologies such as hypertension and ischemia-reperfusion injury. Mitogen-activated protein kinases (MAPKs) are activated in response to osmotic stress, as well as by signals act... | Just as organisms must adapt to a challenging environment, cells must respond to chemical or physical changes that occur within the organism. Regardless of the environmental cue, all cells use molecular signaling pathways to respond to those changes. Many are transmitted by G protein-coupled receptors (GPCRs) or the hi... | Cells routinely experience changing and often unfavorable conditions in their environment. The ability to adapt to environmental stress and re-establish homeostasis is essential not only to the survival of a cell, but also to the well-being of the organism. The response to such physical or chemical stresses is mediated... |
10.1371/journal.pbio.1000244 | The Multicopy Gene Sly Represses the Sex Chromosomes in the Male Mouse Germline after Meiosis | Studies of mice with Y chromosome long arm deficiencies suggest that the male-specific region (MSYq) encodes information required for sperm differentiation and postmeiotic sex chromatin repression (PSCR). Several genes have been identified on MSYq, but because they are present in more than 40 copies each, their functio... | During meiosis in the male mouse, the X and Y chromosomes are transcriptionally silenced, and retain a significant degree of repression after meiosis. Postmeiotically, X and Y chromosome–encoded genes are consequently expressed at a low level, with the exception of genes present in many copies, which can achieve a high... | During spermatogenesis, germ cells progress through three phases to become functional sperm: proliferation, meiosis, and spermiogenesis. In the latter phase, haploid germ cells (spermatids) undergo dramatic remodeling and DNA compaction as they differentiate into spermatozoa.
The X and Y chromosomes are transcriptiona... |
10.1371/journal.pgen.1000204 | Intronic Alus Influence Alternative Splicing | Examination of the human transcriptome reveals higher levels of RNA editing than in any other organism tested to date. This is indicative of extensive double-stranded RNA (dsRNA) formation within the human transcriptome. Most of the editing sites are located in the primate-specific retrotransposed element called Alu. A... | The human genome is crowded with over one million copies of primate-specific retrotransposed elements, termed Alu. A large fraction of Alu elements are located within intronic sequences. The human transcriptome undergoes extensive RNA editing (A-to-I), to higher levels than any other tested organism. RNA editing requir... | Alternative splicing enhances transcriptomic diversity and presumably leads to speciation and higher organism complexity, especially in mammals [1]–[3]. There are four major types of alternative splicing: exon skipping, which is the most prevalent form in higher vertebrates; alternative 5′ and 3′ splice site (5′ss and ... |
10.1371/journal.pgen.1002977 | The p38/MK2-Driven Exchange between Tristetraprolin and HuR Regulates AU–Rich Element–Dependent Translation | TNF expression of macrophages is under stringent translational control that depends on the p38 MAPK/MK2 pathway and the AU–rich element (ARE) in the TNF mRNA. Here, we elucidate the molecular mechanism of phosphorylation-regulated translation of TNF. We demonstrate that translation of the TNF-precursor at the ER requir... | For immediate response and better control of gene expression, eukaryotic cells have developed means to specifically regulate the stability and translation of pre-formed mRNA transcripts. This post-transcriptional regulation of gene expression is realized by a variety of mRNA-binding proteins, which target specific mRNA... | TNF is a master cytokine of inflammatory signaling of macrophages. Its biosynthesis is tightly controlled to allow rapid secretion but also to avoid delay or leakiness in its down-regulation, which could result in exaggerated or persistent inflammation. The levels of regulation comprise transcription, processing, nucle... |
10.1371/journal.pcbi.1006118 | Effects of growth rate, cell size, motion, and elemental stoichiometry on nutrient transport kinetics | Nutrient acquisition is a critical determinant for the competitive advantage for auto- and osmohetero- trophs alike. Nutrient limited growth is commonly described on a whole cell basis through reference to a maximum growth rate (Gmax) and a half-saturation constant (KG). This empirical application of a Michaelis-Menten... | Relating environmental nutrient concentration and nutrient acquisition to cell growth is an important feature of numerical simulations describing ecological systems of microbes. Here we investigate the critical role of the combined effects of maximum growth rate, cell size, motion, and elemental stoichiometry on nutrie... | The relationship between nutrient uptake kinetics and growth rate is seen as a critical determinate in competition for organisms reliant on the transport of dissolved nutrients, and often plays a key role in structuring marine ecosystem models [1–3]. Here we consider interactions between cell size and cellular carbon d... |
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