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10.1371/journal.pcbi.1002733 | The Laminar Cortex Model: A New Continuum Cortex Model Incorporating Laminar Architecture | Local field potentials (LFPs) are widely used to study the function of local networks in the brain. They are also closely correlated with the blood-oxygen-level-dependent signal, the predominant contrast mechanism in functional magnetic resonance imaging. We developed a new laminar cortex model (LCM) to simulate the am... | Local field potentials (LFPs) are low-frequency fluctuations of the electric fields produced by the brain. They have been widely studied to understand brain function and activity. LFPs reflect the activity of neurons within a few square millimeters of the cerebral cortex, an area containing more than 10,000 neurons. To... | Neuronal activity changes the distribution of electric potentials in the brain [1], [2]. Local field potentials (LFPs) are the low-frequency (<100 Hz) fluctuations in electric potentials in the extracellular space of the brain [2], [3]. They represent a weighted average of the potential changes produced by neuronal act... |
10.1371/journal.pntd.0001903 | Projecting the Long-Term Impact of School- or Community-Based Mass-Treatment Interventions for Control of Schistosoma Infection | Schistosomiasis remains a significant health burden in many areas of the world. Morbidity control, focused on limiting infection intensity through periodic delivery of anti-schistosomal medicines, is the thrust of current World Health Organization guidelines (2006) for reduction of Schistosoma-related disease. A new ap... | Debate persists about how best to prevent disease caused by Schistosoma parasites. Current guidelines focus on suppressing morbidity by limiting average intensity of infection during childhood. However, this may not be sufficient to cure infection or prevent reinfection, leaving risk for sub-clinical morbidities such a... | Schistosomiasis is an environmentally transmitted parasitic disease that results in increased morbidity and mortality among millions of people living in tropical and subtropical regions [1]–[3]. Different control initiatives have had success in reducing either the prevalence or the mean intensity of Schistosoma infecti... |
10.1371/journal.ppat.1006427 | Wolbachia elevates host methyltransferase expression to block an RNA virus early during infection | Wolbachia pipientis is an intracellular endosymbiont known to confer host resistance against RNA viruses in insects. However, the causal mechanism underlying this antiviral defense remains poorly understood. To this end, we have established a robust arthropod model system to study the tripartite interaction involving S... | Effective vector control is critically important to reduce the incidence of diseases caused by arthropod transmitted viruses. One proposed strategy involves the use of endosymbiotic bacteria Wolbachia pipientis as a novel biocontrol agent to prevent RNA virus transmission in mosquitoes. Previous work in the field sugge... | Heritable symbioses are pervasive in nature and exceedingly common in the insect world, where many endosymbiotic associations have been described [1]. Wolbachia pipientis is an alpha-proteobacterial, maternally transmitted endosymbiont that invades insect host populations by manipulating host reproduction, favoring inf... |
10.1371/journal.ppat.1003130 | Memory T Cells in Latent Mycobacterium tuberculosis Infection Are Directed against Three Antigenic Islands and Largely Contained in a CXCR3+CCR6+ Th1 Subset | An understanding of the immunological footprint of Mycobacterium tuberculosis (MTB) CD4 T cell recognition is still incomplete. Here we report that human Th1 cells specific for MTB are largely contained in a CXCR3+CCR6+ memory subset and highly focused on three broadly immunodominant antigenic islands, all related to b... | Mycobacterium tuberculosis is one of the most life-threatening pathogens of all time, having infected one-third of the present human population. There is an urgent need for both novel vaccines and diagnostic strategies. Here, we were able to identify the targets most dominantly recognized by latently infected individua... | Tuberculosis is one of the major causes of death from infectious disease. Current diagnostics do not distinguish active and latent infection, and the only available vaccine has limited efficacy. Hence, there is an urgent need for both novel vaccines and diagnostic strategies.
Human T cell responses to MTB involv... |
10.1371/journal.pgen.1002638 | Hypoxia Disruption of Vertebrate CNS Pathfinding through EphrinB2 Is Rescued by Magnesium | The mechanisms of hypoxic injury to the developing human brain are poorly understood, despite being a major cause of chronic neurodevelopmental impairments. Recent work in the invertebrate Caenorhabditis elegans has shown that hypoxia causes discrete axon pathfinding errors in certain interneurons and motorneurons. How... | How hypoxia damages the developing human brain is poorly understood, despite being a major cause of life-long neurologic and psychiatric problems. Premature infants are especially at risk for these problems, with increased rates of attention-deficit disorder, autism, cerebral palsy, epilepsy, psychiatric disorders, and... | Hypoxic injury to the developing human brain is a major cause of both acute and chronic neurodevelopmental impairments. Premature infants, particularly those characterized by very-low birth weights (VLBW; less than 1,500 g) are the population at greatest risk for chronic hypoxic injury and for adverse neurocognitive ou... |
10.1371/journal.ppat.1004243 | Arabidopsis LIP5, a Positive Regulator of Multivesicular Body Biogenesis, Is a Critical Target of Pathogen-Responsive MAPK Cascade in Plant Basal Defense | Multivesicular bodies (MVBs) play essential roles in many cellular processes. The MVB pathway requires reversible membrane association of the endosomal sorting complexes required for transports (ESCRTs) for sustained protein trafficking. Membrane dissociation of ESCRTs is catalyzed by the AAA ATPase SKD1, which is stim... | Pathogen- and stress-responsive mitogen-activated protein kinases 3 and 6 (MPK3/6) cascade plays an important role in plant basal resistance to microbial pathogens. Here we showed that Arabidopsis MPK3 and MPK6 interact with and phosphorylate the LIP5 positive regulator of biogenesis of multivesicular bodies (MVBs), wh... | Endosomes traffic molecules from the plasma membrane to intracellular compartments and transport molecules from the biosynthetic apparatus to the sites of action [1], [2]. Several different endosomes have been described based on biochemical composition, morphology, and function. Multivesicular bodies (MVBs) are late en... |
10.1371/journal.ppat.1002249 | Structural and Functional Analysis of Laninamivir and its Octanoate Prodrug Reveals Group Specific Mechanisms for Influenza NA Inhibition | The 2009 H1N1 influenza pandemic (pH1N1) led to record sales of neuraminidase (NA) inhibitors, which has contributed significantly to the recent increase in oseltamivir-resistant viruses. Therefore, development and careful evaluation of novel NA inhibitors is of great interest. Recently, a highly potent NA inhibitor, l... | The influenza neuraminidase (NA) enzyme is the most successful drug target against the seasonal and pandemic flu. The 2009 H1N1 flu pandemic led to record sales of the NA inhibitors oseltamivir (Tamiflu) and zanamivir (Relenza). Recently, a new drug, laninamivir (Inavir), has been approved for use in Japan can also be ... | The 2009 pandemic swine origin influenza A H1N1 virus (pH1N1) has reminded the world of the threat of pandemic influenza [1], [2], [3]. In 2009, the total sales of Tamiflu (oseltamivir phosphate) increased to over 3 billion US dollars (Annual General Meeting of Roche Holding Ltd, 2 March 2010). The total sales of Relen... |
10.1371/journal.pcbi.1004611 | Unbiased Rare Event Sampling in Spatial Stochastic Systems Biology Models Using a Weighted Ensemble of Trajectories | The long-term goal of connecting scales in biological simulation can be facilitated by scale-agnostic methods. We demonstrate that the weighted ensemble (WE) strategy, initially developed for molecular simulations, applies effectively to spatially resolved cell-scale simulations. The WE approach runs an ensemble of par... | Stochastic simulations (simulations where randomness plays a role) of even simple biological systems are often so computationally intensive that it is impossible, in practice, to simulate them exhaustively and gather good statistics about the likelihood of different outcomes. The difficulty is compounded for the observ... | Stochastic effects are of crucial importance in many biological processes, from protein dynamics [1], to gene expression [2], to phenotypic heterogeneity [3]. Unfortunately, due to the high computational cost of simulating complex stochastic biological systems, the effects of stochasticity on system response remain und... |
10.1371/journal.ppat.1000569 | Plasmodium falciparum Heterochromatin Protein 1 Marks Genomic Loci Linked to Phenotypic Variation of Exported Virulence Factors | Epigenetic processes are the main conductors of phenotypic variation in eukaryotes. The malaria parasite Plasmodium falciparum employs antigenic variation of the major surface antigen PfEMP1, encoded by 60 var genes, to evade acquired immune responses. Antigenic variation of PfEMP1 occurs through in situ switches in mo... | Plasmodium falciparum causes the most severe form of malaria in humans. The high virulence of this unicellular parasite is in part related to the selective expression of members of falciparum-specific gene families. These genes encode proteins that are exported into the cytoplasm and onto the surface of infected red bl... | Plasmodium falciparum causes the most severe form of malaria in humans with over one million deaths annually [1]. Severe and fatal outcomes of infections with this protozoan parasite result from a multitude of syndromes triggered by repeated rounds of asexual reproduction within erythrocytes. After invasion into red bl... |
10.1371/journal.pgen.1004064 | Natural Selection Reduced Diversity on Human Y Chromosomes | The human Y chromosome exhibits surprisingly low levels of genetic diversity. This could result from neutral processes if the effective population size of males is reduced relative to females due to a higher variance in the number of offspring from males than from females. Alternatively, selection acting on new mutatio... | The human Y chromosome is found only in males, and exhibits surprisingly low levels of genetic diversity. This low diversity could result from neutral processes, for example, if there are fewer males successfully mating (and thus fewer Y chromosomes being inherited) relative to the number of females who successfully ma... | The Y chromosome has often been used as a marker for studying human demographic history [1], but one implicit assumption in these analyses is that the Y chromosome is not affected by natural selection at linked sites [2]. However, formal tests of models of selection have been lacking. In part, this has been due to a pa... |
10.1371/journal.ppat.1004203 | Toxoplasma gondii Profilin Promotes Recruitment of Ly6Chi CCR2+ Inflammatory Monocytes That Can Confer Resistance to Bacterial Infection | Ly6C+ inflammatory monocytes are essential to host defense against Toxoplasma gondii, Listeria monocytogenes and other infections. During T. gondii infection impaired inflammatory monocyte emigration results in severe inflammation and failure to control parasite replication. However, the T. gondii factors that elicit t... | Toxoplasma gondii is an apicomplexan parasite that can infect all warm blooded animals, but rodent species are considered the primary reservoirs. Mice that are infected with T. gondii become more resistant to lethal infection with other pathogens. Ly6C+ inflammatory monocytes are innate immune cells that are critical f... | Toxoplasma gondii is an obligate intracellular Apicomplexan parasite that can infect nearly any nucleated cell of all warm blooded animals. Within warm blooded hosts, T. gondii replicates as a fast growing tachyzoite form, which disseminates throughout the body during acute infection. Over time and under immune pressur... |
10.1371/journal.pntd.0003088 | MicroRNA-30e* Suppresses Dengue Virus Replication by Promoting NF-κB–Dependent IFN Production | MicroRNAs have been shown to contribute to a repertoire of host-pathogen interactions during viral infection. Our previous study demonstrated that microRNA-30e* (miR-30e*) directly targeted the IκBα 3′-UTR and disrupted the NF-κB/IκBα negative feedback loop, leading to hyperactivation of NF-κB. This current study inves... | Dengue is one of the most prevalent mosquito-borne viral diseases; though it is caused by the Dengue virus (DENV) in tropical/subtropical areas, it has shown tendency toward becoming a global public health concern, with estimated annual numbers of 50–100 million dengue infection cases and 500,000 people with severe dis... | Dengue is an important mosquito-borne viral disease affecting humans, characterized by a spectrum of symptoms ranging from relatively mild dengue fever (DF) to more severe, and commonly lethal, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) [1], [2]. Dengue virus (DENV), the causative agent of dengue, i... |
10.1371/journal.pmed.1002178 | Educational Outreach with an Integrated Clinical Tool for Nurse-Led Non-communicable Chronic Disease Management in Primary Care in South Africa: A Pragmatic Cluster Randomised Controlled Trial | In many low-income countries, care for patients with non-communicable diseases (NCDs) and mental health conditions is provided by nurses. The benefits of nurse substitution and supplementation in NCD care in high-income settings are well recognised, but evidence from low- and middle-income countries is limited. Primary... | Non-communicable diseases (NCDs) are the leading cause of deaths worldwide, even in low- and middle-income countries (LMICs) that continue to battle to control communicable diseases like HIV and tuberculosis (TB).
Effective and affordable treatments prevent complications from NCDs like heart attacks and strokes, but ac... | South Africa is facing a quadruple burden of disease: HIV and tuberculosis (TB); non-communicable diseases (NCDs), including mental health conditions; injury and violence; and maternal, neonatal, and childhood illnesses [1]. The past 15 years have seen concentrated efforts to strengthen the capacity of the public healt... |
10.1371/journal.pgen.1000733 | Mu Transposon Insertion Sites and Meiotic Recombination Events Co-Localize with Epigenetic Marks for Open Chromatin across the Maize Genome | The Mu transposon system of maize is highly active, with each of the ∼50–100 copies transposing on average once each generation. The approximately one dozen distinct Mu transposons contain highly similar ∼215 bp terminal inverted repeats (TIRs) and generate 9-bp target site duplications (TSDs) upon insertion. Using a n... | Genomic insertion sites of Mu transposons were amplified and sequenced via next generation technology, revealing more than 40,000 non-redundant Mu insertion sites that are non-uniformly distributed across the maize genome and within genes. Along chromosomes, frequencies of Mu transposon insertions are strongly correlat... | Gene knockouts are indispensable tools for genetic and functional genomics. The maize Mutator (Mu) transposon is the most active DNA transposon in plants [1]. In maize, a model species for which transformation can be achieved at only a low efficiency, Mu insertion mutagenesis has been an important tool for cloning gene... |
10.1371/journal.pgen.1003626 | miR-133a Regulates Adipocyte Browning In Vivo | Prdm16 determines the bidirectional fate switch of skeletal muscle/brown adipose tissue (BAT) and regulates the thermogenic gene program of subcutaneous white adipose tissue (SAT) in mice. Here we show that miR-133a, a microRNA that is expressed in both BAT and SATs, directly targets the 3′ UTR of Prdm16. The expressio... | Global obesity and associated health issues have raised the significance of adipocyte biology. Adipose tissues are classified as brown and white adipose. White adipose tissues store lipids, leading to overweight, obesity, insulin resistance and Type2 diabetes. In contrast, brown adipose tissues use lipid storage to gen... | Adipose tissues are classified as brown (BAT) and white (WAT), and an intermediate category of “brite” or “beige” adipocytes exist within subcutaneous WAT [1], [2]. WAT are located in multiple subcutaneous or visceral locations of body, in the form of distinct fat depots, and contribute to overweight, obesity, insulin ... |
10.1371/journal.pgen.1004766 | Plasmid Flux in Escherichia coli ST131 Sublineages, Analyzed by Plasmid Constellation Network (PLACNET), a New Method for Plasmid Reconstruction from Whole Genome Sequences | Bacterial whole genome sequence (WGS) methods are rapidly overtaking classical sequence analysis. Many bacterial sequencing projects focus on mobilome changes, since macroevolutionary events, such as the acquisition or loss of mobile genetic elements, mainly plasmids, play essential roles in adaptive evolution. Existin... | Plasmids are difficult to analyze in WGS datasets, due to the fragmented nature of the obtained sequences. We developed a method, called PLACNET, which greatly facilitates this analysis. As an example, we analyzed the plasmidome of E. coli ST131, an ExPEC clonal group involved in human urinary tract infections and sept... | Clinical microbiology is being transformed by whole genome sequencing (WGS) [1]. A case in point is Escherichia coli: there were 1,618 E. coli projects submitted to NCBI compared to just 68 complete genomes by year 2013. Within the realms of clinical and environmental microbiology, plasmid analysis is increasingly used... |
10.1371/journal.pgen.1003973 | An Lmx1b-miR135a2 Regulatory Circuit Modulates Wnt1/Wnt Signaling and Determines the Size of the Midbrain Dopaminergic Progenitor Pool | MicroRNAs regulate gene expression in diverse physiological scenarios. Their role in the control of morphogen related signaling pathways has been less studied, particularly in the context of embryonic Central Nervous System (CNS) development. Here, we uncover a role for microRNAs in limiting the spatiotemporal range of... | To achieve exquisitely complex behavior, the mammalian CNS is comprised of numerous neuron types, each with different functions. These distinct neuron types are produced from neural progenitors during embryonic development. How the embryonic neural progenitors are programmed to produce distinct neuron types, in the cor... | MicroRNAs regulate gene expression in various aspects of central nervous system (CNS) and peripheral nervous system (PNS) development and function, including neurogenesis, glial differentiation, fate specification, synaptogenesis, spine formation and plasticity [1]–[7]. Less studied is their role in modulating the most... |
10.1371/journal.pntd.0003928 | Development of Resistance to Pyrethroid in Culex pipiens pallens Population under Different Insecticide Selection Pressures | Current vector control programs are largely dependent on pyrethroids, which are the most commonly used and only insecticides recommended by the World Health Organization for insecticide-treated nets (ITNs). However, the rapid spread of pyrethroid resistance worldwide compromises the effectiveness of control programs an... | Successful population control of mosquitoes is key to preventing transmission and epidemics of mosquito-borne diseases. This strategy relies heavily on insecticides, particularly pyrethroids. However, widespread pyrethroid resistance has hindered vector control implementation and sustainability. Generally, pyrethroid r... | Culex mosquitoes are important vectors responsible for transmission of lymphatic filariasis (LF) and several viral pathogens to millions of people worldwide, including St. Louis encephalitis, West Nile encephalitis, eastern equine encephalitis, Venezuelan equine encephalitis and Japanese encephalitis [1]. The World Hea... |
10.1371/journal.pbio.1000055 | Regulation of Embryonic Cell Adhesion by the Prion Protein | Prion proteins (PrPs) are key players in fatal neurodegenerative disorders, yet their physiological functions remain unclear, as PrP knockout mice develop rather normally. We report a strong PrP loss-of-function phenotype in zebrafish embryos, characterized by the loss of embryonic cell adhesion and arrested gastrulati... | Unlike conventional pathogens, prions are infectious particles devoid of nucleic acids and composed entirely of a misfolded host protein, PrP. It is widely assumed that the neurodegeneration observed in prion disorders may be related to an aberrant function of PrP in the misfolded state. However, the normal physiologic... | The prion protein (PrP) is a membrane-anchored glycoprotein, best known for its unique ability to undergo structural conversion from a normal “cellular” isoform (PrPC) into a pathogenic conformer known as “scrapie” (PrPSc) [1]. The accumulation of scrapie aggregates—prions—in the brain is a distinctive feature of trans... |
10.1371/journal.pntd.0002746 | Development of a Novel, Single-Cycle Replicable Rift Valley Fever Vaccine | Rift Valley fever virus (RVFV) (genus Phlebovirus, family Bunyaviridae) is an arbovirus that causes severe disease in humans and livestock in sub-Saharan African countries. Although the MP-12 strain of RVFV is a live attenuated vaccine candidate, neuroinvasiveness and neurovirulence of MP-12 in mice may be a concern wh... | Rift Valley fever virus (RVFV) is a mosquito-borne zoonotic pathogen, which causes febrile illness, encephalitis and fatal hemorrhagic fever in humans and severe hepatic disease with high mortality and spontaneous abortion rates in ruminants. RVFV is endemic to the African continent. Because many different mosquito spe... | Rift Valley fever virus (RVFV), a member of the genus Phlebovirus within the family Bunyaviridae, carries a tripartite, single-stranded and negative–sense RNA genome [1]–[3]. The L RNA encodes the L protein, a viral RNA-dependent RNA polymerase; the M RNA encodes four proteins, including two accessory proteins, the NSm... |
10.1371/journal.pcbi.1003284 | A Brain-Machine Interface for Control of Medically-Induced Coma | Medically-induced coma is a drug-induced state of profound brain inactivation and unconsciousness used to treat refractory intracranial hypertension and to manage treatment-resistant epilepsy. The state of coma is achieved by continually monitoring the patient's brain activity with an electroencephalogram (EEG) and man... | Brain-machine interfaces (BMI) for closed-loop control of anesthesia have the potential to enable fully automated and precise control of brain states in patients requiring anesthesia care. Medically-induced coma is one such drug-induced state in which the brain is profoundly inactivated and unconscious and the electroe... | Medically-induced coma (also referred to as medical coma) is a drug-induced state of profound brain inactivation and unconsciousness used to treat refractory intracranial hypertension and status epilepticus, i.e., epilepsy that is refractory to standard medical therapies [1]–[3]. Following a traumatic brain injury, an ... |
10.1371/journal.ppat.1006217 | Multi-layered control of Galectin-8 mediated autophagy during adenovirus cell entry through a conserved PPxY motif in the viral capsid | Cells employ active measures to restrict infection by pathogens, even prior to responses from the innate and humoral immune defenses. In this context selective autophagy is activated upon pathogen induced membrane rupture to sequester and deliver membrane fragments and their pathogen contents for lysosomal degradation.... | Cells have developed surveillance systems to detect invading pathogens, e.g. when they damage the membrane upon cell entry. Cells respond to membrane damage by activating selective autophagy to target pathogens for lysosomal degradation and pathogen removal. In this manuscript we show that endosome penetrating adenovir... | Intracellular pathogens, such as viruses, penetrate the limiting membrane of the cell to access cellular functions for propagation support. In response, cells try to detect and eliminate entering viruses through multiple pre-existing defense mechanisms referred to as restriction factors or intrinsic immunity [1]. To es... |
10.1371/journal.pntd.0004432 | Rabies in the Baltic States: Decoding a Process of Control and Elimination | Rabies is a fatal zoonosis that still causes nearly 70, 000 human deaths every year. In Europe, the oral rabies vaccination (ORV) of red foxes (Vulpes vulpes) was developed in the late 1970s and has demonstrated its effectiveness in the eradication of the disease in Western and some Central European countries. Followin... | This paper reviews ten years of rabies epidemiology in the three Baltic countries. Both surveillance efforts and oral rabies vaccination campaigns have resulted in the near eradication of the disease. Multivariate analysis assessed with generalized linear models (GLM) suggested lower oral vaccination effectiveness in r... | Rabies disease is a fatal mammalian encephalomyelitis caused by the rabies virus of the genus Lyssavirus (family Rhabdoviridae) [1]. The virus is distributed worldwide, with the exception of the Antarctic, Australia and several islands and although all species of mammals are susceptible to this virus, it infects princi... |
10.1371/journal.pntd.0002791 | The Challenge of Producing Skin Test Antigens with Minimal Resources Suitable for Human Application against a Neglected Tropical Disease; Leprosy | True incidence of leprosy and its impact on transmission will not be understood until a tool is available to measure pre-symptomatic infection. Diagnosis of leprosy disease is currently based on clinical symptoms, which on average take 3–10 years to manifest. The fact that incidence, as defined by new case detection, e... | Despite reaching the global elimination target for leprosy, the need for a diagnostic tool to detect pre-symptomatic disease remains. Transmission has not been completely intercepted despite over 30 years of extensive curative treatment. With limited resources, two new leprosy skin test antigens, MLSA-LAM and MLCwA, su... | Detection of pre-symptomatic leprosy continues to be identified by the World Health Organization (WHO) as a priority [1]. With the introduction of multiple drug therapy (MDT) by the WHO in 1982 to subvert extensive resistance of Mycobacterium leprae resulting from years of dapsone monotherapy, the prevalence of leprosy... |
10.1371/journal.ppat.0030069 | Structure of GrlR and the Implication of Its EDED Motif in Mediating the Regulation of Type III Secretion System in EHEC | Enterohemorrhagic Escherichia coli (EHEC) is a common cause of severe hemorrhagic colitis. EHEC's virulence is dependent upon a type III secretion system (TTSS) encoded by 41 genes. These genes are organized in several operons clustered in the locus of enterocyte effacement. Most of the locus of enterocyte effacement g... | Attaching and effacing pathogens are a group of enteric pathogens that includes the closely related enterohemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC). EPEC causes severe diarrhea in young children in developing countries, while EHEC is a causative agent of hemorrhagic colitis. A major infect... | The enterohemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC) are closely related human enteric pathogens [1]. EPEC causes severe diarrhea in young children in developing countries, while EHEC is a causative agent of hemorrhagic colitis, which is more common in the industrialized world [2]. EPEC, EH... |
10.1371/journal.pgen.1004501 | Determinative Developmental Cell Lineages Are Robust to Cell Deaths | All forms of life are confronted with environmental and genetic perturbations, making phenotypic robustness an important characteristic of life. Although development has long been viewed as a key component of phenotypic robustness, the underlying mechanism is unclear. Here we report that the determinative developmental... | It is widely believed that development plays an important role in the phenotypic robustness of organisms to environmental and genetic perturbations. But, the developmental process and cell fate are largely predetermined and fixed in some species, including for example mollusks, annelids, tunicates, and nematodes. How t... | Phenotypic robustness, often referred to as canalization, is the phenomenon that a phenotypic trait is invariant in the face of environmental or genetic perturbations [1]–[7]. Phenotypic robustness allows the maintenance of high fitness even under suboptimal conditions, which are not uncommon in nature [1]–[7]. Phenoty... |
10.1371/journal.pgen.1007954 | The complex genetic architecture of shoot growth natural variation in Arabidopsis thaliana | One of the main outcomes of quantitative genetics approaches to natural variation is to reveal the genetic architecture underlying the phenotypic space. Complex genetic architectures are described as including numerous loci (or alleles) with small-effect and/or low-frequency in the populations, interactions with the ge... | The question of the complexity of the genetic variants underlying diversity in plant size and shape is central in evolutionary biology to better understand the impacts of selection and adaptation. In this work, we have combined the high resolution of a robotized platform designed to grow Arabidopsis plants under strict... | Fine-tuning plant growth throughout development and in response to environmental limitations is a decisive process to optimize fitness and population survival in the wild. As a sessile organism, plants have to cope with environmental fluctuations and evolved a wide range of responses. This is well illustrated by their ... |
10.1371/journal.pgen.1003303 | JNK-Interacting Protein 3 Mediates the Retrograde Transport of Activated c-Jun N-Terminal Kinase and Lysosomes | Retrograde axonal transport requires an intricate interaction between the dynein motor and its cargo. What mediates this interaction is largely unknown. Using forward genetics and a novel in vivo imaging approach, we identified JNK-interacting protein 3 (Jip3) as a direct mediator of dynein-based retrograde transport o... | To form and maintain connections, neurons require the active transport of proteins and organelles between the neuronal cell body and axon terminals. Inhibition of this “axonal” transport has been linked to neurodegenerative diseases. Despite the importance of this process, to date there was no vertebrate model system w... | Active transport of proteins and organelles between the neuronal cell body and axon terminals is necessary for the formation and maintenance of functional neural circuits. Anterograde (to axon terminals) and retrograde (to the cell body) transport rely on motor proteins of the Kinesin and Dynein families respectively. ... |
10.1371/journal.pcbi.1005174 | Temperature-Dependent Model of Multi-step Transcription Initiation in Escherichia coli Based on Live Single-Cell Measurements | Transcription kinetics is limited by its initiation steps, which differ between promoters and with intra- and extracellular conditions. Regulation of these steps allows tuning both the rate and stochasticity of RNA production. We used time-lapse, single-RNA microscopy measurements in live Escherichia coli to study how ... | Temperature affects the behavior of cells, such as their growth rate. However, it is not well understood how these changes result from the changes at the single molecule level. We observed the production of individual RNA molecules in live cells under a wide range of temperatures. This allowed us to determine not only ... | Temperature is known to affect gene expression patterns in cells. This has profound effects, as changes in transcription and translation dynamics propagate to the behavior of genetic networks, which manifests in their sensitivity to temperature changes [1–3].
The expression patterns are not solely characterized by the... |
10.1371/journal.pgen.1003979 | Genome-Wide Screen Reveals Replication Pathway for Quasi-Palindrome Fragility Dependent on Homologous Recombination | Inverted repeats capable of forming hairpin and cruciform structures present a threat to chromosomal integrity. They induce double strand breaks, which lead to gross chromosomal rearrangements, the hallmarks of cancers and hereditary diseases. Secondary structure formation at this motif has been proposed to be the driv... | Inverted repeats are found in many eukaryotic genomes including humans. They have a potential to cause chromosomal breakage and rearrangements that contribute to genome polymorphism and the development of diseases. Instability of inverted repeats is accounted for by their propensity to adopt DNA secondary structures th... | Long palindromic sequences (inverted repeats ∼100 bp or more each without a spacer or with a short spacer) present a threat to both prokaryotic and eukaryotic genome stability. In E. coli, long palindromes placed on plasmids are frequently excised and cause cell inviability when introduced to chromosome [1]. In yeast, ... |
10.1371/journal.pntd.0004716 | Cathepsin B-Deficient Mice Resolve Leishmania major Inflammation Faster in a T Cell-Dependent Manner | A critical role for intracellular TLR9 has been described in recognition and host resistance to Leishmania parasites. As TLR9 requires endolysosomal proteolytic cleavage to achieve signaling functionality, we investigated the contribution of different proteases like asparagine endopeptidase (AEP) or cysteine protease c... | Cutaneous forms of leishmaniasis are characterized by lesions that progress over months or years and that often leave permanent scars. Toll like receptors play an important role in the recognition and initiation of immune responses, and the intracellular TLR9, a sensor of pathogen double-stranded DNA, plays a crucial r... | A protective immune response against intracellular protozoan parasites of the genus Leishmania is characterized by the development of IFNγ-producing T cells. This supports macrophages in the induction of anti-leishmanial effector functions, such as production of nitric oxide [1,2]. IL-12, a cytokine produced largely by... |
10.1371/journal.ppat.1000755 | Neutrophil-Derived CCL3 Is Essential for the Rapid Recruitment of Dendritic Cells to the Site of Leishmania major Inoculation in Resistant Mice | Neutrophils are rapidly and massively recruited to sites of microbial infection, where they can influence the recruitment of dendritic cells. Here, we have analyzed the role of neutrophil released chemokines in the early recruitment of dendritic cells (DCs) in an experimental model of Leishmania major infection. We sho... | When infectious agents enter our body, neutrophils are the first cells recruited to the scene. In addition to their capacity to kill microbes, neutrophils secrete molecules that attract other cells also involved in immune defense, such as dendritic cells (DCs). Here, we investigate the secretion of DC-attracting chemok... | Neutrophils rapidly accumulate at the site of microbial infection and recent evidence show that they play a major role in immunity to several pathogens. Neutrophils, through the early release of cytokines and chemokines, create a microenvironment critical for the shaping of the development of an antigen-specific immune... |
10.1371/journal.pgen.1005206 | Accounting for Experimental Noise Reveals That mRNA Levels, Amplified by Post-Transcriptional Processes, Largely Determine Steady-State Protein Levels in Yeast | Cells respond to their environment by modulating protein levels through mRNA transcription and post-transcriptional control. Modest observed correlations between global steady-state mRNA and protein measurements have been interpreted as evidence that mRNA levels determine roughly 40% of the variation in protein levels,... | Cells respond to their environment by making proteins using transcription and translation of mRNA. Modest observed correlations between global steady-state mRNA and protein measurements have been interpreted as evidence that mRNA levels determine roughly 40% of the variation in protein levels, indicating dominant post-... | Cellular protein levels reflect the balance of mRNA levels, protein production by translation initiation and completion, and protein removal by degradation, secretion, and dilution due to growth [1–3](Fig 1A). A standard quantitative model for protein-level regulation [4, 5] is
∂ P i ∂ t = τ i M i - δ i P i (1)
where P... |
10.1371/journal.pntd.0003584 | Association of Symptoms and Severity of Rift Valley Fever with Genetic Polymorphisms in Human Innate Immune Pathways | Multiple recent outbreaks of Rift Valley Fever (RVF) in Africa, Madagascar, and the Arabian Peninsula have resulted in significant morbidity, mortality, and financial loss due to related livestock epizootics. Presentation of human RVF varies from mild febrile illness to meningoencephalitis, hemorrhagic diathesis, and/o... | The underlying risk factors that lead to severe human Rift Valley Fever disease are unknown, but are likely multi-factorial. Host factors, such as innate immune genetic makeup, are likely important determinants of disease phenotype. This study investigated the association of 46 single nucleotide polymorphisms (SNPs) in... | Rift Valley fever virus (RVFV) is a negative strand RNA virus of the family Bunyaviridae. Episodic epidemics of Rift Valley Fever (RVF) present a significant natural threat to human health in many countries of Africa and the Middle East, causing retinitis, encephalitis and hemorrhagic fever [1,2]. Epizootics of RVFV al... |
10.1371/journal.pcbi.1002458 | What Can Causal Networks Tell Us about Metabolic Pathways? | Graphical models describe the linear correlation structure of data and have been used to establish causal relationships among phenotypes in genetic mapping populations. Data are typically collected at a single point in time. Biological processes on the other hand are often non-linear and display time varying dynamics. ... | High-throughput profiling data are pervasive in modern genetic studies. The large-scale nature of the data can make interpretation challenging. Methods that estimate networks or graphs have become popular tools for proposing causal relationships among traits. However, it is not obvious that these methods are able to ca... | Understanding the nature of cause and effect is fundamental to all fields of scientific investigation, but the concept of causality can present special difficulties in biology [1]. Experiments that utilize controlled interventions represent the most widely used approach to establishing causality. However, in his semina... |
10.1371/journal.pntd.0006164 | Changing demographics of visceral leishmaniasis in northeast Brazil: Lessons for the future | Visceral leishmaniasis (VL) caused by Leishmania infantum became a disease of urban areas in Brazil in the last 30 years and there has been an increase in asymptomatic L. infantum infection with these areas.
A retrospective study of human VL was performed in the state of Rio Grande do Norte, Brazil, for the period of 1... | We studied factors associated with the changing demographics of visceral leishmaniasis (VL) in Northeast Brazil, including environmental and socioeconomic determinants of disease, during the period 1990 to 2014. The incidence of VL was higher in urban areas, and regions with higher levels of canine L. infantum infectio... | Visceral leishmaniasis (VL) is a life-threatening disease caused by L. infantum [1], which was first recognized in Brazil in 1932 [2–4]. It is likely the parasite initially arrived in northeastern Brazil with people and/or dogs previously infected with L. infantum in southern Europe or North Africa [5;6]. Lu. longipalp... |
10.1371/journal.pgen.1000294 | Effects of cis and trans Genetic Ancestry on Gene Expression in African Americans | Variation in gene expression is a fundamental aspect of human phenotypic variation. Several recent studies have analyzed gene expression levels in populations of different continental ancestry and reported population differences at a large number of genes. However, these differences could largely be due to non-genetic ... | Variation in gene expression is a fundamental aspect of human phenotypic variation, and understanding how this variation is apportioned among human populations is an important aim. Previous studies have compared gene expression levels between distinct populations, but it is unclear whether the differences that were obs... | Admixed populations are uniquely useful for analyzing the genetic contribution to phenotypic differences among humans. Phenotypic differences that are observed among human populations may have systematic non-genetic causes, such as differences in environment [1],[2]. However, in an admixed population such as African Am... |
10.1371/journal.pgen.1007346 | Synergistic co-regulation and competition by a SOX9-GLI-FOXA phasic transcriptional network coordinate chondrocyte differentiation transitions | The growth plate mediates bone growth where SOX9 and GLI factors control chondrocyte proliferation, differentiation and entry into hypertrophy. FOXA factors regulate hypertrophic chondrocyte maturation. How these factors integrate into a Gene Regulatory Network (GRN) controlling these differentiation transitions is inc... | In the development of the mammalian growth plate, while several transcription factors are individually well known for their key roles in regulating phases of chondrocyte differentiation, there is little information on how they interact and cooperate with each other. We took an unbiased genome wide approach to identify ... | In the formation and longitudinal growth of endochondral bones, committed mesenchymal cells condense and differentiate into chondrocytes to form a growth plate, within which chondrocytes undergo coordinated and sequential differentiation phases of proliferation, cell cycle exit and hypertrophy, resulting in longitudina... |
10.1371/journal.pcbi.0030084 | Enhancer Responses to Similarly Distributed Antagonistic Gradients in Development | Formation of spatial gene expression patterns in development depends on transcriptional responses mediated by gene control regions, enhancers. Here, we explore possible responses of enhancers to overlapping gradients of antagonistic transcriptional regulators in the Drosophila embryo. Using quantitative models based on... | The early development of the fruit fly embryo depends on an intricate but well-studied gene regulatory network. In fly eggs, maternally deposited gene products—morphogenes—form spatial concentration gradients. The graded distribution of the maternal morphogenes initiates a cascade of gene interactions leading to embryo... | With the availability of complete genome sequences and quantitative gene expression data, it becomes possible to explore the relationships between sequence features of regulatory DNAs and the transcriptional responses of their associated genes [1–7]. Developmental genes regulated by multiple enhancer regions and their ... |
10.1371/journal.ppat.1003811 | The Malarial Serine Protease SUB1 Plays an Essential Role in Parasite Liver Stage Development | Transmission of the malaria parasite to its vertebrate host involves an obligatory exoerythrocytic stage in which extensive asexual replication of the parasite takes place in infected hepatocytes. The resulting liver schizont undergoes segmentation to produce thousands of daughter merozoites. These are released to init... | Malaria is caused by a single-celled parasite and is transmitted by the bite of an infected mosquito. The inoculated sporozoite forms of the parasite invade liver cells where they replicate, eventually releasing thousands of merozoites into the bloodstream to initiate the blood stage parasite life cycle which causes cl... | Transmission of the malaria parasite to a vertebrate host is initiated by the bite of an infected Anopheline mosquito. The inoculated sporozoites migrate from the site of inoculation, enter the circulation, and are arrested in liver sinusoids where they traverse the vascular endothelium and invade hepatocytes, coming t... |
10.1371/journal.pcbi.1000696 | Parameter Estimation and Model Selection in Computational Biology | A central challenge in computational modeling of biological systems is the determination of the model parameters. Typically, only a fraction of the parameters (such as kinetic rate constants) are experimentally measured, while the rest are often fitted. The fitting process is usually based on experimental time course m... | Parameter estimation is a key issue in systems biology, as it represents the crucial step to obtaining predictions from computational models of biological systems. This issue is usually addressed by “fitting” the model simulations to the observed experimental data. Such approach does not take the measurement noise into... | Many biological processes are modeled using ordinary differential equations (ODEs) that describe the evolution over time of certain quantities of interest. At the molecular level, the variables considered in the models often represent concentrations (or number of molecules) of chemical species, such as proteins and mRN... |
10.1371/journal.pgen.1000375 | The Individual Blood Cell Telomere Attrition Rate Is Telomere Length Dependent | Age-associated telomere shortening is a well documented feature of peripheral blood cells in human population studies, but it is not known to what extent these data can be transferred to the individual level. Telomere length (TL) in two blood samples taken at ∼10 years interval from 959 individuals was investigated usi... | An age-dependent telomere shortening has been frequently observed in cross-sectional studies on human blood cells. Telomerase is an enzyme capable of lengthening telomeres, and it is activated in most tumor cells in order for them to become immortalized. This is one of the first longitudinal studies on telomere length,... | Telomeres are protective end structures of the chromosomes. Telomere length is dictated partly by hereditary [1]–[6] and partly by environmental [7],[8] and epigenetic factors [9]. The hereditary impact on TL has been estimated to range between 36–84% [3]–[6]. An equally strong telomere length inheritance was reported ... |
10.1371/journal.pcbi.1003561 | The Spatial Resolution of Epidemic Peaks | The emergence of novel respiratory pathogens can challenge the capacity of key health care resources, such as intensive care units, that are constrained to serve only specific geographical populations. An ability to predict the magnitude and timing of peak incidence at the scale of a single large population would help ... | Fundamental spatial processes such as individuals' interactions and movement are not sufficiently well understood and yet they define the transmission of infectious diseases through populations. Spatial models of epidemics represent the region of interest (such as a city or country) as a collection of spatial units. To... | Novel respiratory pathogens continue to pose substantial public health challenges, not least because of the risk that large epidemics may overwhelm key health care resources such as vaccination stockpiles and intensive care facilities. Recent epidemics of concern include: SARS [1], influenza [2]–[4], H7N9 [5], [6] and ... |
10.1371/journal.pgen.1007430 | Drosophila species learn dialects through communal living | Many species are able to share information about their environment by communicating through auditory, visual, and olfactory cues. In Drosophila melanogaster, exposure to parasitoid wasps leads to a decline in egg laying, and exposed females communicate this threat to naïve flies, which also depress egg laying. We find ... | In this study, we find that many different Drosophila species never having been exposed to parasitoid wasps can trigger caspase activation in the ovary and depress egg-laying when placed next to flies that had visual experience with wasps. Interestingly, when teacher flies of one species are placed with a student of a ... | The ability to interpret environmental information is a phenomenon found throughout all life forms. From bacteria to plants and to mammals, communication occurs within as well as between species. In some cases, information that is being shared can be highly specific, such as in the case of honeybees communicating instr... |
10.1371/journal.pgen.1007607 | Identification of expression quantitative trait loci associated with schizophrenia and affective disorders in normal brain tissue | Schizophrenia and the affective disorders, here comprising bipolar disorder and major depressive disorder, are psychiatric illnesses that lead to significant morbidity and mortality worldwide. Whilst understanding of their pathobiology remains limited, large case-control studies have recently identified single nucleoti... | An estimated 21 million people live worldwide with schizophrenia, 60 million with bipolar disorder, and 400 million with major depressive disorder. Recent genome-wide association studies have shed light on the genetic variants linked to these disorders, and increasing evidence suggests that their genetic architectures ... | Schizophrenia and affective disorders, comprising bipolar disorder and major depressive disorder, constitute a significant global burden of disease. Worldwide it is estimated that more than 21 million individuals are living with schizophrenia, 60 million with bipolar disorder and over 400 million with major depressive ... |
10.1371/journal.pcbi.1007024 | Predicting three-dimensional genome organization with chromatin states | We introduce a computational model to simulate chromatin structure and dynamics. Starting from one-dimensional genomics and epigenomics data that are available for hundreds of cell types, this model enables de novo prediction of chromatin structures at five-kilo-base resolution. Simulated chromatin structures recapitul... | Three-dimensional genome organization is expected to play crucial roles in regulating gene expression and establishing cell fate, and has inspired the development of numerous innovative experimental techniques for its characterization. Though significant progress has been made, it remains challenging to construct chrom... | The human genome contains about 2 meters of DNA that is packaged as chromatin inside a nucleus of only 10 micrometers in diameter [1]. The way in which chromatin is organized in the three-dimensional space, i.e., the chromatin structure, has been shown to play important roles for all DNA-templated processes, including ... |
10.1371/journal.pgen.1005426 | mTORC1 Prevents Preosteoblast Differentiation through the Notch Signaling Pathway | The mechanistic target of rapamycin (mTOR) integrates both intracellular and extracellular signals to regulate cell growth and metabolism. However, the role of mTOR signaling in osteoblast differentiation and bone formation is undefined, and the underlying mechanisms have not been elucidated. Here, we report that activ... | The coordinated activities of osteoblasts and osteoclasts in bone deposition and resorption form the internal structure of bone. Disruption of the balance between bone formation and resorption results in loss of bone mass and causes bone diseases such as osteoporosis. Current therapies for osteoporosis are limited to a... | The skeleton is a highly specialized and dynamic structure undergoing constant remodeling [1]. The remodeling process is executed by temporary cellular structures that comprise teams of coupled osteoblasts and osteoclasts. The rate of genesis as well as death of these two cell types is vital for the maintenance of bone... |
10.1371/journal.pgen.1006306 | RNA-Binding Protein FXR1 Regulates p21 and TERC RNA to Bypass p53-Mediated Cellular Senescence in OSCC | RNA-binding proteins (RBP) regulate numerous aspects of co- and post-transcriptional gene expression in cancer cells. Here, we demonstrate that RBP, fragile X-related protein 1 (FXR1), plays an essential role in cellular senescence by utilizing mRNA turnover pathway. We report that overexpressed FXR1 in head and neck s... | Understanding the mechanisms underlying evasion of cellular senescence in tumor cells is expected to provide better treatment outcomes. Here, we identify RNA-binding proteins FXR1 (Fragile X-Related protein 1), that is overexpressed in oral cancer tissues and cells bypasses cellular senescence through p53/p21-dependent... | Cellular senescence is a critical biological process occurring in normal and aging cells either due to developmentally programmed or DNA damage-induced causes. Cancer cells escape senescence by utilizing either transcriptional and/or co-transcriptional gene regulatory processes to control gene expression. For example, ... |
10.1371/journal.pntd.0006569 | The small non-coding RNA response to virus infection in the Leishmania vector Lutzomyia longipalpis | Sandflies are well known vectors for Leishmania but also transmit a number of arthropod-borne viruses (arboviruses). Few studies have addressed the interaction between sandflies and arboviruses. RNA interference (RNAi) mechanisms utilize small non-coding RNAs to regulate different aspects of host-pathogen interactions.... | Sandflies are important insect vectors that transmit many species of Leishmania, bacteria and viruses. We know very little about how this insect vector responds to viral infection. RNA interference (RNAi) utilizes small non-coding RNAs to regulate different aspects of animal physiology, including immune responses. Smal... | Phlebotomine sandflies (Diptera: Pshychodidae) are important vectors for a wide range of pathogens [1]. Protozoans of the Leishmania genus are the most studied of sandfly-borne pathogens but these insects can also transmit bacteria and viruses. Arthropod-borne viruses (arboviruses) transmitted by sandflies are associat... |
10.1371/journal.pgen.1006429 | Proteomic Landscape of Tissue-Specific Cyclin E Functions in Vivo | E-type cyclins (cyclins E1 and E2) are components of the cell cycle machinery that has been conserved from yeast to humans. The major function of E-type cyclins is to drive cell division. It is unknown whether in addition to their ‘core’ cell cycle functions, E-type cyclins also perform unique tissue-specific roles. He... | The proliferation of mammalian cells is driven by proteins called cyclins, which bind and activate their catalytic partners, the cyclin-dependent kinases (Cdks). Cyclin-Cdk complexes drive cell proliferation by phosphorylating several cellular proteins. This study focuses on the E-type cyclins (cyclins E1 and E2). Thes... | E-type cyclins (cyclins E1 and E2, collectively referred to as ‘cyclin E’) represent components of the core cell cycle machinery. The two E-cyclins are encoded by separate genes, but they show substantial amino acid sequence similarity. In proliferating cells, E-cyclins become upregulated during the late G1 phase. Once... |
10.1371/journal.ppat.1000300 | Species-Specific Activity of HIV-1 Vpu and Positive Selection of Tetherin Transmembrane Domain Variants | Tetherin/BST-2/CD317 is a recently identified antiviral protein that blocks the release of nascent retrovirus, and other virus, particles from infected cells. An HIV-1 accessory protein, Vpu, acts as an antagonist of tetherin. Here, we show that positive selection is evident in primate tetherin sequences and that HIV-1... | Tetherin is a cell surface protein that acts as an antiviral defense. It functions by tethering newly assembled HIV-1 particles to the surface of the infected cell, such that the viral particle is unable to depart and disseminate to other, uninfected cells. HIV-1 possesses an antagonist of tetherin, termed Vpu, that ab... | Eukaryotic cells can constitutively or inducibly express a variety of molecules that inhibit the replication of viruses. Among these antiviral defenses are components of the type-I interferon (IFN) -induced innate immune system [1],[2]. In turn, viruses have evolved to express proteins that either limit IFN-induced gen... |
10.1371/journal.pcbi.0030233 | Small Regulatory RNAs May Sharpen Spatial Expression Patterns | The precise establishment of gene expression patterns is a crucial step in development. Formation of a sharp boundary between high and low spatial expression domains requires a genetic mechanism that exhibits sensitivity, yet is robust to fluctuations, a demand that may not be easily achieved by morphogens alone. Recen... | Early embryonic development depends on robust patterning along the axes of the embryo. At the cellular level, neighboring segments are often identified via the concentrations of several gene products: the expression of such a gene may, for example, be high in the cells of one segment, and negligible in those of another... | Morphogenesis proceeds by sequential divisions of a developing embryo into domains, each expressing a distinct set of genes. Each combination of genes is associated with a particular cell identity. At advanced stages of development, most genes that define cell identity are either highly expressed (“on”) or strongly inh... |
10.1371/journal.pgen.1008129 | Regulation of ectopic heterochromatin-mediated epigenetic diversification by the JmjC family protein Epe1 | H3K9 methylation (H3K9me) is a conserved marker of heterochromatin, a transcriptionally silent chromatin structure. Knowledge of the mechanisms for regulating heterochromatin distribution is limited. The fission yeast JmjC domain-containing protein Epe1 localizes to heterochromatin mainly through its interaction with S... | Suppression of unscheduled epigenetic alterations is important for maintenance of homogeneity among clones, while emergence of epigenetic differences is also important for adaptation or differentiation. The mechanisms that balance both processes warrant further investigation. Epe1, a fission yeast JmjC domain-containin... | Heterochromatin is a silent chromatin structure characterized by methylation of histone H3 at lysine 9 (H3K9me), to which heterochromatin protein 1 (HP1) binds and recruits various effectors including silencing factors. Euchromatin, another well-defined chromatin structure, is generally open and accessible to the trans... |
10.1371/journal.pcbi.1002738 | A Structural Systems Biology Approach for Quantifying the Systemic Consequences of Missense Mutations in Proteins | Gauging the systemic effects of non-synonymous single nucleotide polymorphisms (nsSNPs) is an important topic in the pursuit of personalized medicine. However, it is a non-trivial task to understand how a change at the protein structure level eventually affects a cell's behavior. This is because complex information at ... | Small changes in protein sequences, such as missense mutations resulting from genetic variations in the genome, can have a large impact on cellular behavior. Consequently, numerous studies have been carried out to evaluate the disease susceptibility of missense mutations by directly analyzing their structural or functi... | How one links genetic information to physiological outcomes is an important issue in the current ‘post-GWAS’ (genome-wide association studies) era [1]. One specific topic regarding this problem is the functional annotation of non-synonymous single nucleotide polymorphisms (nsSNPs) that cause amino acid changes in prote... |
10.1371/journal.pcbi.1002546 | Prosthetic Avian Vocal Organ Controlled by a Freely Behaving Bird Based on a Low Dimensional Model of the Biomechanical Periphery | Because of the parallels found with human language production and acquisition, birdsong is an ideal animal model to study general mechanisms underlying complex, learned motor behavior. The rich and diverse vocalizations of songbirds emerge as a result of the interaction between a pattern generator in the brain and a hi... | Brain Machine Interfaces (BMIs) decode motor instructions from neuro-physiological recordings and feed them to bio-mimetic effectors. Many applications achieve high accuracy on a limited number of tasks by applying statistical methods to these data to extract features corresponding to certain motor instructions. We bui... | The complex motor behavior originating the rich vocalizations of adult oscine birds results from the interaction between a central pattern generator (the brain) and a nonlinear biomechanical periphery (the bird's vocal organ) [1], [2]. The fact that this complex behavior is learned, together with the parallels between ... |
10.1371/journal.pcbi.1004517 | A Generative Statistical Algorithm for Automatic Detection of Complex Postures | This paper presents a method for automated detection of complex (non-self-avoiding) postures of the nematode Caenorhabditis elegans and its application to analyses of locomotion defects. Our approach is based on progressively detailed statistical models that enable detection of the head and the body even in cases of se... | The roundworm Caenorhabditis elegans is a widely used model organism. Its locomotion, for instance, enables the study of genetic and cellular mechanisms that underlie behavior and may be broadly conserved. Characterizing C. elegans locomotion requires identifying its body posture and tracking how posture changes with t... | The nematode Caenorhabditis elegans is a simple animal model system, widely used to study the genetic foundations of behavior. Among its key advantages are its tractable genetics, short life cycle, relatively simple anatomy and behavior patterns, and evolutionary conserved pathways [1–3]. The locomotion patterns of C. ... |
10.1371/journal.pgen.1001193 | A Coastal Cline in Sodium Accumulation in Arabidopsis thaliana Is Driven by Natural Variation of the Sodium Transporter AtHKT1;1 | The genetic model plant Arabidopsis thaliana, like many plant species, experiences a range of edaphic conditions across its natural habitat. Such heterogeneity may drive local adaptation, though the molecular genetic basis remains elusive. Here, we describe a study in which we used genome-wide association mapping, gene... | The unusual geographical distribution of certain animal and plant species has provided puzzling questions to the scientific community regarding the interrelationship of evolutionary and geographic histories for generations. With DNA sequencing, such puzzles have now extended to the geographical distribution of genetic ... | Uncovering the genetic polymorphisms that underlie adaptation to environmental gradients is a critical goal in evolutionary biology, and will lead to a better understanding of both the types of genetic changes and the gene functions involved. Such understanding will not only provide insight into how organisms may respo... |
10.1371/journal.ppat.1003284 | HPV16 E7 Protein and hTERT Proteins Defective for Telomere Maintenance Cooperate to Immortalize Human Keratinocytes | Previous studies have shown that wild-type human telomerase reverse transcriptase (hTERT) protein can functionally replace the human papillomavirus type 16 (HPV-16) E6 protein, which cooperates with the viral E7 protein in the immortalization of primary keratinocytes. In the current study, we made the surprising findin... | The human papillomaviruses (HPVs) are critical elements in the etiology of cervical cancer, as well as several other human cancers. The E6 protein, in combination with the E7 protein of these viruses, immortalizes epithelial cells and increases the expression of the hTERT protein. In the current study we show that the ... | Cell immortality is a hallmark of cancer cells [1] and the high-risk oncogenic HPVs encode two major transforming genes, E6 and E7, which are required for the immortalization of human primary genital keratinocytes [2], [3]. These two oncogenes are uniformly retained and expressed in cervical cancers and their continued... |
10.1371/journal.pbio.1002319 | Prolonged Intracellular Na+ Dynamics Govern Electrical Activity in Accessory Olfactory Bulb Mitral Cells | Persistent activity has been reported in many brain areas and is hypothesized to mediate working memory and emotional brain states and to rely upon network or biophysical feedback. Here, we demonstrate a novel mechanism by which persistent neuronal activity can be generated without feedback, relying instead on the slow... | The accessory olfactory system is essential for chemical communication in animals during social interactions. During this process, the principle cells of the accessory olfactory bulb (AOB) may respond to transient stimulation with prolonged activity, sometimes lasting for minutes—a property known as persistent activity... | The accessory olfactory system, also known as the vomeronasal system, mediates chemical communication between conspecifics of most mammalian and reptilian species during social interactions [1]. Inputs to this chemosensory system originate from the sensory neurons of the vomeronasal organ (VNO) that synapse on the mitr... |
10.1371/journal.pcbi.1002189 | Identification of Potent EGFR Inhibitors from TCM Database@Taiwan | Overexpression of epidermal growth factor receptor (EGFR) has been associated with cancer. Targeted inhibition of the EGFR pathway has been shown to limit proliferation of cancerous cells. Hence, we employed Traditional Chinese Medicine Database (TCM Database@Taiwan) (http://tcm.cmu.edu.tw) to identify potential EGFR i... | Tumor growth is associated with overexpression of epidermal growth factors receptors. Targeted control of EGFR by EGFR inhibitors is an attractive therapy alternative to conventional cancer treatment that offers specificity and reduced adverse effects. The purpose of this study was to identify natural compounds from tr... | Target-specific therapies have generated much attention in addition to conventional cancer treatments [1]–[3]. By targeting key molecules essential for cellular function, replication, or tumorigenesis, such therapies may exert cytostatic or cytotoxic effects on tumors while minimizing nonspecific toxicities associated ... |
10.1371/journal.pcbi.1006864 | Identification of pathways associated with chemosensitivity through network embedding | Basal gene expression levels have been shown to be predictive of cellular response to cytotoxic treatments. However, such analyses do not fully reveal complex genotype- phenotype relationships, which are partly encoded in highly interconnected molecular networks. Biological pathways provide a complementary way of under... | Gene expression levels have been used to study the cellular response to drug treatments. However, analysis of gene expression without considering gene interactions cannot fully reveal complex genotype-phenotype relationships. Biological pathways reveal the interactions among genes, thus providing a complementary way of... | Large-scale cancer genomics projects, such as the Cancer Genome Atlas [1], the Cancer Genome project [2], and the Cancer Cell Line Encyclopedia project [3], and cancer pharmacology projects, such as the Genomics of Drug Sensitivity in Cancer project [2], have generated a large volume of genomics and pharmacological pro... |
10.1371/journal.pntd.0005260 | The Fleas (Siphonaptera) in Iran: Diversity, Host Range, and Medical Importance | Flea-borne diseases have a wide distribution in the world. Studies on the identity, abundance, distribution and seasonality of the potential vectors of pathogenic agents (e.g. Yersinia pestis, Francisella tularensis, and Rickettsia felis) are necessary tools for controlling and preventing such diseases outbreaks. The i... | The data about flea-borne emerging or re-emerging infections throughout Iran are limited. This paper showed that the flea fauna of Iran were dominated by seven families. Moreover flea-host association analysis indicates that rodents are common hosts of flea families and most vertebrates hosted fleas belonging to the su... | Vector-borne diseases (VBDs) are globally responsible for more than 17% of all infectious diseases [1]. There are a large number of viral, rickettsial, bacterial and parasitic diseases that are transmitted by insect vectors [2]. In the last two decades, many zoonotic VBDs have emerged in areas where they previously did... |
10.1371/journal.pntd.0004780 | Discovery of Point Mutations in the Voltage-Gated Sodium Channel from African Aedes aegypti Populations: Potential Phylogenetic Reasons for Gene Introgression | Yellow fever is endemic in some countries in Africa, and Aedes aegpyti is one of the most important vectors implicated in the outbreak. The mapping of the nation-wide distribution and the detection of insecticide resistance of vector mosquitoes will provide the beneficial information for forecasting of dengue and yello... | Aedes aegpyti is one of the most important vectors of yellow fever and dengue fever. Pyrethroid insecticides are emerging as the predominant insecticides for vector control, and resistance of vector mosquitoes to pyrethroid is a major problem for the vector control program. Several mutations in the voltage-gated sodium... | Aedes aegypti (L.) is found throughout West Africa from sea-level to at least 1,220 m in Nigeria, and from the coastal swamp zone to the northern Guinea savannas. Various types of breeding sites have been reported for this species, including crab burrows, holes in trees, fallen leaves, rock pools, anthropogenic contain... |
10.1371/journal.pgen.1001303 | Genome-Wide Transcript Profiling of Endosperm without Paternal Contribution Identifies Parent-of-Origin–Dependent Regulation of AGAMOUS-LIKE36 | Seed development in angiosperms is dependent on the interplay among different transcriptional programs operating in the embryo, the endosperm, and the maternally-derived seed coat. In angiosperms, the embryo and the endosperm are products of double fertilization during which the two pollen sperm cells fuse with the egg... | Seeds of flowering plants consist of three different organisms that develop in parallel. In contrast to animals, a double fertilization event takes place in plants, producing two fertilization products, the embryo and the endosperm. Imprinting, the parent-of-origin–specific expression of genes, typically takes place in... | Seed development is a tightly regulated process that is controlled, both before and after fertilization and requires tight coordination of parental gene expression [1]. A paradigm for the importance of balanced parental contribution is the observation that certain genes in the developing offspring of flowering plants a... |
10.1371/journal.ppat.1000919 | The Haemophilus influenzae HMW1C Protein Is a Glycosyltransferase That Transfers Hexose Residues to Asparagine Sites in the HMW1 Adhesin | The Haemophilus influenzae HMW1 adhesin is a high-molecular weight protein that is secreted by the bacterial two-partner secretion pathway and mediates adherence to respiratory epithelium, an essential early step in the pathogenesis of H. influenzae disease. In recent work, we discovered that HMW1 is a glycoprotein and... | Decoration of proteins with carbohydrates has an important impact on protein function throughout biology and has been recognized increasingly in pathogenic bacteria. Haemophilus influenzae is a common cause of both bacterial respiratory tract disease and bacterial invasive disease and initiates infection by colonizing ... | Glycosylation of proteins is an essential process that plays an important role in protein structure and function and represents a strategy to fine tune cell-cell recognition and signaling. For a long period of time, glycosylation of proteins was believed to be restricted to eukaryotes. However, in recent years glycopro... |
10.1371/journal.pcbi.1000593 | The GAAS Metagenomic Tool and Its Estimations of Viral and Microbial Average Genome Size in Four Major Biomes | Metagenomic studies characterize both the composition and diversity of uncultured viral and microbial communities. BLAST-based comparisons have typically been used for such analyses; however, sampling biases, high percentages of unknown sequences, and the use of arbitrary thresholds to find significant similarities can... | Metagenomics uses DNA or RNA sequences isolated directly from the environment to determine what viruses or microorganisms exist in natural communities and what metabolic activities they encode. Typically, metagenomic sequences are compared to annotated sequences in public databases using the BLAST search tool. Our meth... | Metagenomic approaches to the study of microbial and viral communities have revealed previously undiscovered diversity on a tremendous scale [1],[2]. Metagenomic sequences are typically compared to sequences from known genomes using BLAST to estimate the taxonomic and functional composition of the original environmenta... |
10.1371/journal.ppat.1004746 | Early Virological and Immunological Events in Asymptomatic Epstein-Barr Virus Infection in African Children | Epstein-Barr virus (EBV) infection often occurs in early childhood and is asymptomatic. However, if delayed until adolescence, primary infection may manifest as acute infectious mononucleosis (AIM), a febrile illness characterised by global CD8+ T-cell lymphocytosis, much of it reflecting a huge expansion of activated ... | Primary infection with EBV, a common human herpesvirus, is typically asymptomatic in childhood but, if occurring in adolescence or later, often presents as AIM. This febrile illness is characterised by high virus loads in the blood and an exaggerated EBV-specific CD8+ T-cell response that pushes total CD8+ T-cell numbe... | Epstein-Barr Virus (EBV) is a ubiquitous gamma herpesvirus associated with occasional severe primary infections, several malignancies and significant pathology in immunosuppressed hosts. It does not, however, cause significant morbidity in the majority of those infected. In The Gambia most children are infected during ... |
10.1371/journal.pgen.1003767 | Reversible and Rapid Transfer-RNA Deactivation as a Mechanism of Translational Repression in Stress | Stress-induced changes of gene expression are crucial for survival of eukaryotic cells. Regulation at the level of translation provides the necessary plasticity for immediate changes of cellular activities and protein levels. In this study, we demonstrate that exposure to oxidative stress results in a quick repression ... | Adequate reprogramming of metabolic activities by environmental stress or suboptimal growth conditions is crucial for cell survival. Cells employ a remarkable diversity of processes to maintain its homeostasis at all levels of gene expression, including chromatin remodeling, mRNA expression and degradation, translation... | Environmental stress or suboptimal growth conditions reduce cell viability and put cells at risk. Cells maintain their internal homeostasis by adequate reprogramming of metabolic activities at all levels of gene expression, including chromatin remodeling, mRNA expression and degradation, translation and protein degrada... |
10.1371/journal.ppat.1008004 | Fas-associated factor 1 mediates NADPH oxidase-induced reactive oxygen species production and proinflammatory responses in macrophages against Listeria infection | Fas-associated factor 1 is a death-promoting protein that induces apoptosis by interacting with the Fas receptor. Until now, FAF1 was reported to interact potentially with diverse proteins and to function as a negative and/or positive regulator of several cellular possesses. However, the role of FAF1 in defense against... | Phagocytic NADPH oxidase plays a pivotal role in generating reactive oxygen species (ROS) and in defense against bacterial infections such as L. monocytogenes. ROS eliminate phagocytosed bacteria directly and are implicated in transduction of signals that mediate inflammatory responses. Here, we show that the apoptotic... | Innate immune cells are the first barrier encountered by invading microbial pathogens. Among these cells, phagocytes such as macrophages and neutrophils play key roles in host protection against bacterial infection. Upon recognition and phagocytosis of bacteria, phagocytes produce reactive oxygen species (ROS) that kil... |
10.1371/journal.pntd.0005795 | Animal-related factors associated with moderate-to-severe diarrhea in children younger than five years in western Kenya: A matched case-control study | Diarrheal disease remains among the leading causes of global mortality in children younger than 5 years. Exposure to domestic animals may be a risk factor for diarrheal disease. The objectives of this study were to identify animal-related exposures associated with cases of moderate-to-severe diarrhea (MSD) in children ... | Diarrheal disease is one of the leading causes of death worldwide in children younger than 5 years. Exposure to animals in homes may be a risk factor for diarrhea in children. To test this, we studied a subset of children in the Global Enteric Multicenter Study (GEMS) in rural western Kenya, whose caretakers reported t... | Diarrheal disease remains among the leading causes of global mortality in children younger than 5 years [1, 2]. Although the mortality rate due to diarrheal disease in this age group in Africa has decreased by nearly 4% per year since 2000, it remains unacceptably high: it is estimated that 12% of deaths in children yo... |
10.1371/journal.pcbi.1000577 | Analyzing Short-Term Noise Dependencies of Spike-Counts in Macaque Prefrontal Cortex Using Copulas and the Flashlight Transformation | Simultaneous spike-counts of neural populations are typically modeled by a Gaussian distribution. On short time scales, however, this distribution is too restrictive to describe and analyze multivariate distributions of discrete spike-counts. We present an alternative that is based on copulas and can account for arbitr... | The brain has an enormous number of neurons that do not work alone but in an ensemble. Yet, mostly individual neurons were measured in the past and therefore models were restricted to independent neurons. With the advent of new multi-electrode techniques, however, it becomes possible to measure a great number of neuron... | So far, it is still unknown which statistics are crucial for analysis in order to understand the neural code. One approach is to analyze simultaneous spike-counts of neural populations. Responses from populations of sensory neurons vary even when the same stimulus is presented repeatedly, and the variations between the... |
10.1371/journal.pgen.1004813 | Genetic Analysis of the Cardiac Methylome at Single Nucleotide Resolution in a Model of Human Cardiovascular Disease | Epigenetic marks such as cytosine methylation are important determinants of cellular and whole-body phenotypes. However, the extent of, and reasons for inter-individual differences in cytosine methylation, and their association with phenotypic variation are poorly characterised. Here we present the first genome-wide st... | Epigenetic marks provide information that is not encoded in the primary DNA sequence itself but in modifications of genomic DNA and of the associated proteins. Methylation of genomic DNA at cytosine residues is an important epigenetic modification that is associated with developmental processes, carcinogenesis and othe... | Cytosine methylation at CpG dinucleotides is a key epigenetic mark with an essential role in regulating gene expression and other cellular and whole body phenotypes. While the molecular mechanisms for de novo and maintenance methylation of CpG cytosines are well established [1]–[3], allele-specific influences on CpG me... |
10.1371/journal.pcbi.1002513 | Measuring Granger Causality between Cortical Regions from Voxelwise fMRI BOLD Signals with LASSO | Functional brain network studies using the Blood Oxygen-Level Dependent (BOLD) signal from functional Magnetic Resonance Imaging (fMRI) are becoming increasingly prevalent in research on the neural basis of human cognition. An important problem in functional brain network analysis is to understand directed functional i... | Modern cognitive neuroscience views cognition in terms of brain network function. A network is a physical system of nodes connected to each other by edges. From the network perspective, cognitive function depends on activity patterns involving the nodes and edges of functional brain networks. It is important then, to a... | The modern understanding of human cognition relies heavily on the concept of large-scale functional brain networks, and large-scale functional network analysis of Blood-Oxygenation-Level-Dependent (BOLD) signals from functional Magnetic Resonance Imaging (fMRI) is playing an increasingly important role in cognitive neu... |
10.1371/journal.pntd.0001971 | Mesenchymal Bone Marrow Cell Therapy in a Mouse Model of Chagas Disease. Where Do the Cells Go? | Chagas disease, resulting from infection with the parasite Trypanosoma cruzi (T. cruzi), is a major cause of cardiomyopathy in Latin America. Drug therapy for acute and chronic disease is limited. Stem cell therapy with bone marrow mesenchymal cells (MSCs) has emerged as a novel therapeutic option for cell death-relate... | Chagas disease, resulting from infection with the parasite Trypanosoma cruzi, is a major cause of heart disease in Latin America. Treatment options are limited to a small number of drugs that were developed more than four decades ago and which have various drawbacks. Stem cell therapy with bone marrow mesenchymal cells... | Chagas disease is a serious public health problem in all Latin American countries [1], where it is estimated that 15–16 million people are infected with the its causative agent, the parasite Trypanosoma cruzi (T. cruzi) [2]. Although T. cruzi is endemic in Latin America, thousands of people are infected in Europe, Unit... |
10.1371/journal.pcbi.1006052 | Epigenetic regulation of cell fate reprogramming in aging and disease: A predictive computational model | Understanding the control of epigenetic regulation is key to explain and modify the aging process. Because histone-modifying enzymes are sensitive to shifts in availability of cofactors (e.g. metabolites), cellular epigenetic states may be tied to changing conditions associated with cofactor variability. The aim of thi... | Cell reprogramming, a process that allows differentiated cells to re-acquire stem-like properties, is increasingly considered a critical phenomenon in tissue regeneration, aging and cancer. In light of the importance of metabolism in controlling cell fate, we designed a computational model capable of predicting the lik... | Aging is associated with profound changes in the epigenome involving large disturbances of the epigenetic landscape and genome architecture [1, 2]. Studies in model organisms have not only revealed the complex changes occurring in chromatin structure and functioning during aging, but also the remarkable plasticity of a... |
10.1371/journal.pcbi.1002427 | A Common Model for Cytokine Receptor Activation: Combined Scissor-Like Rotation and Self-Rotation of Receptor Dimer Induced by Class I Cytokine | The precise mechanism by which the binding of a class I cytokine to the extracellular domain of its corresponding receptor transmits a signal through the cell membrane remains unclear. Receptor activation involves a cytokine-receptor complex with a 1∶2 stoichiometry. Previously we used our transient-complex theory to c... | Class I cytokines activate their receptors via a 1∶2 complex, but the conformational rearrangements leading to receptor activation remain unclear. To elucidate the activation mechanism, here we calculated the transient complex, an on-pathway intermediate close to the 1∶2 complex. Similar rotational motions were found f... | Cytokines are a large family of small proteins that bind to specific cell surface receptors to initiate signals critical for cell proliferation, differentiation, and apoptosis. Among the best characterized cytokines are class I helical cytokines, including growth hormone (GH), erythropoietin (EPO), and prolactin (PRL).... |
10.1371/journal.pmed.1002573 | Future cost-effectiveness and equity of the NHS Health Check cardiovascular disease prevention programme: Microsimulation modelling using data from Liverpool, UK | Aiming to contribute to prevention of cardiovascular disease (CVD), the National Health Service (NHS) Health Check programme has been implemented across England since 2009. The programme involves cardiovascular risk stratification—at 5-year intervals—of all adults between the ages of 40 and 74 years, excluding any with... | Previous evidence for population cardiovascular screening (e.g., National Health Service [NHS] Health Check in England) has failed to conclusively provide answers around effectiveness, cost-effectiveness, and equity.
A recent systematic review found some evidence of cost-effectiveness, but some of the studies included ... | Cardiovascular disease (CVD) is a leading cause of morbidity and mortality globally [1]. In 2015, almost 500,000 deaths across the United Kingdom were attributed to CVD, more than any other cause of death [2]. As part of the prevention of CVD, the National Health Service (NHS) Health Check programme was implemented acr... |
10.1371/journal.pcbi.1005970 | The exclusive effects of chaperonin on the behavior of proteins with 52 knot | The folding of proteins with a complex knot is still an unresolved question. Based on representative members of Ubiquitin C-terminal Hydrolases (UCHs) that contain the 52 knot in the native state, we explain how UCHs are able to unfold and refold in vitro reversibly within the structure-based model. In particular, we i... | Self-tying of knotted proteins remains a challenge both for theoreticians and experimentalist. In this work, we study the proteins with complex, the 52 knot, in a bulk and confined within a chaperonin box. We show that in our model we recreate the experimental results, identify two topologically distinct folding pathwa... | The role of knots in protein structures is still not fully understood. The topological complexity induces stability to the structure [1, 2] and enforces local motifs favorable for active sites of enzymes [3]. The latter fact may explain, why over 80% of known knotted proteins are enzymes with the active site located at... |
10.1371/journal.pcbi.1004658 | NINJA-OPS: Fast Accurate Marker Gene Alignment Using Concatenated Ribosomes | The explosion of bioinformatics technologies in the form of next generation sequencing (NGS) has facilitated a massive influx of genomics data in the form of short reads. Short read mapping is therefore a fundamental component of next generation sequencing pipelines which routinely match these short reads against refer... | The analysis of the microbial communities in and around us is a growing field of study, partly because of its major implications for human health, and partly because high-throughput DNA sequencing technology has only recently emerged to enable us to quantitatively study them. One of the most fundamental steps in analyz... | The advent of next-generation sequencing technologies, combined with major advances in molecular and bioinformatics techniques, have enabled rapid growth in the culture-independent sequencing of amplified marker genes (amplicons) from environmental microbial communities. The major benefit of amplicon sequencing is that... |
10.1371/journal.pntd.0005318 | Identification of Functional Determinants in the Chikungunya Virus E2 Protein | Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes high fever, rash, and recurrent arthritis in humans. It has efficiently adapted to Aedes albopictus, which also inhabits temperate regions, including Europe and the United States of America. In the past, CHIKV has mainly affected developing coun... | The chikungunya virus (CHIKV) glycoprotein E2 mediates cell attachment and consists of three domains A, B and C. Since the cell entry process of CHIKV is not understood in detail, we analyzed the binding properties of the three E2 domains with proteins expressed in E. coli or as Fc-fusion proteins and the role of glyco... | The Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes high fever, rash, and recurrent arthritis in humans. The majority of symptoms disappear after about one week. However, in about 30% of cases, arthritis can last for months or even years, which may cause substantial economic losses [1], [2]. ... |
10.1371/journal.ppat.1003483 | Mechanism of HIV-1 Virion Entrapment by Tetherin | Tetherin, an interferon-inducible membrane protein, inhibits the release of nascent enveloped viral particles from the surface of infected cells. However, the mechanisms underlying virion retention have not yet been fully delineated. Here, we employ biochemical assays and engineered tetherin proteins to demonstrate con... | The cellular restriction factor, tetherin, prevents HIV-1 and other enveloped virus particles from being disseminated into the extracellular milieu by infiltrating their envelopes and by physically crosslinking them to the cell surface. It is known that tetherin consists of pairs of membrane anchors, situated at either... | Cells have evolved numerous defense measures to inhibit the replication of infectious agents. In animal cells, sensing of viruses by pattern recognition receptors leads to interferon production and signaling, which induces the expression of hundreds of interferon-stimulated genes (ISGs) in infected and bystander cells ... |
10.1371/journal.pgen.1005243 | The Centrosomal Linker and Microtubules Provide Dual Levels of Spatial Coordination of Centrosomes | The centrosome is the principal microtubule organizing center in most animal cells. It consists of a pair of centrioles surrounded by pericentriolar material. The centrosome, like DNA, duplicates exactly once per cell cycle. During interphase duplicated centrosomes remain closely linked by a proteinaceous linker. This ... | During most of interphase, the two centrosomes of a cell are kept together by a proteinaceous linker, called the centrosomal linker. It is clear that the linker has to be dissolved by Nek2 kinase and other mechanisms before mitosis in order to assemble a functional bipolar mitotic spindle. Yet the relevance of the cent... | The centrosome is the principal microtubule organizing center (MTOC) in most animal cells. By nucleating and anchoring microtubules, the centrosome influences microtubule directed processes including shape, polarity, organelle transport, adhesion, motility and division of cells [1]. Centrosomes consist of the centriole... |
10.1371/journal.ppat.1003907 | Competitive and Cooperative Interactions Mediate RNA Transfer from Herpesvirus Saimiri ORF57 to the Mammalian Export Adaptor ALYREF | The essential herpesvirus adaptor protein HVS ORF57, which has homologs in all other herpesviruses, promotes viral mRNA export by utilizing the cellular mRNA export machinery. ORF57 protein specifically recognizes viral mRNA transcripts, and binds to proteins of the cellular transcription-export (TREX) complex, in part... | Herpes viruses invade cells, hijacking cellular components to sustain their lifecycle and replicate. A critical step of infection is the export of viral mRNA from the nucleus to the cytoplasm, where the molecular machinery to produce proteins is located. To provide a link between their mRNA and cellular components of t... | Mammalian gene expression is coupled with mRNA maturation, where nascent transcripts undergo a continuous series of splicing and processing events finally leading to nuclear export to the cytoplasm [1]. This process is tightly regulated and orchestrated, ensuring that only mature and fully-processed cellular mRNA is ex... |
10.1371/journal.pntd.0002757 | Gentamicin-Attenuated Leishmania infantum Vaccine: Protection of Dogs against Canine Visceral Leishmaniosis in Endemic Area of Southeast of Iran | An attenuated line of Leishmania infantum (L. infantum H-line) has been established by culturing promastigotes in vitro under gentamicin pressure. A vaccine trial was conducted using 103 naive dogs from a leishmaniosis non-endemic area (55 vaccinated and 48 unvaccinated) brought into an endemic area of southeast Iran. ... | A 24 month vaccine trial was conducted using 103 leishmania free dogs in an area of southeast Iran endemic for visceral leishmaniosis. The dogs were vaccinated with gentamicin-attenuated line of Leishmania infantum. No local and/or general indications of disease were observed in the vaccinated dogs immediately after va... | Leishmania infantum (L. infantum) is a causative agent of visceral leishmaniasis (VL), which is a severe and frequently lethal protozoan disease of humans and dogs. Canine visceral leishmaniosis (CVL) is widely distributed in large areas of Europe, South America, the Middle-East, Central Asia, China, and Africa, partic... |
10.1371/journal.ppat.1003071 | MiniCD4 Microbicide Prevents HIV Infection of Human Mucosal Explants and Vaginal Transmission of SHIV162P3 in Cynomolgus Macaques | In complement to an effective vaccine, development of potent anti-HIV microbicides remains an important priority. We have previously shown that the miniCD4 M48U1, a functional mimetic of sCD4 presented on a 27 amino-acid stable scaffold, inhibits a broad range of HIV-1 isolates at sub-nanomolar concentrations in cellul... | This report describes the protective effect of a CD4 peptide mimetic against HIV infection on human mucosal explants and further on, when used in a microbicide gel, against a SHIV challenge in cynomolgus macaques. Evidence is given that our “miniprotein engineering” strategy, which corresponds to miniaturizing a bindin... | In complement to an effective vaccine against HIV transmission, development of potent anti-HIV microbicides remains important strategies to consider for HIV prevention [1]–[2]. The CAPRISA-004 clinical trial of 1% tenofovir gel provides the first encouraging results from a randomized phase IIb efficacy trial with a 39%... |
10.1371/journal.ppat.1002155 | Cross-Species Transmission of a Novel Adenovirus Associated with a Fulminant Pneumonia Outbreak in a New World Monkey Colony | Adenoviruses are DNA viruses that naturally infect many vertebrates, including humans and monkeys, and cause a wide range of clinical illnesses in humans. Infection from individual strains has conventionally been thought to be species-specific. Here we applied the Virochip, a pan-viral microarray, to identify a novel a... | Infection from adenoviruses, viruses that cause a variety of illnesses in humans, monkeys, and other animals, has conventionally been thought to be species-specific. We used the Virochip, a microarray designed to detect all viruses, to identify a new species of adenovirus (TMAdV, or titi monkey adenovirus) that caused ... | Adenoviruses, first isolated in the 1950s from explanted adenoid tissue, are double-stranded nonenveloped DNA viruses that naturally infect many vertebrates, including humans and nonhuman primates. The human adenoviruses in the Mastadenovirus genus, comprised of all mammalian adenoviruses, are classified into 7 species... |
10.1371/journal.pcbi.1000483 | Evolutionary Triplet Models of Structured RNA | The reconstruction and synthesis of ancestral RNAs is a feasible goal for paleogenetics. This will require new bioinformatics methods, including a robust statistical framework for reconstructing histories of substitutions, indels and structural changes. We describe a “transducer composition” algorithm for extending pai... | A number of leading methods for bioinformatics analysis of structural RNAs use probabilistic grammars as models for pairs of homologous RNAs. We show that any such pairwise grammar can be extended to an entire phylogeny by treating the pairwise grammar as a machine (a “transducer”) that models a single ancestor-descend... | In 1968, Francis Crick hypothesized that the first ribosome consisted entirely of RNA, without any protein cofactors [1]. A domain structure for this primeval ribosome was recently proposed [2]. To synthesize such a reconstructed ribosome or reconstructions of other evolutionarily significant RNAs such as group II intr... |
10.1371/journal.pmed.1002656 | Delivery outcomes in term births after bariatric surgery: Population-based matched cohort study | Obesity increases the risk of adverse delivery outcomes. Whether weight loss induced by bariatric surgery influences these risks remains to be determined. The objective was to investigate the risk of adverse delivery outcomes among post-surgery women compared with women without bariatric surgery history but with simila... | Obesity is prevalent and is a major health problem in pregnancy and childbirth.
Bariatric surgery induces large and sustained weight loss and is becoming more common in Sweden and other developed countries.
Whether bariatric-surgery-induced weight loss influences delivery outcomes is not well described.
We compared 1,4... | Obesity in women of childbearing age has increased in the US and many other developed countries during the last decades [1]. The proportion of US women 20–39 years of age with obesity (body mass index [BMI] ≥ 30 kg/m2) was 35.7% in 2015–2016, and the corresponding proportion for class III obesity (BMI ≥ 40 kg/m2) was 7... |
10.1371/journal.pcbi.1003742 | Membrane Interaction of Bound Ligands Contributes to the Negative Binding Cooperativity of the EGF Receptor | The epidermal growth factor receptor (EGFR) plays a key role in regulating cell proliferation, migration, and differentiation, and aberrant EGFR signaling is implicated in a variety of cancers. EGFR signaling is triggered by extracellular ligand binding, which promotes EGFR dimerization and activation. Ligand-binding m... | Epidermal growth factor receptor (EGFR) molecules are of central importance in cellular communication. Embedded in the cell membrane, these receptors bind epidermal growth factor (EGF) molecules outside the cell and translate this binding into specific biochemical signals inside the cell, which in turn trigger cell pro... | The epidermal growth factor receptor (EGFR), a member of the Her (ErbB) family of cell-surface receptors, is critical to a variety of cellular processes and is implicated in the development of several forms of cancer and other diseases [1]–[3]. In normal cells, EGFR activation is initiated by the binding of extracellul... |
10.1371/journal.pgen.1000143 | FHY1 Mediates Nuclear Import of the Light-Activated Phytochrome A Photoreceptor | The phytochrome (phy) family of photoreceptors is of crucial importance throughout the life cycle of higher plants. Light-induced nuclear import is required for most phytochrome responses. Nuclear accumulation of phyA is dependent on two related proteins called FHY1 (Far-red elongated HYpocotyl 1) and FHL (FHY1 Like), ... | In response to changes in the environment, animals can take shelter while the sessile plants must adapt to the prevalent conditions. Great plasticity in growth and development are striking examples of how plants cope with a changing environment. In plants, light is both a source of energy and an essential informational... | Plants are sessile organisms and therefore have to adapt growth and development to the environmental conditions at their site of germination. Light is one of the most important factors directing such adaptive responses and it is involved in many developmental steps throughout the life of plants [1],[2]. To detect inten... |
10.1371/journal.pgen.1004301 | Evolutionarily Diverged Regulation of X-chromosomal Genes as a Primal Event in Mouse Reproductive Isolation | Improper gene regulation is implicated in reproductive isolation, but its genetic and molecular bases are unknown. We previously reported that a mouse inter-subspecific X chromosome substitution strain shows reproductive isolation characterized by male-specific sterility due to disruption of meiotic entry in spermatoge... | Reproductive isolation characterized by male sterility and decreased viability is important for speciation, because it suppresses free genetic exchange between two diverged populations and accelerates the genetic divergence. One of the reproductive isolation phenomena, hybrid sterility (sterility in hybrid animals), is... | Reproductive isolation is a typical consequence of deleterious epistatic interactions between genes that have evolutionarily diverged in species or subspecies [1]–[3]. One of the most common types of postzygotic reproductive isolation is sterility of interspecific (or intersubspecific) hybrid progeny in F1 or later int... |
10.1371/journal.pcbi.1000750 | Structural Characteristics of Novel Protein Folds | Folds are the basic building blocks of protein structures. Understanding the emergence of novel protein folds is an important step towards understanding the rules governing the evolution of protein structure and function and for developing tools for protein structure modeling and design. We explored the frequency of oc... | Structural genomics efforts aim at exploring the repertoire of three-dimensional structures of protein molecules. While genome scale sequencing projects have already provided us with all the genes of many organisms, it is the three dimensional shape of gene encoded proteins that defines all the interactions among these... | Under physiological conditions most proteins self-assemble into unique structures that dictate their interactions with other molecules and determine their function. Protein structures can be decomposed into individually folding units, so called folds [1]. A fold is determined from the number, arrangement, and connectiv... |
10.1371/journal.pcbi.1002218 | Robust Signal Processing in Living Cells | Cellular signaling networks have evolved an astonishing ability to function reliably and with high fidelity in uncertain environments. A crucial prerequisite for the high precision exhibited by many signaling circuits is their ability to keep the concentrations of active signaling compounds within tightly defined bound... | Cellular signaling networks have to function reliably and with high fidelity in an uncertain environment. In this paper, we investigate the topological principles to achieve such robust signal processing in living cells. Specifically, we identify the topological organizing principles that enable a signaling network to ... | All living cells rely on the capacity to respond to intra- or extracellular signals and have evolved a dedicated biochemical machinery to continuously sense, transmit, and process a variety of internal and environmental cues. A key requisite for reliable signal processing is the capability of living cells to keep the s... |
10.1371/journal.pgen.1003983 | Basolateral Mg2+ Extrusion via CNNM4 Mediates Transcellular Mg2+ Transport across Epithelia: A Mouse Model | Transcellular Mg2+ transport across epithelia, involving both apical entry and basolateral extrusion, is essential for magnesium homeostasis, but molecules involved in basolateral extrusion have not yet been identified. Here, we show that CNNM4 is the basolaterally located Mg2+ extrusion molecule. CNNM4 is strongly exp... | Magnesium is an essential element for living organisms. Its absorption occurs at the intestine through the barrier comprised of epithelial cells. In this process, transcellular Mg2+ transport across epithelia, involving both entry from one side and extrusion from the other side, is important. Previous studies have reve... | Magnesium is an essential element involved in a wide variety of biological activities. Homeostasis of the magnesium level is strictly regulated by intestinal absorption and renal reabsorption, in which epithelia function as a barrier that permits selective and regulated transport of Mg2+ from apical to basolateral surf... |
10.1371/journal.pgen.1002145 | Foxp2 Regulates Gene Networks Implicated in Neurite Outgrowth in the Developing Brain | Forkhead-box protein P2 is a transcription factor that has been associated with intriguing aspects of cognitive function in humans, non-human mammals, and song-learning birds. Heterozygous mutations of the human FOXP2 gene cause a monogenic speech and language disorder. Reduced functional dosage of the mouse version (F... | Foxp2 codes for an intriguing regulatory protein that provides a window into unusual aspects of brain function in multiple species. For example, the gene is implicated in speech and language disorders in humans, song learning in songbirds, and learning of rapid movement sequences in mice. Foxp2 acts by tuning the expre... | Forkhead-box protein P2 is a highly conserved vertebrate protein, belonging to an important group of transcription factors [1]. By modulating the expression of downstream target genes, forkhead-box proteins influence a diverse array of processes, including cell-cycle regulation, signal transduction, differentiation, pa... |
10.1371/journal.ppat.1003758 | Conservative Sex and the Benefits of Transformation in Streptococcus pneumoniae | Natural transformation has significant effects on bacterial genome evolution, but the evolutionary factors maintaining this mode of bacterial sex remain uncertain. Transformation is hypothesized to have both positive and negative evolutionary effects on bacteria. It can facilitate adaptation by combining beneficial mut... | Transformation of environmental DNA can provide bacteria with a means to adapt quickly to a changing environment. While this can benefit microbes by facilitating the spread of antibiotic resistance, it can also be harmful if it causes the loss of beneficial alleles from a population. Therefore, it is unclear what evolu... | Natural transformation is an important cause of genome evolution in bacteria, but the evolutionary factors maintaining natural transformation, or competence, in bacteria remain uncertain [1], [2], [3], [4]. Transformation is widely believed to have evolved to facilitate adaptation, especially in a clinical context wher... |
10.1371/journal.ppat.1002040 | Human Neutrophil Clearance of Bacterial Pathogens Triggers Anti-Microbial γδ T Cell Responses in Early Infection | Human blood Vγ9/Vδ2 T cells, monocytes and neutrophils share a responsiveness toward inflammatory chemokines and are rapidly recruited to sites of infection. Studying their interaction in vitro and relating these findings to in vivo observations in patients may therefore provide crucial insight into inflammatory events... | The immune system of all jawed vertebrates harbors three distinct lymphocyte populations – αβ T cells, γδ T cells and B cells – yet only higher primates including humans possess so-called Vγ9/Vδ2 T cells, an enigmatic γδ T cell subset that uniformly responds to the majority of bacterial pathogens. For reasons that are ... | The cellular immune system consists of an ‘innate’ arm of phagocytes and antigen-presenting cells, and an ‘adaptive’ arm of antigen-specific lymphocytes capable of developing immunological memory. Yet, there is increasing evidence of considerable crosstalk between the two [1]. Innate responses directly influence the sh... |
10.1371/journal.pgen.1001393 | Comparative Analysis of Proteome and Transcriptome Variation in Mouse | The relationships between the levels of transcripts and the levels of the proteins they encode have not been examined comprehensively in mammals, although previous work in plants and yeast suggest a surprisingly modest correlation. We have examined this issue using a genetic approach in which natural variations were us... | An old dogma in biology states that, in every cell, the flow of biological information is from DNA to RNA to proteins and that the latter act as a working force to determine the organism's phenotype. This model predicts that changes in DNA that affect the clinical phenotype should also similarly change the cellular lev... | An underlying assumption in many biological studies is the concordance of transcript and protein levels during the flow of information from DNA to phenotype. Clearly, protein levels are greatly influenced by post-translational processing and inherent variations in stability but, in general, it is assumed that perturbat... |
10.1371/journal.ppat.1006130 | Leishmania HASP and SHERP Genes Are Required for In Vivo Differentiation, Parasite Transmission and Virulence Attenuation in the Host | Differentiation of extracellular Leishmania promastigotes within their sand fly vector, termed metacyclogenesis, is considered to be essential for parasites to regain mammalian host infectivity. Metacyclogenesis is accompanied by changes in the local parasite environment, including secretion of complex glycoconjugates ... | Millions of people around the world are at risk of infection with single-celled Leishmania parasites that cause a wide range of infectious diseases of the immune system, the leishmaniases. There is no effective vaccine for these infections while available drugs have toxic side-effects and resistance is an increasing pr... | Kinetoplastid parasites of the genus Leishmania cause a diverse spectrum of mammalian infectious diseases, the leishmaniases, ranging from cutaneous and mucosal pathologies to potentially fatal visceral infections [1]. Endemic human cases have been reported on all continents except Australia and Antarctica [2]. Leishma... |
10.1371/journal.pntd.0001015 | Oviposition Site Selection by the Dengue Vector Aedes aegypti and Its Implications for Dengue Control | Because no dengue vaccine or antiviral therapy is commercially available, controlling the primary mosquito vector, Aedes aegypti, is currently the only means to prevent dengue outbreaks. Traditional models of Ae. aegypti assume that population dynamics are regulated by density-dependent larval competition for food and ... | Controlling the mosquito Aedes aegypti is of public health importance because, at present, it is the only means to stop dengue virus transmission. Implementing successful mosquito control programs requires understanding what factors regulate population abundance, as well as anticipating how mosquitoes may adapt to cont... | Dengue viruses are transmitted to humans primarily by the mosquito Aedes aegypti and represent an increasing public health concern in tropical and subtropical regions worldwide. Because no vaccine or antiviral therapy is commercially available, controlling the mosquito vector is the only current means to prevent dengue... |
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