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10.1371/journal.pntd.0004020 | The Effect of Deworming on Growth in One-Year-Old Children Living in a Soil-Transmitted Helminth-Endemic Area of Peru: A Randomized Controlled Trial | Appropriate health and nutrition interventions to prevent long-term adverse effects in children are necessary before two years of age. One such intervention may include population-based deworming, recommended as of 12 months of age by the World Health Organization in soil-transmitted helminth (STH)-endemic areas; howev... | The World Health Organization recommends starting population-based deworming interventions as of 12 months of age where intestinal worm infection is common; however, little is known about the benefits in early preschool-age children. We conducted a clinical trial to determine the effect of deworming on growth in one-ye... | The soil-transmitted helminth (STH) disease cluster includes ascariasis, trichuriasis and hookworm disease. It is considered to be one of the most common Neglected Tropical Diseases (NTD), affecting an estimated 1.45 billion people worldwide [1]. STHs are transmitted in contaminated food, water and the environment in a... |
10.1371/journal.pntd.0004180 | Changes in the Proteome of Langat-Infected Ixodes scapularis ISE6 Cells: Metabolic Pathways Associated with Flavivirus Infection | Ticks (Family Ixodidae) transmit a variety of disease causing agents to humans and animals. The tick-borne flaviviruses (TBFs; family Flaviviridae) are a complex of viruses, many of which cause encephalitis and hemorrhagic fever, and represent global threats to human health and biosecurity. Pathogenesis has been well s... | High-throughput proteomics offers an approach to evaluate changes in cell protein levels following arboviral infection. Research to understand the molecular basis of human-flavivirus interactions has advanced significantly over the past decade, but comparatively little is known regarding interactions between ticks and ... | Tick-borne flaviviruses (TBFs; family Flaviviridae) are a complex of positive, single-stranded RNA viruses, many of which cause hemorrhagic fever and encephalitis in humans and are associated with high morbidity and mortality [1, 2]. Humans are incidental hosts for TBFs that are transmitted by an infected tick (subphyl... |
10.1371/journal.pbio.2001402 | Digital Health: Tracking Physiomes and Activity Using Wearable Biosensors Reveals Useful Health-Related Information | A new wave of portable biosensors allows frequent measurement of health-related physiology. We investigated the use of these devices to monitor human physiological changes during various activities and their role in managing health and diagnosing and analyzing disease. By recording over 250,000 daily measurements for u... | A new wave of wearable sensors allows frequent and continuous measurements of body functions (physiology), including heart rate, skin temperature, blood oxygen levels, and physical activity. We investigated the ability of wearable sensors to follow physiological changes that occur over the course of a day, during illne... | Physiological parameters such as heart rate (HR), blood pressure, and body temperature can provide critical information about the physical health status of a person. Elevation of any of these parameters can be of concern; elevated HR and blood pressure are associated with cardiovascular disease, and elevated body tempe... |
10.1371/journal.pntd.0002787 | Epidemiology of Coxiella burnetii Infection in Africa: A OneHealth Systematic Review | Q fever is a common cause of febrile illness and community-acquired pneumonia in resource-limited settings. Coxiella burnetii, the causative pathogen, is transmitted among varied host species, but the epidemiology of the organism in Africa is poorly understood. We conducted a systematic review of C. burnetii epidemiolo... | Coxiella burnetii is a bacterium that can cause acute and chronic fever illness and pneumonia in humans. It is also a known cause of abortion in livestock species, and is principally transmitted to humans through contact with infected animal birth products. With growing awareness of the over-diagnosis and misclassifica... | Coxiella burnetii, a zoonotic bacterial pathogen found worldwide except in New Zealand, is transmitted to humans through direct contact with milk, urine, feces, or semen from infected animals as well as inhalation of aerosolized particles from animal placentas, parturient fluids, aborted fetuses, and environmental dust... |
10.1371/journal.pntd.0002216 | Incidence of Rabies in Humans and Domestic Animals and People's Awareness in North Gondar Zone, Ethiopia | Rabies is a zoonotic disease that has been prevalent in humans and animals for centuries in Ethiopia and it is often dealt with using traditional practices. There is lack of accurate quantitative information on rabies both in humans and animals in Ethiopia and little is known about the awareness of the people about the... | Rabies is a fatal viral disease that affects all mammals including humans. Domestic dog is the main source of rabies for humans and livestock in developing countries. Rabies has been prevalent in Ethiopia for centuries, affecting humans and livestock. In this study we estimated the incidence of the disease in North Gon... | Rabies is an acute encephalitis illness caused by rabies virus. Rabies virus is the prototype species of the genus Lyssavirus in the family of Rhabdoviridae. The virus affects virtually all mammals and infected species invariably die from the disease once clinical signs are manifested [1].
Rabies is endemic in d... |
10.1371/journal.pbio.1002125 | Dynamic Endothelial Cell Rearrangements Drive Developmental Vessel Regression | Patterning of functional blood vessel networks is achieved by pruning of superfluous connections. The cellular and molecular principles of vessel regression are poorly understood. Here we show that regression is mediated by dynamic and polarized migration of endothelial cells, representing anastomosis in reverse. Estab... | The question of how blood vessel networks achieve their branching patterns is key to our understanding of organ formation as well as diseases that involve vascular anomalies. Regression (or pruning) of blood vessel segments is required for functional vascular branching patterns; however, the molecular basis for this is... | The formation of a functionally perfused and hierarchically branched network of blood vessels is essential for vertebrate development, tissue growth, and organ physiology [1]. Together, vasculogenic vessel assembly and angiogenic sprouting establish the major axial vessels and form a rough draft of a network, which und... |
10.1371/journal.ppat.1004691 | Antibiotic Modulation of Capsular Exopolysaccharide and Virulence in Acinetobacter baumannii | Acinetobacter baumannii is an opportunistic pathogen of increasing importance due to its propensity for intractable multidrug-resistant infections in hospitals. All clinical isolates examined contain a conserved gene cluster, the K locus, which determines the production of complex polysaccharides, including an exopolys... | Acinetobacter baumannii has gained notoriety as a cause of hospital-acquired infections that are difficult to treat due to extensive antibiotic resistance. While the microorganism rarely causes disease in the community, it commonly infects patients receiving antibiotics. The factors intrinsic to the bacterium that enab... | Hospital-acquired infections with multidrug resistant (MDR) bacteria pose increasingly difficult challenges for patient care. These diseases are often intransigent to initial empiric broad-spectrum antibiotic therapy, delaying effective treatment and resulting in significant morbidity and mortality in already vulnerabl... |
10.1371/journal.pbio.1001194 | Elimination of the Vesicular Acetylcholine Transporter in the Striatum Reveals Regulation of Behaviour by Cholinergic-Glutamatergic Co-Transmission | Cholinergic neurons in the striatum are thought to play major regulatory functions in motor behaviour and reward. These neurons express two vesicular transporters that can load either acetylcholine or glutamate into synaptic vesicles. Consequently cholinergic neurons can release both neurotransmitters, making it diffic... | The neurotransmitters dopamine and acetylcholine play opposite roles in the striatum (a brain region involved in motor control and reward-related behaviour), and their balance is thought to be critical for striatal function. Acetylcholine in the striatum has been linked to a number of functions, including control of lo... | The striatum is the major input gateway to the basal ganglia. Striatal activity plays important roles in controlling motor functions and goal-directed and reward-related behaviours [1]–[4]. The striatum is the brain region mostly affected in motor diseases, such as Parkinson's disease (PD), Huntington's disease, and dy... |
10.1371/journal.ppat.1006451 | A human endogenous retrovirus-derived gene that can contribute to oncogenesis by activating the ERK pathway and inducing migration and invasion | Endogenous retroviruses are cellular genes of retroviral origin captured by their host during the course of evolution and represent around 8% of the human genome. Although most are defective and transcriptionally silenced, some are still able to generate retroviral-like particles and proteins. Among these, the HERV-K(H... | Nearly half the DNA of mammals consists of reitarated, selfish elements that can move and amplify within the genome. With time, some of these elements are recruited by the host and the proteins they encode are used to fulfill physiological functions, whereas other elements have conserved some of their pathological prop... | Retroviruses are responsible for a broad range of diseases in animals and humans, the most common of which is the development of cancers. The mechanisms by which they contribute to oncogenesis are diverse and include: (i) insertional mutagenesis, due to activation of cellular proto-oncogenes by inserted proviruses, (ii... |
10.1371/journal.pmed.1002532 | Cost-effectiveness of multidisciplinary care in mild to moderate chronic kidney disease in the United States: A modeling study | Multidisciplinary care (MDC) programs have been proposed as a way to alleviate the cost and morbidity associated with chronic kidney disease (CKD) in the US.
We assessed the cost-effectiveness of a theoretical Medicare-based MDC program for CKD compared to usual CKD care in Medicare beneficiaries with stage 3 and 4 CKD... | Chronic kidney disease is a major cause of morbidity and mortality in the US.
Multidisciplinary care—when healthcare providers of different expertise collaborate to treat a single disease—has successfully reduced mortality and the incidence of end-stage renal disease in patients with chronic kidney disease.
Understandi... | Chronic kidney disease (CKD) affects approximately 10% of Medicare beneficiaries in the US but accounts for a disproportionate 20% of expenditures [1]. Patients with end-stage renal disease (ESRD) are more costly, representing 1.6% of Medicare beneficiaries and responsible for 7.2% of costs [1]. At the same time, life ... |
10.1371/journal.ppat.1007259 | A pathogen-derived effector modulates host glucose metabolism by arginine GlcNAcylation of HIF-1α protein | The essential role of pathogens in host metabolism is widely recognized, yet the mechanisms by which they affect host physiology remain to be fully defined. Here, we found that NleB, an enteropathogenic Escherichia coli (EPEC) type III secretion system effector known to possess N-acetylglucosamine (GlcNAc) transferase ... | Accumulating evidence shows that pathogens can affect host metabolism, resulting in human diseases such as obesity and type 2 diabetes. However, how pathogens influence their hosts is still not clear, and this results in a lack of effective and specific clinical treatments. Further investigations into the causes of pat... | Over the past decade, it has become clear that pathogens play an important role in host metabolism, but the mechanisms by which they affect host metabolism remain poorly defined [1–10]. Although pathogenic organisms likely rely on effectors to communicate with their host, the identity and function of pathogen-encoded e... |
10.1371/journal.pgen.1002086 | STAT Is an Essential Activator of the Zygotic Genome in the Early
Drosophila Embryo | In many organisms, transcription of the zygotic genome begins during the
maternal-to-zygotic transition (MZT), which is characterized by a dramatic
increase in global transcriptional activities and coincides with embryonic stem
cell differentiation. In Drosoph... | In the initial phase of the early embryo, transcription is inactive and
development is supported by maternally derived gene products. During a time
window termed the maternal-to-zygotic transition (MZT), the maternal gene
products are degraded and the zygotica... | Embryonic pattern formation is a complex and progressive process. In many
multicellular organisms, the initial period of embryogenesis relies on gene products
inherited from the mother. In Drosophila, maternally derived
morphogen proteins form broad gradients along the ma... |
10.1371/journal.ppat.1002931 | Identification of Alternatively Translated Tetherin Isoforms with Differing Antiviral and Signaling Activities | Tetherin (BST-2/CD317/HM1.24) is an IFN induced transmembrane protein that restricts release of a broad range of enveloped viruses. Important features required for Tetherin activity and regulation reside within the cytoplasmic domain. Here we demonstrate that two isoforms, derived by alternative translation initiation ... | Regulation of innate immunity is critical to maintain a balance between control of a perceived threat and immunopathology. The interferon induced cellular factor Tetherin has been shown to restrict budding of a broad range of enveloped viruses including the human immunodeficiency virus. Though Tetherin appears to be a ... | Tetherin (BST-2/CD317/HM1.24) is an interferon (IFN) induced, type II transmembrane glycoprotein which has been shown to function as an intrinsic antiviral factor that restricts release of a broad range of enveloped viruses, including members of the arenavirus [1], [2], filovirus [2], [3], gamma-herpesvirus [4], [5], p... |
10.1371/journal.pgen.1003341 | Both the Caspase CSP-1 and a Caspase-Independent Pathway Promote Programmed Cell Death in Parallel to the Canonical Pathway for Apoptosis in Caenorhabditis elegans | Caspases are cysteine proteases that can drive apoptosis in metazoans and have critical functions in the elimination of cells during development, the maintenance of tissue homeostasis, and responses to cellular damage. Although a growing body of research suggests that programmed cell death can occur in the absence of c... | Caspases are cysteine proteases that in many cases drive apoptosis, an evolutionarily conserved and highly stereotyped form of cellular suicide with functions in animal development and tissue maintenance. The dysregulation of apoptosis can contribute to diseases as diverse as cancer, autoimmunity, and neurodegeneration... | The elimination of unnecessary or dangerous cells is fundamental to development, tissue homeostasis and disease mitigation in multicellular organisms. The primary mechanism of cell elimination is apoptosis, a form of cell suicide that was originally defined by evolutionarily conserved morphological characteristics that... |
10.1371/journal.pbio.1000545 | The Translation Initiation Factor 3f (eIF3f) Exhibits a Deubiquitinase Activity Regulating Notch Activation | Activation of the mammalian Notch receptor after ligand binding relies on a succession of events including metalloprotease-cleavage, endocytosis, monoubiquitination, and eventually processing by the gamma-secretase, giving rise to a soluble, transcriptionally active molecule. The Notch1 receptor was proposed to be mono... | The highly conserved signaling pathway involving the transmembrane receptor Notch is essential for development, and misregulation of this pathway is linked to many diseases. We previously proposed that the Notch1 receptor is monoubiquitinated during its activation. With the aim of identifying a deubiquinating enzyme th... | Notch signaling relies on two consecutive cleavages of the receptor after binding of its ligand expressed by a neighboring cell. These two processing steps successively performed by a protease of the ADAM family and by the γ-secretase complex can occur only if the activated receptors on one side, the ligands on the oth... |
10.1371/journal.pntd.0001892 | Impact of Wolbachia on Infection with Chikungunya and Yellow Fever Viruses in the Mosquito Vector Aedes aegypti | Incidence of disease due to dengue (DENV), chikungunya (CHIKV) and yellow fever (YFV) viruses is increasing in many parts of the world. The viruses are primarily transmitted by Aedes aegypti, a highly domesticated mosquito species that is notoriously difficult to control. When transinfected into Ae. aegypti, the intrac... | Mosquito-transmitted viruses such as dengue, yellow fever and chikungunya, are responsible for significant morbidity and mortality throughout tropical and sub-tropical regions of the world. These viruses are primarily transmitted by Aedes aegypti, a mosquito that due to its close association with humans has historicall... | Mosquito-transmitted viruses cause significant human morbidity and mortality throughout the world and impose particularly heavy health and economic burdens on developing countries. Dengue, caused by infection with any of the four dengue virus (DENV) serotypes, is currently the leading arboviral disease, with millions o... |
10.1371/journal.pcbi.1005671 | Reconstructing the regulatory circuit of cell fate determination in yeast mating response | Massive technological advances enabled high-throughput measurements of proteomic changes in biological processes. However, retrieving biological insights from large-scale protein dynamics data remains a challenging task. Here we used the mating differentiation in yeast Saccharomyces cerevisiae as a model and developed ... | A systematic characterization of the proteomic changes during the process of cell differentiation is critical for understanding the underlying molecular mechanisms. However, protein expression can be largely affected by changes in cell physiological state, which hampers the detection of regulatory interactions. Here we... | Retrieving gene regulatory networks from experimental measurements lies at the foundation for deciphering the mechanistic basis of cellular responses. To date, several strategies have been proposed to reconstruct biological networks. It is possible to infer network connectivity directly from genome-wide localization an... |
10.1371/journal.pntd.0005732 | High prevalence of epilepsy in onchocerciasis endemic regions in the Democratic Republic of the Congo | An increased prevalence of epilepsy has been reported in many onchocerciasis endemic areas. The objective of this study was to determine the prevalence of epilepsy in onchocerciasis endemic areas in the Democratic Republic of the Congo (DRC) and investigate whether a higher annual intake of Ivermectin was associated wi... | An increased prevalence of epilepsy has been reported in many onchocerciasis endemic areas. Between July 2014 and February 2016, house-to-house epilepsy prevalence surveys were carried out in the Bas-Uele, Tshopo and Ituri province of the Democratic Republic of the Congo, in areas with a high level of onchocerciasis en... | A high prevalence of epilepsy (>1%) has been reported in many onchocerciasis endemic regions. In Africa, a special form of epilepsy referred to as “nodding syndrome” has been reported solely in onchocerciasis endemic areas [1]. The Democratic Republic of the Congo (DRC) is the country with the largest population at ris... |
10.1371/journal.pntd.0005797 | Temperature modulates dengue virus epidemic growth rates through its effects on reproduction numbers and generation intervals | Epidemic growth rate, r, provides a more complete description of the potential for epidemics than the more commonly studied basic reproduction number, R0, yet the former has never been described as a function of temperature for dengue virus or other pathogens with temperature-sensitive transmission. The need to underst... | Recurrent, rapidly intensifying epidemics of dengue–the world’s most prevalent mosquito-borne viral disease–pose a challenge to healthcare systems throughout the tropical and subtropical world. An acute disease that tends to respond well to proper treatment, the sometimes intense nature of dengue epidemics has been kno... | Dengue virus (DENV) is a mosquito-borne pathogen that infects hundreds of millions of people each year across as many as 128 countries [1]. Along with numerous other arthropod-borne viruses (arboviruses), including chikungunya and Zika viruses [2,3], DENV causes epidemics with considerable public health impact. Rapidly... |
10.1371/journal.pntd.0004636 | Zika Virus Outbreak in Rio de Janeiro, Brazil: Clinical Characterization, Epidemiological and Virological Aspects | In 2015, Brazil was faced with the cocirculation of three arboviruses of major public health importance. The emergence of Zika virus (ZIKV) presents new challenges to both clinicians and public health authorities. Overlapping clinical features between diseases caused by ZIKV, Dengue (DENV) and Chikungunya (CHIKV) and t... | Zika virus (ZIKV) has been identified in 2015 in Brazil for the first time, causing outbreaks of an illness characterized by skin rash and absent or low grade and short-termed fever. It is difficult to distinguish ZIKV from Dengue (DENV) or (CHIKV) based on the acute clinical presentation. The virus is closely related ... | Since 2015, Brazil is faced with the challenge of three co-circulating arboviruses of major public health importance. For the last 30 years, dengue virus (DENV) infection has been the main mosquito-transmitted threat in the country, which has suffered several epidemics caused by all four serotypes, [1, 2] fostered by t... |
10.1371/journal.pbio.2002930 | Cell signaling heterogeneity is modulated by both cell-intrinsic and -extrinsic mechanisms: An integrated approach to understanding targeted therapy | During the last decade, our understanding of cancer cell signaling networks has significantly improved, leading to the development of various targeted therapies that have elicited profound but, unfortunately, short-lived responses. This is, in part, due to the fact that these targeted therapies ignore context and avera... | A signaling pathway is a network of molecules in a cell that is typically initiated by stimuli (e.g., microenvironmental cues) acting on receptors and internal signaling molecules to determine cell fate. Signaling pathways in cancer cells are different from those in normal cells, and this difference helps cancer cells ... | Normal cell signaling is significantly altered in cancer as a result of genetic and epigenetic changes, facilitating uncontrolled proliferation and cell survival [1, 2]. Targeted therapies directly exploit these alterations by blocking the activity of specific proteins typically mutated or abnormally up-regulated [3]. ... |
10.1371/journal.pgen.1006204 | dachshund Potentiates Hedgehog Signaling during Drosophila Retinogenesis | Proper organ patterning depends on a tight coordination between cell proliferation and differentiation. The patterning of Drosophila retina occurs both very fast and with high precision. This process is driven by the dynamic changes in signaling activity of the conserved Hedgehog (Hh) pathway, which coordinates cell fa... | Molecules of the Hedgehog (Hh) family are involved in the control of many developmental processes in both vertebrates and invertebrates. One of these processes is the formation of the retina in the fruitfly Drosophila. Here, Hh orchestrates a differentiation wave that allows the fast and precise differentiation of the ... | Temporal and spatial coordination between cell proliferation and differentiation is essential for proper organ patterning. A way to ensure this coordination is through the use of regulatory signaling pathways that control both processes. Among those is the Hedgehog (Hh) signaling pathway that regulates organ growth and... |
10.1371/journal.pntd.0005234 | Naloxonazine, an Amastigote-Specific Compound, Affects Leishmania Parasites through Modulation of Host-Encoded Functions | Host-directed therapies (HDTs) constitute promising alternatives to traditional therapy that directly targets the pathogen but is often hampered by pathogen resistance. HDT could represent a new treatment strategy for leishmaniasis, a neglected tropical disease caused by the obligate intracellular parasite Leishmania. ... | Leishmaniasis is a poverty-related disease threatening 350 million people throughout the world. It is caused by the protozoan parasite Leishmania, a digenetic organism that switches from an extracellular stage in the sand fly vector to an intracellular stage in phagocytes of the vertebrate host. Drugs currently availab... | Protozoan parasites of the genus Leishmania are the causative agents of a wide variety of diseases ranging from self-healing or severe mucocutaneous lesions to a visceral disease which is lethal in the absence of treatment. Leishmaniasis is one of the most significant neglected tropical diseases, with an estimated 12 m... |
10.1371/journal.pgen.1004383 | Bayesian Test for Colocalisation between Pairs of Genetic Association Studies Using Summary Statistics | Genetic association studies, in particular the genome-wide association study (GWAS) design, have provided a wealth of novel insights into the aetiology of a wide range of human diseases and traits, in particular cardiovascular diseases and lipid biomarkers. The next challenge consists of understanding the molecular bas... | Genome-wide association studies (GWAS) have found a large number of genetic regions (“loci”) affecting clinical end-points and phenotypes, many outside coding intervals. One approach to understanding the biological basis of these associations has been to explore whether GWAS signals from intermediate cellular phenotype... | In the last decade, hundreds of genomic loci affecting complex diseases and disease relevant intermediate phenotypes have been found and robustly replicated using genome-wide association studies (GWAS, [1]). At the same time, gene expression measurements derived from microarray [2] or RNA sequencing [3] studies have be... |
10.1371/journal.pntd.0000231 | Human TLR1 Deficiency Is Associated with Impaired Mycobacterial Signaling and Protection from Leprosy Reversal Reaction | Toll-like receptors (TLRs) are important regulators of the innate immune response to pathogens, including Mycobacterium leprae, which is recognized by TLR1/2 heterodimers. We previously identified a transmembrane domain polymorphism, TLR1_T1805G, that encodes an isoleucine to serine substitution and is associated with ... | Mycobacterium leprae (ML) causes a disabling and stigmatizing disease that is characterized by distinct immune responses. ML produces a spectrum of illness in humans, and several lines of evidence indicate that host genetic factors influence susceptibility and clinical manifestations. Leprosy can occur as the lepromato... | Mycobacterium tuberculosis (MTb) has established latent infection in one-third of the world's population and, among those with progressive disease, causes about 2 million deaths per year [1]. Mycobacterium leprae (ML), a related organism, is the etiologic agent of leprosy, an ancient scourge that still causes illness i... |
10.1371/journal.pntd.0007768 | The association of depression, anxiety, and stress with caring for a child with Congenital Zika Syndrome in Brazil; Results of a cross-sectional study | Zika virus (ZIKV) infection in pregnancy can cause microcephaly and a wide spectrum of severe adverse outcomes, collectively called “Congenital Zika Syndrome” (CZS). Parenting a child with disabilities can have adverse mental health impacts, but these associations have not been fully explored in the context of CZS in B... | The 2015 Zika epidemic in Brazil gained international attention with the birth of thousands of babies with severe adverse outcomes, collectively called “Congenital Zika Syndrome” (CZS). Parenting a child with disabilities can be extremely stressful, and in other settings is linked to depression, anxiety and other menta... | Brazil hit international headlines in late 2015 with the birth of thousands of babies with microcephaly, which was soon linked to congenital infection with the Zika Virus (ZIKV). It was quickly apparent that babies born after congenital ZIKV infection experience a range of severe conditions beyond microcephaly alone, w... |
10.1371/journal.pntd.0000798 | Interactions between Global Health Initiatives and Country Health Systems: The Case of a Neglected Tropical Diseases Control Program in Mali | Recently, a number of Global Health Initiatives (GHI) have been created to address single disease issues in low-income countries, such as poliomyelitis, trachoma, neonatal tetanus, etc.. Empirical evidence on the effects of such GHIs on local health systems remains scarce. This paper explores positive and negative effe... | Prevention of neglected tropical diseases was recently significantly scaled up in sub-Saharan Africa, protecting entire populations with mass distribution of drugs: five different diseases are now addressed simultaneously with a package of four drugs. Some argue however that, similarly to other major control programs d... | Since 2000, global health initiatives (GHIs) have become a dominant international aid strategy, drawing on effective methods to control specific diseases, and accounting for a substantial increase of resources for global health [1]. Very soon, however, concerns emerged that, beyond anticipated benefits for targeted dis... |
10.1371/journal.pgen.1000360 | Reduced Neutrophil Count in People of African Descent Is Due To a Regulatory Variant in the Duffy Antigen Receptor for Chemokines Gene | Persistently low white blood cell count (WBC) and neutrophil count is a well-described phenomenon in persons of African ancestry, whose etiology remains unknown. We recently used admixture mapping to identify an approximately 1-megabase region on chromosome 1, where ancestry status (African or European) almost entirely... | Many African Americans have white blood cell counts (WBC) that are persistently below the normal range for people of European descent, a condition called “benign ethnic neutropenia.” Because most African Americans have both African and European ancestors, selected genetic variants can be analyzed to assign probable Afr... | A large proportion of healthy African Americans have been observed to have a white blood cell count (WBC) that is persistently lower than the normal range defined for individuals of European ancestry [1]–[5]. This condition, called “benign ethnic neutropenia”, can have important effects on medical decision-making, sinc... |
10.1371/journal.ppat.1000364 | Distinct Roles for FOXP3+ and FOXP3− CD4+ T Cells in Regulating Cellular Immunity to Uncomplicated and Severe Plasmodium falciparum Malaria | Failure to establish an appropriate balance between pro- and anti-inflammatory immune responses is believed to contribute to pathogenesis of severe malaria. To determine whether this balance is maintained by classical regulatory T cells (CD4+ FOXP3+ CD127−/low; Tregs) we compared cellular responses between Gambian chil... | While Tregs have been implicated in regulation of the immune response to chronic infections, their potential in determining disease outcome in acute infections is unclear. In this study we have found that Tregs are unable to control the florid inflammation during acute, severe P. falciparum malaria infections, suggesti... | The clinical spectrum of P. falciparum infection ranges from asymptomatic parasite carriage to a febrile disease that may develop into a severe, life-threatening illness. The factors that determine disease severity are not completely understood but are likely to include both parasite and host components [1]–[3]. Ultima... |
10.1371/journal.pntd.0000269 | Intestinal Transcriptomes of Nematodes: Comparison of the Parasites Ascaris suum and Haemonchus contortus with the Free-living Caenorhabditis elegans | The nematode intestine is a major organ responsible for nutrient digestion and absorption; it is also involved in many other processes, such as reproduction, innate immunity, stress responses, and aging. The importance of the intestine as a target for the control of parasitic nematodes has been demonstrated. However, t... | Biological properties of the nematode intestine warrant in-depth investigation, the results of which can be utilized in the control of parasitic nematodes that infect humans, livestock, and plants. Both the importance of intestinal antigens from Haemonchus contortus in immunity and the damage to H. contortus intestine ... | The intestine is one of the major organs in nematodes, creating a key surface at the intestinal apical membrane that interacts with the environment. While specific cellular characteristics of the intestine can be diverse among nematode species, they typically conform to polarized epithelial cells with the apical membra... |
10.1371/journal.pgen.1000265 | A Motor Function for the DEAD-Box RNA Helicase, Gemin3, in Drosophila | The survival motor neuron (SMN) protein, the determining factor for spinal muscular atrophy (SMA), is complexed with a group of proteins in human cells. Gemin3 is the only RNA helicase in the SMN complex. Here, we report the identification of Drosophila melanogaster Gemin3 and investigate its function in vivo. Like in ... | The childhood disease spinal muscular atrophy (SMA) has a drastic impact on motor neurons and muscles. The cause has been linked to a deficiency in the survival motor neuron (SMN) protein. SMN interacts with various proteins termed Gemins to form the SMN complex, among which Gemin3 is the only one with an RNA unwinding... | Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterised by degeneration of spinal cord motor neurons, as well as progressive muscular weakness, dysphagia, dyspnoea, and in severe cases, death [1],[2]. The majority of SMA patients harbour deletions or mutations in the survival motor neuron (SMN1) ... |
10.1371/journal.pgen.0030148 | Gene Duplication and Adaptive Evolution of Digestive Proteases in Drosophila arizonae Female Reproductive Tracts | It frequently has been postulated that intersexual coevolution between the male ejaculate and the female reproductive tract is a driving force in the rapid evolution of reproductive proteins. The dearth of research on female tracts, however, presents a major obstacle to empirical tests of this hypothesis. Here, we empl... | In a broad range of organisms, including humans, molecular interactions between the male ejaculate and the female reproductive tract play integral roles in sexual reproduction. Although these interactions are essential, the biochemical composition of the male ejaculate can change rapidly over short evolutionary time pe... | Extensive research across a broad range of taxa has revealed that the proteins involved in sexual reproduction often evolve rapidly due to positive selection (reviewed in [1–3]). Although the selective forces that underlie this pattern remain unclear, it frequently has been postulated that adaptive evolution of reprodu... |
10.1371/journal.pgen.1004633 | Identification of a Regulatory Variant That Binds FOXA1 and FOXA2 at the CDC123/CAMK1D Type 2 Diabetes GWAS Locus | Many of the type 2 diabetes loci identified through genome-wide association studies localize to non-protein-coding intronic and intergenic regions and likely contain variants that regulate gene transcription. The CDC123/CAMK1D type 2 diabetes association signal on chromosome 10 spans an intergenic region between CDC123... | GWAS have identified more than 1200 loci contributing to risk of disease, including more than 70 loci associated with type 2 diabetes. With a majority of associated variants localized to non-coding regions of the genome, focus has moved to identifying the functional variants explaining the association signals. One mech... | Type 2 diabetes is a complex metabolic disease with a substantial heritable component [1]. Over the past seven years, genome-wide association studies (GWAS) have successfully identified over 70 common risk variants associated with type 2 diabetes [2]–[5]. Association signals at many of these loci localize to non-protei... |
10.1371/journal.pntd.0002766 | Trypsin- and Chymotrypsin-Like Serine Proteases in Schistosoma mansoni – ‘The Undiscovered Country’ | Blood flukes (Schistosoma spp.) are parasites that can survive for years or decades in the vasculature of permissive mammalian hosts, including humans. Proteolytic enzymes (proteases) are crucial for successful parasitism, including aspects of invasion, maturation and reproduction. Most attention has focused on the ‘ce... | Schistosomes are blood flukes that live in the blood system and cause chronic and debilitating infection in hundreds of millions of people. Proteolytic enzymes (proteases) produced by the parasite allow it to survive and reproduce. We focused on understanding the repertoire of trypsin- and chymotrypsin-like Schistosoma... | Schistosomiasis caused by Schistosoma blood flukes is a chronic disease with more than 200 million people infected [1]. Schistosome larvae (cercariae), released into an aquatic environment from snail intermediate hosts, penetrate human skin and subsequently develop into adult worms. Adult worms reside in the host vascu... |
10.1371/journal.ppat.1006191 | Selective expansion of high functional avidity memory CD8 T cell clonotypes during hepatitis C virus reinfection and clearance | The dynamics of the memory CD8 T cell receptor (TCR) repertoire upon virus re-exposure and factors governing the selection of TCR clonotypes conferring protective immunity in real life settings are poorly understood. Here, we examined the dynamics and functionality of the virus-specific memory CD8 TCR repertoire before... | In this study we examined the diversity and dynamics of the repertoire of receptors of CD8 T cells that are selected and enriched upon real-life multiple exposures to viral infections. Using hepatitis C virus (HCV) infection in a cohort of high risk people who inject drugs, we demonstrate that protection upon two subse... | The capacity of CD8 T cells to recognize and respond to various pathogen-derived antigens is dictated by the diversity of their T cell receptor (TCR) repertoire. The TCR is a heterodimer of two chains, α and β, that comprise constant and variable regions. The most variable region in both chains is generated by somatic ... |
10.1371/journal.pntd.0006433 | Entomopathogenic fungal infection leads to temporospatial modulation of the mosquito immune system | Alternative methods of mosquito control are needed to tackle the rising burden of mosquito-borne diseases while minimizing the use of synthetic insecticides, which are threatened by the rapid increase in insecticide resistance in mosquito populations. Fungal biopesticides show great promise as potential alternatives be... | Fungal biopesticides constitute potential alternative methods of vector control to tackle the rising burden of mosquito-borne diseases and the development of insecticide resistance in mosquitoes. Insect-fungi interactions represent an intricate co-evolutionary arms race between the invading pathogen and its arthropod h... | The global increase in new and re-emergent vector-borne diseases has put into perspective once more the need for effective methods of vector control. Although insecticide-based interventions to manage mosquito populations remain important components of vector control programs, the use of biological control agents, such... |
10.1371/journal.pcbi.1002435 | Hemodynamic Traveling Waves in Human Visual Cortex | Functional MRI (fMRI) experiments rely on precise characterization of the blood oxygen level dependent (BOLD) signal. As the spatial resolution of fMRI reaches the sub-millimeter range, the need for quantitative modelling of spatiotemporal properties of this hemodynamic signal has become pressing. Here, we find that a ... | Functional magnetic resonance imaging (fMRI) experiments have advanced our understanding of the structure and function of the human brain. Dynamic changes in the flow and concentration of oxygen in blood are observed experimentally in fMRI data via the blood oxygen level dependent (BOLD) signal. Since neuronal activity... | Functional magnetic resonance imaging (fMRI) experiments have substantially advanced our understanding of the structure and function of the human brain [1]. Hemodynamic responses to neuronal activity are observed experimentally in fMRI data via the blood oxygenation dependent (BOLD) signal, which provides a noninvasive... |
10.1371/journal.pgen.1006700 | Probing the canonicity of the Wnt/Wingless signaling pathway | The hallmark of canonical Wnt signaling is the transcriptional induction of Wnt target genes by the beta-catenin/TCF complex. Several studies have proposed alternative interaction partners for beta-catenin or TCF, but the relevance of potential bifurcations in the distal Wnt pathway remains unclear. Here we study on a ... | Our manuscript addresses the question of whether either of the canonical transduction components, beta-catenin or TCF, can be bypassed when the Wnt pathway is activated. By using somatic cell genetics in Drosophila cells (via CRISPR/Cas9 editing) in combination with RNA-seq and STARR-seq (Self-transcribing-active-regul... | Wnt proteins are highly conserved signaling molecules specifying the fate and behavior of cells in multicellular animals ranging from nematodes to humans [1]. They play crucial roles in embryogenesis, pattern formation and tissue homeostasis during development and in adult life. Therefore it is not surprising that aber... |
10.1371/journal.pbio.2006422 | Neural timing of stimulus events with microsecond precision | Temporal analysis of sound is fundamental to auditory processing throughout the animal kingdom. Echolocating bats are powerful models for investigating the underlying mechanisms of auditory temporal processing, as they show microsecond precision in discriminating the timing of acoustic events. However, the neural basis... | We routinely rely on a stopwatch to precisely measure the time it takes for an athlete to reach the finish line. Without the assistance of such a timing device, our measurement of elapsed time becomes imprecise. By contrast, some animals, such as echolocating bats, naturally perform timing tasks with remarkable precisi... | Diverse groups of animals, such as electric fish, owls, and echolocating bats show remarkable temporal precision in the processing of sensory events. Specifically, weakly electric fish can detect a stimulus time disparity on the order of 0.4–1 μs [1,2], barn owls can distinguish an interaural time difference of approxi... |
10.1371/journal.pbio.2005130 | High-dimensional single-cell phenotyping reveals extensive haploinsufficiency | Haploinsufficiency, a dominant phenotype caused by a heterozygous loss-of-function mutation, has been rarely observed. However, high-dimensional single-cell phenotyping of yeast morphological characteristics revealed haploinsufficiency phenotypes for more than half of 1,112 essential genes under optimal growth conditio... | Diploid organisms harboring a wild-type gene and a loss-of-function mutation are called heterozygotes. They are expected to have weak or no individual phenotypes because the mutation is compensated for by the intact allele. The dominant inheritance of phenotypes in heterozygotes is an exceptional phenomenon called hapl... | The concepts of dominance and recessiveness were originally formulated by Gregor Mendel [1] and are still fundamental to modern genetics. Loss-of-function mutations are mostly recessive and rarely dominant in diploid organisms. Haploinsufficiency is a rare manifestation of the dominant phenotype arising from a copy of ... |
10.1371/journal.pcbi.1003475 | Escherichia coli Peptidoglycan Structure and Mechanics as Predicted by Atomic-Scale Simulations | Bacteria face the challenging requirement to maintain their shape and avoid rupture due to the high internal turgor pressure, but simultaneously permit the import and export of nutrients, chemical signals, and virulence factors. The bacterial cell wall, a mesh-like structure composed of cross-linked strands of peptidog... | The structure of the bacterial cell wall has been a point of controversy and contention since it was first discovered. Although the basic chemical composition of peptidoglycan, the key constituent of the cell wall, is now well established, its long-range organization is not. This dearth of information at the mesoscopic... | The cell wall rests outside the cytoplasmic membrane and provides bacteria with shape, rigidity, and protection from lysis due to the significant turgor pressure emanating from within [1]. It is primarily composed of a porous, mesh-like network of polymerized peptidoglycan, a repeating disaccharide/oligopeptide molecul... |
10.1371/journal.pgen.1004280 | Isl1 Directly Controls a Cholinergic Neuronal Identity in the Developing Forebrain and Spinal Cord by Forming Cell Type-Specific Complexes | The establishment of correct neurotransmitter characteristics is an essential step of neuronal fate specification in CNS development. However, very little is known about how a battery of genes involved in the determination of a specific type of chemical-driven neurotransmission is coordinately regulated during vertebra... | Neurons utilize various chemicals to transmit signals to a target cell. Distinct types of neurons in the spinal cord and forebrain, collectively termed cholinergic neurons, utilize the same chemical, acetylcholine, for signal transmission. These neurons play critical roles in controlling locomotion and cognition. In th... | The choice of neurotransmitter is one of the most fundamental aspects of neuronal fate decision. Cholinergic neurons are located in diverse regions of the CNS, which do not share the developmental origin, and regulate complex behaviors. In the spinal cord, cholinergic motor neurons (MNs) control locomotion, whereas in ... |
10.1371/journal.pcbi.1000238 | Formation and Growth of Oligomers: A Monte Carlo Study of an Amyloid Tau Fragment | Small oligomers formed early in the process of amyloid fibril formation may be the major toxic species in Alzheimer's disease. We investigate the early stages of amyloid aggregation for the tau fragment AcPHF6 (Ac-VQIVYK-NH2) using an implicit solvent all-atom model and extensive Monte Carlo simulations of 12, 24, and ... | It is believed that the self association of certain protein molecules into aggregated structures, known as amyloid fibrils, plays an important role in a variety of human diseases, such as Alzheimer's disease and Parkinson's disease. Although the ability to form such amyloid fibrils is a common property for proteins, th... | A century ago, Alois Alzheimer reported dense extracellular deposits and intracellular neuronal aggregates in the brain of a patient suffering from memory loss, focal symptoms, delusions, and hallucinations [1]. The extracellular deposits have been subsequently identified as amyloid plaques composed of an accumulation ... |
10.1371/journal.ppat.1000658 | Potential Benefits of Sequential Inhibitor-Mutagen Treatments of RNA Virus Infections | Lethal mutagenesis is an antiviral strategy consisting of virus extinction associated with enhanced mutagenesis. The use of non-mutagenic antiviral inhibitors has faced the problem of selection of inhibitor-resistant virus mutants. Quasispecies dynamics predicts, and clinical results have confirmed, that combination th... | RNA viruses are associated with many important human and animal diseases such as AIDS, influenza, hemorrhagic fevers and several forms of hepatitis. RNA viruses mutate at very high rates and, therefore, can adapt easily to environmental changes. Viral mutants resistant to antiviral inhibitors are readily selected, resu... | The capacity of rapidly multiplying parasites to adapt to the changing environment of their host organisms is a formidable obstacle for the control of the diseases they bring about, and an unsolved problem in medical and veterinary practice. RNA viruses are remarkably adaptable due to their elevated mutation rates and ... |
10.1371/journal.pgen.1002964 | UTX and UTY Demonstrate Histone Demethylase-Independent Function in Mouse Embryonic Development | UTX (KDM6A) and UTY are homologous X and Y chromosome members of the Histone H3 Lysine 27 (H3K27) demethylase gene family. UTX can demethylate H3K27; however, in vitro assays suggest that human UTY has lost enzymatic activity due to sequence divergence. We produced mouse mutations in both Utx and Uty. Homozygous Utx mu... | Trimethylation at Lysine 27 of histone H3 (H3K27me3) establishes a repressive chromatin state in silencing an array of crucial developmental genes. Polycomb repressive complex 2 (PRC2) catalyzes this precise posttranslational modification and is required in several critical aspects of development including Hox gene rep... | Post-translational modifications of histones establish and maintain active or repressive chromatin states throughout cell lineages. Thus, the enzymes that catalyze these modifications often have crucial roles in establishing genomic transcriptional states in developmental decision-making. Histone methylation can stimul... |
10.1371/journal.pntd.0005007 | Predictors of Post-operative Mycetoma Recurrence Using Machine-Learning Algorithms: The Mycetoma Research Center Experience | Post-operative recurrence in mycetoma after adequate medical and surgical treatment is common and a serious problem. It has health, socio-economic and psychological detrimental effects on patients and families. It is with this in mind, we set out to determine the predictors of post-operative recurrence in mycetoma. The... | Post-operative recurrence in mycetoma is a thoughtful problem. It has numerous undesirable medical, health, socio-economic and psychological impacts on the affected patients and their families, communities and health authorities in endemic regions. It is an important motive for patients to drop out follow up and treatm... | Eumycetoma is a chronic granulomatous destructive and mutilating subcutaneous fungal infection [1, 2]. The disease is endemic in many tropical and subtropical regions in what is known as the Mycetoma Belt [3, 4]. It has many medical, health, socio-economic detrimental bearings on the affected patients and communities [... |
10.1371/journal.pbio.1001968 | The Chromatin Assembly Factor 1 Promotes Rad51-Dependent Template Switches at Replication Forks by Counteracting D-Loop Disassembly by the RecQ-Type Helicase Rqh1 | At blocked replication forks, homologous recombination mediates the nascent strands to switch template in order to ensure replication restart, but faulty template switches underlie genome rearrangements in cancer cells and genomic disorders. Recombination occurs within DNA packaged into chromatin that must first be rel... | Obstacles to the progression of DNA replication forks can result in genome rearrangements that are often observed in cancer cells and genomic disorders. Homologous recombination is a mechanism of restarting stalled replication fork that involves synthesis of the new DNA strands switching templates to a second (allelic)... | The maintenance of genome stability requires a complex network to coordinate multiple pathways, including DNA replication, repair, and recombination in a chromatin context. Replication stress, including obstacles to replication fork progression, has emerged as a major source of genome instability that fuels cancer deve... |
10.1371/journal.pntd.0007722 | Prevalence and environmental determinants of cutaneous leishmaniasis in rural communities in Tigray, northern Ethiopia | In Ethiopia guidelines for diagnoses and treatment of leishmaniases are available, but only a few hundred people are diagnosed and receive treatment. A field study has been carried out to determine the status and environmental determinants of cutaneous leishmaniasis (CL) and assess the degree of awareness of the rural ... | Cutaneous leishmaniasis (CL) is a skin infection, transmitted by sandflies. It is most common in Ethiopia, but so far only a few hundred people have received treatment. Five rural villages in Tigray Region, in the north of Ethiopia, were visited to assess the status and determinants of CL. In a door-to-door survey 9,62... | Ethiopia is among the 98 leishmaniasis endemic countries of the world with both the visceral and cutaneous forms prevalent in the country [1]. An estimated 0.2 to 0.4 million visceral leishmaniasis (VL) cases and 0.7 to 1.2 million cutaneous leishmaniasis (CL) cases occur each year globally [2].CL due to Leishmania aet... |
10.1371/journal.pgen.1004951 | Modeling of the Human Alveolar Rhabdomyosarcoma Pax3-Foxo1 Chromosome Translocation in Mouse Myoblasts Using CRISPR-Cas9 Nuclease | Many recurrent chromosome translocations in cancer result in the generation of fusion genes that are directly implicated in the tumorigenic process. Precise modeling of the effects of cancer fusion genes in mice has been inaccurate, as constructs of fusion genes often completely or partially lack the correct regulatory... | Many cancers carry recurrent chromosome translocations, which often result in the formation of fusion genes that are directly involved in the tumorigenic process. Alveolar rhabdomyosarcoma, a muscle tumor in children, is typified by a translocation that fuses the PAX3 gene on chromosome 2 to the FOXO1 gene on chromosom... | Rhabdomyosarcoma (RMS) is the third most common soft-tissue sarcoma in children with an annual incidence of five new cases per million. It accounts for 5–8% of all pediatric cancer. RMS belongs to the family of small round blue cell tumors of childhood and exhibits histological features of skeletal muscle. Two major hi... |
10.1371/journal.pntd.0007229 | Culex species diversity, susceptibility to insecticides and role as potential vector of Lymphatic filariasis in the city of Yaoundé, Cameroon | Culex species are widespread across Cameroon and responsible for high burden of nuisance in most urban settings. However, despite their high nuisance, they remain less studied compared to anophelines. The present study aimed to assess Culex species distribution, susceptibility to insecticide, bionomics and role in Lymp... | Culex species are highly prevalent in both urban and rural settings in Cameroon and are responsible for high nuisance and transmission of pathogens such as Wuchereria bancrofti and arbovirus. Despite the important epidemiological role, that Culex could play, they are still less studied. The current study was conducted ... | Culex species are the most widespread mosquito species across the world [1]. They are known to be highly opportunistic feeding on both humans and animals, a behaviour which increases their potential to transmit zoonotic diseases and makes them important threat to public health [2]. Culex have over decades adapted to hu... |
10.1371/journal.pmed.1002081 | Duration of Adulthood Overweight, Obesity, and Cancer Risk in the Women’s Health Initiative: A Longitudinal Study from the United States | High body mass index (BMI) has become the leading risk factor of disease burden in high-income countries. While recent studies have suggested that the risk of cancer related to obesity is mediated by time, insights into the dose-response relationship and the cumulative impact of overweight and obesity during the life c... | Excess weight has become the leading risk factor for disease burden in high-income countries and has been offsetting or surpassing the decreasing disease burden attributable to tobacco smoking. Excess weight has been linked to the development of several types of cancer.
To date, most studies exploring the relationship ... | High body mass index (BMI) has become the leading risk factor for disease burden in high-income countries and has been offsetting or surpassing the decreasing disease burden attributable to tobacco smoking [1]. In the US, currently about 70% of all adults are considered overweight (BMI ≥ 25 kg/m2) and 36% obese (BMI ≥ ... |
10.1371/journal.ppat.1001307 | Human Macrophage Responses to Clinical Isolates from the Mycobacterium tuberculosis Complex Discriminate between Ancient and Modern Lineages | The aim of the present study was to determine whether there is a correlation between phylogenetic relationship and inflammatory response amongst a panel of clinical isolates representative of the global diversity of the human Mycobacterium tuberculosis Complex (MTBC). Measurement of cytokines from infected human periph... | Mycobacterium tuberculosis is a long-standing human pathogen spread by aerosol transmission between individuals interacting in close social groups. It can be anticipated that the evolution of M. tuberculosis will parallel the evolution of human societies, and the phylogeny as determined by whole genome sequencing of cl... | High-throughput sequence analysis has allowed reconstruction of the evolution of human Mycobacterium tuberculosis Complex (MTBC), differentiating the bacteria into six main phylogenetic lineages [1], [2]. Three lineages, including two whose members are known as M. africanum [3], which branched off from a common ancesto... |
10.1371/journal.ppat.1006075 | Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility | Many natural prion diseases of humans and animals are considered to be acquired through oral consumption of contaminated food or pasture. Determining the route by which prions establish host infection will identify the important factors that influence oral prion disease susceptibility and to which intervention strategi... | Prion diseases are infectious neurodegenerative disorders that affect humans and animals. Many natural prion diseases are orally acquired through consumption of contaminated food or pasture. An understanding of how prions infect the intestine will help identify factors that influence disease susceptibility and allow th... | Prion diseases (transmissible spongiform encephalopathies) are a unique group of subacute neurodegenerative diseases that affect humans and animals. During prion disease, aggregations of PrPSc, an abnormally folded isoform of cellular PrP (PrPC), accumulate in affected tissues. Prion infectivity co-purifies with PrPSc ... |
10.1371/journal.pcbi.1002408 | Impact of Network Structure and Cellular Response on Spike Time Correlations | Novel experimental techniques reveal the simultaneous activity of larger and larger numbers of neurons. As a result there is increasing interest in the structure of cooperative – or correlated – activity in neural populations, and in the possible impact of such correlations on the neural code. A fundamental theoretical... | Is neural activity more than the sum of its individual parts? What is the impact of cooperative, or correlated, spiking among multiple cells? We can start addressing these questions, as rapid advances in experimental techniques allow simultaneous recordings from ever-increasing populations. However, we still lack a gen... | New multielectrode and imaging techniques are revealing the simultaneous activity of neural ensembles and, in some cases, entire neural populations [1]–[4]. This has thrust upon the computational biology community the challenge of characterizing a potentially complex set of interactions – or correlations – among pairs ... |
10.1371/journal.ppat.1000237 | The Chromatin Remodeler SPLAYED Regulates Specific Stress Signaling Pathways | Organisms are continuously exposed to a myriad of environmental stresses. Central to an organism's survival is the ability to mount a robust transcriptional response to the imposed stress. An emerging mechanism of transcriptional control involves dynamic changes in chromatin structure. Alterations in chromatin structur... | In eukaryotes, genomic DNA is organized into a complex DNA-protein structure termed chromatin. The organization of chromatin serves to compact DNA within the nucleus and plays a central role in regulating transcription by controlling the access of DNA to transcriptional machinery. Chromatin structure can be altered thr... | In eukaryotic organisms genomic DNA is packaged into chromatin, which can repress transcription by blocking the access of regulatory proteins to DNA. Dynamic changes in chromatin structure are now recognized as a robust mechanism of transcriptional control [1]–[3]. Changes in chromatin structure are brought about by a ... |
10.1371/journal.ppat.1006467 | Septins restrict inflammation and protect zebrafish larvae from Shigella infection | Shigella flexneri, a Gram-negative enteroinvasive pathogen, causes inflammatory destruction of the human intestinal epithelium. Infection by S. flexneri has been well-studied in vitro and is a paradigm for bacterial interactions with the host immune system. Recent work has revealed that components of the cytoskeleton h... | Shigella are human-adapted Escherichia coli and cause bacillary dysentery via inflammatory destruction of the gut epithelium. In this study, we use a zebrafish (Danio rerio) model of Shigella infection to discover new roles for the cytoskeleton in inflammation and infection control. Septins, a poorly understood compone... | Septins, a poorly understood component of the cytoskeleton, are highly-conserved guanosine triphosphate (GTP) binding proteins organized into 4 groups based on sequence homology (the SEPT2, SEPT3, SEPT6, and SEPT7 groups). Septins from different groups assemble into hetero-oligomeric complexes which can form non-polar ... |
10.1371/journal.pcbi.1000722 | Investigating Homology between Proteins using Energetic Profiles | Accumulated experimental observations demonstrate that protein stability is often preserved upon conservative point mutation. In contrast, less is known about the effects of large sequence or structure changes on the stability of a particular fold. Almost completely unknown is the degree to which stability of different... | Protein structure and function are fundamentally determined by thermodynamics. However, for technical as well as historical reasons, current evolutionary classification schemes and bioinformatics tools do not fully utilize thermodynamic information to describe or analyze proteins. In this work, we address this deficien... | Protein structure and function are ultimately determined by thermodynamics. For example, Anfinsen's seminal work [1] demonstrated that the native state of a protein exists at a minimum in Gibbs free energy of stability under physiological conditions. Binding and catalysis are also governed by free energy: the sign and ... |
10.1371/journal.pntd.0006760 | Transcriptomic and functional analyses of the piRNA pathway in the Chagas disease vector Rhodnius prolixus | The piRNA pathway is a surveillance system that guarantees oogenesis and adult fertility in a range of animal species. The pathway is centered on PIWI clade Argonaute proteins and the associated small non-coding RNAs termed piRNAs. In this study, we set to investigate the evolutionary conservation of the piRNA pathway ... | Rhodnius prolixus together with other blood-feeding bugs of the Triatominae family are primary vectors of the protozoan Trypanosoma cruzi, the causative agent of the Chagas disease. It has been estimated that 7–8 million people are affected by this life-threatening illness worldwide, which makes the Chagas disease one ... | PIWI-clade Argonaute proteins have been implicated in a range of cellular and developmental events by regulating gene expression and imposing transposon silencing [1–3]. These proteins appear to be particularly critical for the maintenance of genomic stability during gametogenesis in a range of animal species including... |
10.1371/journal.pcbi.1004355 | Reconciling Estimates of Cell Proliferation from Stable Isotope Labeling Experiments | Stable isotope labeling is the state of the art technique for in vivo quantification of lymphocyte kinetics in humans. It has been central to a number of seminal studies, particularly in the context of HIV-1 and leukemia. However, there is a significant discrepancy between lymphocyte proliferation rates estimated in di... | Stable isotope labeling is used to quantify the rate at which living cells proliferate and die in humans. It has been central to a number of seminal studies, particularly in viral infections such as HIV-1, and leukemia. However, different labels (deuterated water or deuterated glucose) yield different estimates for the... | Quantification of lymphocyte kinetics is vital for our understanding of immune cell dynamics in health and disease. The development [1,2] of stable isotope labeling techniques, using either deuterium labeled glucose (D2-glucose) or deuterium labeled water (D2O), has enabled the safe quantification of lymphocyte turnove... |
10.1371/journal.ppat.1004282 | Ly6Chi Monocyte Recruitment Is Responsible for Th2 Associated Host-Protective Macrophage Accumulation in Liver Inflammation due to Schistosomiasis | Accumulation of M2 macrophages in the liver, within the context of a strong Th2 response, is a hallmark of infection with the parasitic helminth, Schistosoma mansoni, but the origin of these cells is unclear. To explore this, we examined the relatedness of macrophages to monocytes in this setting. Our data show that bo... | Schistosomiasis is an important neglected tropical disease caused by parasitic worms of the genus Schistosoma. During infection with S. mansoni, parasite eggs become trapped in the liver and elicit granulomatous inflammation characterized by accumulations of immune cells intermixed with liver cells around the eggs. Thi... | Schistosomiasis is a complex multiorgan disease caused by infection with helminth parasites of the genus Schistosoma, and characterized by the development of granulomatous lesions around parasite eggs trapped within organs such as the liver and intestine. Granulomas are, by definition, macrophage-rich, but in schistoso... |
10.1371/journal.pgen.1003721 | Environmental Stresses Disrupt Telomere Length Homeostasis | Telomeres protect the chromosome ends from degradation and play crucial roles in cellular aging and disease. Recent studies have additionally found a correlation between psychological stress, telomere length, and health outcome in humans. However, studies have not yet explored the causal relationship between stress and... | Over 70 years ago, Barbara McClintock described telomeres and hypothesized about their role in protecting the integrity of chromosomes. Since then, scientists have shown that telomere length is highly regulated and associated with cell senescence and longevity, as well as with age-related disorders and cancer. Here, we... | Telomeres are nucleoprotein structures located at the ends of chromosomes. Telomeres are essential for chromosome replication and stability [1], and protect chromosome ends from degradation and deleterious chromosomal rearrangements [1], [2]. In human embryonic cells, telomeres are elongated by the enzyme telomerase [3... |
10.1371/journal.pntd.0004177 | Population Dynamics of Owned, Free-Roaming Dogs: Implications for Rabies Control | Rabies is a serious yet neglected public health threat in resource-limited communities in Africa, where the virus is maintained in populations of owned, free-roaming domestic dogs. Rabies elimination can be achieved through the mass vaccination of dogs, but maintaining the critical threshold of vaccination coverage for... | Rabies is a deadly disease caused by a virus that in Africa is maintained in populations of owned, free-roaming domestic dogs. Rabies can be controlled by mass vaccination, by ensuring that a certain proportion of the dog population is immune to the disease. Maintaining this proportion of immune animals creates herd im... | Rabies is a serious yet neglected public health threat in resource-limited communities in sub-Saharan Africa [1]. In these settings, the virus that causes this deadly disease is largely maintained in populations of free-roaming domestic dogs, and is transmitted to people through bites or other contact with the saliva o... |
10.1371/journal.pgen.1004328 | Epistatically Interacting Substitutions Are Enriched during Adaptive Protein Evolution | Most experimental studies of epistasis in evolution have focused on adaptive changes—but adaptation accounts for only a portion of total evolutionary change. Are the patterns of epistasis during adaptation representative of evolution more broadly? We address this question by examining a pair of protein homologs, of whi... | Mutations can fix during evolution for two reasons: they can be beneficial and fix for adaptive reasons, or they can be neutral or deleterious and fix solely by chance. Most studies focus on adaptation, where the evolving population is increasing in fitness due to a new selection pressure. Such studies have found an im... | Epistasis occurs when the effect of a change at one site in a genome depends on the presence or absence of a change at another site. Understanding epistasis is of profound importance in evolutionary biology, as epistasis can constrain evolutionary pathways and shape patterns of sequence change. As a result, epistasis h... |
10.1371/journal.ppat.1003585 | Viral Membrane Fusion and Nucleocapsid Delivery into the Cytoplasm are Distinct Events in Some Flaviviruses | Flaviviruses deliver their genome into the cell by fusing the viral lipid membrane to an endosomal membrane. The sequence and kinetics of the steps required for nucleocapsid delivery into the cytoplasm remain unclear. Here we dissect the cell entry pathway of virions and virus-like particles from two flaviviruses using... | Many viruses package their genetic material into a lipid envelope. In order to deliver their genome into the host-cell cytoplasm, where it can be replicated, viruses must fuse their envelope with a cellular lipid membrane. This fusion event is therefore a critical step in the entry of an enveloped virus into the cell. ... | Many enveloped RNA viruses utilize the endocytic pathway to enter host cells [1], [2]. Endocytosis begins at the cell membrane, where these viruses bind to their cellular receptors and ends at the lysosome, the “stomach” of the cell. Along the endocytic pathway, changes in the lipid composition and environmental pH pro... |
10.1371/journal.pntd.0003319 | Progress and Impact of 13 Years of the Global Programme to Eliminate Lymphatic Filariasis on Reducing the Burden of Filarial Disease | A Global Programme to Eliminate Lymphatic Filariasis was launched in 2000, with mass drug administration (MDA) as the core strategy of the programme. After completing 13 years of operations through 2012 and with MDA in place in 55 of 73 endemic countries, the impact of the MDA programme on microfilaraemia, hydrocele an... | The mass drug administration (MDA) programme to eliminate lymphatic filariasis (LF) was initiated in 2000. By the end of 2012, the programme was in place in 55 endemic countries. During these first 13 years (2000–2012) of programme implementation, 6.37 billion annual single dose anti-filarial treatments were offered an... | Lymphatic filariasis (LF) is a disease of the poor that is prevalent in 73 tropical and sub-tropical countries. LF is caused by three species of filarial worms – Wuchereria bancrofti, Brugia malayi and B. timori – and is transmitted by multiple species of mosquitoes. The disease is expressed in a variety of clinical ma... |
10.1371/journal.pgen.1003739 | Conserved Translatome Remodeling in Nematode Species Executing a Shared Developmental Transition | Nematodes of the genus Caenorhabditis enter a developmental diapause state after hatching in the absence of food. To better understand the relative contributions of distinct regulatory modalities to gene expression changes associated with this developmental transition, we characterized genome-wide changes in mRNA abund... | Working with a set of four related animal species, we have studied a conserved developmental and metabolic transition at the level of protein production and regulation of RNA levels. Strikingly, regulatory effects at the level of RNA accumulation and protein synthesis act together to achieve the observed metabolic shif... | Animals of diverse genera react to unfavorable growth conditions by entering developmentally arrested states known as diapause [1], [2]. Nematodes of the genus Caenorhabditis can enter and exit diapause at several developmental time points, allowing populations to reproduce through boom and bust cycles of nutrient avai... |
10.1371/journal.pntd.0006454 | Adverse events following single dose treatment of lymphatic filariasis: Observations from a review of the literature | WHO’s Global Programme to Eliminate Lymphatic Filariasis (LF) uses mass drug administration (MDA) of anthelmintic medications to interrupt LF transmission in endemic areas. Recently, a single dose combination of ivermectin (IVM), diethylcarbamazine (DEC), and albendazole (ALB) was shown to be markedly more effective th... | WHO’s Global Programme to Eliminate Lymphatic Filariais (LF) supports annual mass drug administration to over 400 million people in LF-endemic areas each year. Two drug combinations (either DEC or ivermectin, given with albendazole) have been recommended in most endemic areas. With the exception of well-described serio... | Infection with the filarial nematode parasites Wuchereria bancrofti, Brugia malayi, or Brugia timori is known as lymphatic filariasis (LF). These infections cause severe, disabling conditions including lymphedema, elephantiasis, and hydroceles in tens of millions of people in tropical and subtropical countries. Annual ... |
10.1371/journal.pcbi.1005932 | Bayesian inference of phylogenetic networks from bi-allelic genetic markers | Phylogenetic networks are rooted, directed, acyclic graphs that model reticulate evolutionary histories. Recently, statistical methods were devised for inferring such networks from either gene tree estimates or the sequence alignments of multiple unlinked loci. Bi-allelic markers, most notably single nucleotide polymor... | The availability of genomic data has revolutionized the study of evolutionary histories and phylogeny inference. Inferring evolutionary histories from genomic data requires, in most cases, accounting for the fact that different genomic regions could have evolutionary histories that differ from each other as well as fro... | The availability of genome-wide data from many species and, in some cases, many individuals per species, has transformed the study of evolutionary histories, and given rise to phylogenomics—the inference of gene and species evolutionary histories from genome-wide data. Consider a data set S = {S1, …, Sm} consisting of ... |
10.1371/journal.pgen.1006343 | No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study | It is well known that inbreeding increases the risk of recessive monogenic diseases, but it is less certain whether it contributes to the etiology of complex diseases such as schizophrenia. One way to estimate the effects of inbreeding is to examine the association between disease diagnosis and genome-wide autozygosity... | It is well known that mating between relatives increases the risk that a child will have a rare recessive genetic disease, but there has also been increasing interest and inconsistent findings on whether inbreeding is a risk factor for common, complex psychiatric disorders such as schizophrenia. The best powered study ... | Close inbreeding (e.g., cousin-cousin mating) is known to decrease fitness in animals[1] and to increase risk for recessive Mendelian diseases in humans[2], a phenomenon known as inbreeding depression. Inbreeding depression is thought to occur due to evolutionary selection against genetic variants that decrease fitness... |
10.1371/journal.pcbi.1005591 | Solving the influence maximization problem reveals regulatory organization of the yeast cell cycle | The Influence Maximization Problem (IMP) aims to discover the set of nodes with the greatest influence on network dynamics. The problem has previously been applied in epidemiology and social network analysis. Here, we demonstrate the application to cell cycle regulatory network analysis for Saccharomyces cerevisiae. Fu... | The Influence Maximization Problem (IMP) has been applied in fields such as epidemiology and social network analysis. Here, we apply the method to biological networks, aiming to discover the set of regulatory genes with the greatest influence on network dynamics. Fundamentally, since gene regulation is linked to the fl... | In order to respond to messages and environmental changes, cells dynamically process information arriving from cell surface receptors [1,2]. Information is transferred, stored, and processed in the cell via molecular mechanisms, often triggering a response in the regulatory program. These types of dynamic genetic regul... |
10.1371/journal.pcbi.1003805 | Spatial Heterogeneity and Peptide Availability Determine CTL Killing Efficiency In Vivo | The rate at which a cytotoxic T lymphocyte (CTL) can survey for infected cells is a key ingredient of models of vertebrate immune responses to intracellular pathogens. Estimates have been obtained using in vivo cytotoxicity assays in which peptide-pulsed splenocytes are killed by CTL in the spleens of immunised mice. H... | Measurements of the rates at which a single cytotoxic T lymphocyte (CTL) can survey for infected cells, and kill them upon encounter, are important for constructing predictive models of vertebrate immune responses to intracellular pathogens. The surveillance rate has been estimated previously using combinations of mode... | Cytotoxic T lymphocytes (CTL) prevent the spread of intracellular pathogens through T cell receptor (TCR) recognition of pathogen-derived peptides presented on MHC class I molecules on the surface of infected cells. CTL may have several modes of action but their canonically understood role is to kill cells recognised a... |
10.1371/journal.pgen.1000751 | Dosage Regulation of the Active X Chromosome in Human Triploid Cells | In mammals, dosage compensation is achieved by doubling expression of X-linked genes in both sexes, together with X inactivation in females. Up-regulation of the active X chromosome may be controlled by DNA sequence–based and/or epigenetic mechanisms that double the X output potentially in response to autosomal factor(... | Many organisms have a single X chromosome in males and two in females, leading to a chromosome imbalance between autosomes and sex chromosomes and between the sexes. In mammals, this dosage imbalance is adjusted by doubling expression of X-linked genes in both sexes and by silencing one X chromosome in females. We used... | Dosage compensation restores a balanced network of gene expression between autosomes and sex chromosomes in males (XY) and females (XX) [1]. Strategies to achieve this vary among species [2]. In Drosophila, a male-specific ribonucleoprotein complex binds to the X chromosome and modifies chromatin structure to increase ... |
10.1371/journal.pntd.0005166 | A Phosphorylcholine-Containing Glycolipid-like Antigen Present on the Surface of Infective Stage Larvae of Ascaris spp. Is a Major Antibody Target in Infected Pigs and Humans | The pig parasite Ascaris suum plays and important role in veterinary medicine and represents a suitable model for A. lumbricoides, which infects over 800 million people. In pigs, continued exposure to Ascaris induces immunity at the level of the gut, protecting the host against migrating larvae. The objective of this s... | Roundworms infect millions of humans and pigs throughout the world. The pig roundworm A. suum is a good model for A. lumbricoides infection in humans due to similar host physiology and the close genetic relationship between the worms. The aim of this study was to identify and characterize early larval antigens that are... | Ascaris lumbricoides is the most prevalent intestinal parasitic nematode of man, infecting approximately 819 million people worldwide in developing countries [1]. Due to the high degree of morphological and genetic similarity, it is still debated as to whether A. lumbricoides from humans is a different species than A. ... |
10.1371/journal.ppat.1002924 | A Novel Rhabdovirus Associated with Acute Hemorrhagic Fever in Central Africa | Deep sequencing was used to discover a novel rhabdovirus (Bas-Congo virus, or BASV) associated with a 2009 outbreak of 3 human cases of acute hemorrhagic fever in Mangala village, Democratic Republic of Congo (DRC), Africa. The cases, presenting over a 3-week period, were characterized by abrupt disease onset, high fev... | We used deep sequencing, a method for generating millions of DNA sequence reads from clinical samples, to discover a novel rhabdovirus (Bas-Congo virus, or BASV) associated with a 2009 outbreak of 3 human cases of acute hemorrhagic fever in Mangala village, Democratic Republic of Congo (DRC), Africa. The cases, present... | Viral hemorrhagic fever (VHF) encompasses a group of diseases characterized by fever, malaise, bleeding abnormalities, and circulatory shock [1], [2], [3]. Quality research on these infections is hindered by the fact that they are sporadic and often occur in geographically remote and politically unstable regions of the... |
10.1371/journal.pbio.2002623 | Transcriptome analysis of hypoxic cancer cells uncovers intron retention in EIF2B5 as a mechanism to inhibit translation | Cells adjust to hypoxic stress within the tumor microenvironment by downregulating energy-consuming processes including translation. To delineate mechanisms of cellular adaptation to hypoxia, we performed RNA-Seq of normoxic and hypoxic head and neck cancer cells. These data revealed a significant down regulation of ge... | Tumor hypoxia is a negative prognostic factor for many solid cancers. Cellular adaptation to hypoxia is largely mediated by widespread changes in gene expression and enables cancer cells to adjust and survive. Recently, alternative splicing has been implicated in this process. To identify biologically impactful hypoxia... | Reduced availability of oxygen, or hypoxia, is a major feature of solid tumors that contributes to metastasis and resistance to therapy [1]. Tumor hypoxia occurs due to several physiological factors, such as limited diffusion of oxygen and irregular vascular structure [2]. While oxygen levels can be measured directly i... |
10.1371/journal.pgen.1004828 | Epigenome-Guided Analysis of the Transcriptome of Plaque Macrophages during Atherosclerosis Regression Reveals Activation of the Wnt Signaling Pathway | We report the first systems biology investigation of regulators controlling arterial plaque macrophage transcriptional changes in response to lipid lowering in vivo in two distinct mouse models of atherosclerosis regression. Transcriptome measurements from plaque macrophages from the Reversa mouse were integrated with ... | Atherosclerosis, a progressive accumulation of lipid-rich plaque within arteries, is an inflammatory disease in which the response of macrophages (a key cell type of the innate immune system) to plasma lipoproteins plays a central role. In humans, the goal of significantly reducing already-established plaque through dr... | Underlying many cardiovascular diseases is atherosclerosis, an arterial accumulation of lipid-laden macrophages (foam cells) with attendant chronic inflammation [1]. Atherosclerosis is endemic in adults [2] and can progress over decades before presenting with overt symptoms [3]. Atherosclerosis is correlated with risk ... |
10.1371/journal.pbio.0050132 | Distinct Functions for Different scl Isoforms in Zebrafish Primitive and Definitive Hematopoiesis | The stem-cell leukemia (SCL, also known as TAL1) gene encodes a basic helix-loop-helix transcription factor that is essential for the initiation of primitive and definitive hematopoiesis, erythrocyte and megakarocyte differentiation, angiogenesis, and astrocyte development. Here we report that the zebrafish produces, t... | Hematopoiesis is the process that generates all the body's blood cells. In vertebrates, hematopoietic development occurs in two phases: a transitory embryonic, or primitive, wave produces only erythrocytes (red blood cells) and myeloid cells; an adult, or definitive, wave gives rise to at least three blood cell lineage... | On the basis of anatomic locations of development, time of initiation, and cell type produced, vertebrate hematopoiesis can be divided into primitive and definitive programs [1–3]. In mouse, the primitive, or first, wave of hematopoiesis initiates in the yolk sac at about embryonic day 7.5 and produces primarily nuclea... |
10.1371/journal.pgen.1006176 | Multiple Rad52-Mediated Homology-Directed Repair Mechanisms Are Required to Prevent Telomere Attrition-Induced Senescence in Saccharomyces cerevisiae | Most human somatic cells express insufficient levels of telomerase, which can result in telomere shortening and eventually senescence, both of which are hallmarks of ageing. Homology-directed repair (HDR) is important for maintaining proper telomere function in yeast and mammals. In Saccharomyces cerevisiae, Rad52 is r... | Telomeres are essential structures located at the ends of chromosomes. The canonical DNA replication machinery is unable to fully replicate DNA at chromosome ends, causing telomeres to shorten with every round of cell division. This shortening can be counteracted by an enzyme called telomerase, but in most human somati... | Telomeres, nucleoprotein structures located at the ends of linear chromosomes, prevent natural chromosome ends from being recognized as DNA double-strand breaks (DSBs) [1]. Due to incomplete DNA replication and nucleolytic degradation, telomeres shorten with each round of replication, which can eventually lead to a gro... |
10.1371/journal.pntd.0002098 | Repeated Schistosoma japonicum Infection Following Treatment in Two Cohorts: Evidence for Host Susceptibility to Helminthiasis? | In light of multinational efforts to reduce helminthiasis, we evaluated whether there exist high-risk subpopulations for helminth infection. Such individuals are not only at risk of morbidity, but may be important parasite reservoirs and appropriate targets for disease control interventions.
We followed two longitudina... | Approximately 1 billion people are infected with one or more helminthes – a class of parasites that can impair physical, mental and economic development. We are interested in whether there exist groups who are repeatedly infected with helminthes over time in areas where treatment is ongoing. Such individuals may be at ... | Recent multinational efforts to control and eliminate helminthiasis have the potential to dramatically reduce morbidity among the rural poor [1], [2]. Approximately one billion people are infected with one or more helminthes and the health impacts of these infections, including impaired growth, cognitive development an... |
10.1371/journal.pntd.0002381 | Metabonomics Reveals Drastic Changes in Anti-Inflammatory/Pro-Resolving Polyunsaturated Fatty Acids-Derived Lipid Mediators in Leprosy Disease | Despite considerable efforts over the last decades, our understanding of leprosy pathogenesis remains limited. The complex interplay between pathogens and hosts has profound effects on host metabolism. To explore the metabolic perturbations associated with leprosy, we analyzed the serum metabolome of leprosy patients. ... | Leprosy is caused by a mycobacterium that has a predilection for the skin and nerve cells, and the disease is treated with a combination of antibiotics (multidrug therapy, MDT). Nerve damage caused by the infection may lead to permanent disabilities, and can happen even during MDT and subsequent to patient release. The... | Leprosy, a chronic infectious disease caused by the obligate intracellular bacterium Mycobacterium leprae, remains a major source of morbidity in developing countries [1]. The disease affects mainly the skin and the peripheral nervous system, in which the leprosy bacillus is preferentially found inside macrophages and ... |
10.1371/journal.pgen.1004826 | Genome-Wide Analysis of leafbladeless1-Regulated and Phased Small RNAs Underscores the Importance of the TAS3 ta-siRNA Pathway to Maize Development | Maize leafbladeless1 (lbl1) encodes a key component in the trans-acting short-interfering RNA (ta-siRNA) biogenesis pathway. Correlated with a great diversity in ta-siRNAs and the targets they regulate, the phenotypes conditioned by mutants perturbing this small RNA pathway vary extensively across species. Mutations in... | Mutations in maize leafbladeless1 (lbl1) that disrupt ta-siRNA biogenesis give rise to plants with thread-like leaves that have lost top/bottom polarity. We used genomic approaches to identify lbl1-dependent small RNAs and their targets to determine the basis for these polarity defects. This revealed substantial divers... | Small RNAs are important regulators of development, particularly in plants, where many of the abundant and conserved microRNAs (miRNAs) target transcription factors that direct or reinforce cell fate decisions [1]. Consequently, mutations in genes required for miRNA processing or function condition defined developmenta... |
10.1371/journal.pcbi.1000230 | Optimal Learning Rules for Discrete Synapses | There is evidence that biological synapses have a limited number of discrete weight states. Memory storage with such synapses behaves quite differently from synapses with unbounded, continuous weights, as old memories are automatically overwritten by new memories. Consequently, there has been substantial discussion abo... | It is believed that the neural basis of learning and memory is change in the strength of synaptic connections between neurons. Much theoretical work on this topic assumes that the strength, or weight, of a synapse may vary continuously and be unbounded. More recent studies have considered synapses that have a limited n... | Memory in biological neural systems is believed to be stored in the synaptic weights. Numerous computational models of such memory systems have been constructed in order to study their properties and to explore potential hardware implementations. Storage capacity and optimal learning rules have been studied both for si... |
10.1371/journal.pntd.0002670 | Deletion of the NSm Virulence Gene of Rift Valley Fever Virus Inhibits Virus Replication in and Dissemination from the Midgut of Aedes aegypti Mosquitoes | Previously, we investigated the role of the Rift Valley fever virus (RVFV) virulence genes NSs and NSm in mosquitoes and demonstrated that deletion of NSm significantly reduced the infection, dissemination, and transmission rates of RVFV in Aedes aegypti mosquitoes. The specific aim of this study was to further charact... | Rift Valley fever virus (RVFV) is a mosquito-borne virus endemic to Africa. Outbreaks of RVFV have resulted in devastating morbidity and mortality in livestock and humans. A novel RVFV vaccine strain has been developed in which two virulence genes, NSs and NSm, have been deleted from the RVFV genome. Previously, we dem... | Rift Valley fever virus (RVFV) (family Bunyaviridae, genus Phlebovirus) is a zoonotic, mosquito-borne virus endemic to Africa. Human illness is typically febrile, but 1–2% of cases develop more severe disease including hepatitis, encephalitis, retinitis, vision loss, jaundice, severe anemia, neurologic manifestations, ... |
10.1371/journal.pntd.0002148 | Antigenicity and Protective Efficacy of a Leishmania Amastigote-specific Protein, Member of the Super-oxygenase Family, against Visceral Leishmaniasis | The present study aimed to evaluate a hypothetical Leishmania amastigote-specific protein (LiHyp1), previously identified by an immunoproteomic approach performed in Leishmania infantum, which showed homology to the super-oxygenase gene family, attempting to select a new candidate antigen for specific serodiagnosis, as... | Life-long immunity to leishmaniasis in recovered patients has inspired the development of vaccines against disease. The present study aimed to evaluate a non-described hypothetical Leishmania amastigote-specific protein, identified by an immunoproteomic approach in L. infantum, attempting to select a new candidate anti... | Visceral leishmaniasis (VL) caused by Leishmania donovani and L. infantum/L. chagasi represents an important disease in the world, leading to nearly 500,000 new cases and 50,000 deaths annually. The first choice of treatment for all forms of leishmaniasis is still based on the use of the parenteral administration of pe... |
10.1371/journal.pgen.1004544 | Chromatin Insulator Factors Involved in Long-Range DNA Interactions and Their Role in the Folding of the Drosophila Genome | Chromatin insulators are genetic elements implicated in the organization of chromatin and the regulation of transcription. In Drosophila, different insulator types were characterized by their locus-specific composition of insulator proteins and co-factors. Insulators mediate specific long-range DNA contacts required fo... | Chromatin insulators mediate specific long-range DNA interactions required for the three dimensional organization of the interphase nucleus and for transcription regulation, but the mechanisms underlying the formation of these interactions is currently unknown. In this manuscript, we investigate the molecular associati... | The physical organization of eukaryotic chromosomes is key for a large number of cellular processes, including DNA replication, repair and transcription [1]–[6]. Chromatin insulators are genetic elements implicated in the organization of chromatin and the regulation of transcription by two independent modes of action: ... |
10.1371/journal.pgen.1005873 | A Novel Epigenetic Silencing Pathway Involving the Highly Conserved 5’-3’ Exoribonuclease Dhp1/Rat1/Xrn2 in Schizosaccharomyces pombe | Epigenetic gene silencing plays a critical role in regulating gene expression and contributes to organismal development and cell fate acquisition in eukaryotes. In fission yeast, Schizosaccharomyces pombe, heterochromatin-associated gene silencing is known to be mediated by RNA processing pathways including RNA interfe... | Epigenetic mechanisms regulate when, where, and how an organism uses the genetic information stored in its genome. They are essential to many cellular processes, such as the regulation of gene expression, genome organization, and cell-fate determination. They also govern growth, development, and ultimately human health... | In eukaryotic cells, DNA coils around histones to form nucleosomes, which are packaged into chromatin. Various post-translational modifications (PTMs) of histones, histone variants, and nucleosome remodeling factors confer distinct chromatin states on genes and facilitate the organization of large chromatin tracts into... |
10.1371/journal.pntd.0006393 | A novel immunotherapy of Brucellosis in cows monitored non invasively through a specific biomarker | Brucellosis is an important zoonotic disease causing huge economic losses worldwide. Currently no effective immunotherapy for Brucellosis or any biomarker to monitor the efficacy of therapy is available. Treatment is ineffective and animals remain carrier lifelong. S19 and RB51 are live attenuated vaccine strains of Br... | We report here a novel immunotherapy for cost effective and simple treatment of Brucellosis, a zoonotic disease of global importance. The two main novelties of this work which have important implications are the following: Plasma RNA (specific to Brucella abortus in this case) has been used as a biomarker for the first... | Brucellosis is a major re-emerging bacterial zoonosis of global importance affecting a range of different animal species and man worldwide and is of importance from economic and public health points of view. It remains an uncontrolled problem in regions of high endemicity such as Africa, the Mediterranean, Middle East,... |
10.1371/journal.ppat.1002294 | Biochemical and Structural Insights into the Mechanisms of SARS Coronavirus RNA Ribose 2′-O-Methylation by nsp16/nsp10 Protein Complex | The 5′-cap structure is a distinct feature of eukaryotic mRNAs, and eukaryotic viruses generally modify the 5′-end of viral RNAs to mimic cellular mRNA structure, which is important for RNA stability, protein translation and viral immune escape. SARS coronavirus (SARS-CoV) encodes two S-adenosyl-L-methionine (SAM)-depe... | The distinctive feature of eukaryotic mRNAs is the presence of methylated cap structure that is required for mRNA stability and protein translation. As all viruses employ cellular ribosomes for protein translation, most cytoplasmically replicating eukaryotic viruses including coronaviruses have evolved strategies to ca... | Coronaviruses are etiological agents of respiratory and enteric diseases in livestock, companion animals and humans, exemplified by severe acute respiratory syndrome coronavirus (SARS-CoV) which was responsible for a worldwide SARS outbreak in 2003 and caused over 8000 cases of infection with about 10% fatality rate. T... |
10.1371/journal.pgen.1008296 | SweC and SweD are essential co-factors of the FtsEX-CwlO cell wall hydrolase complex in Bacillus subtilis | The peptidoglycan (PG) sacculus is composed of long glycan strands cross-linked together by short peptides forming a covalently closed meshwork that protects the bacterial cell from osmotic lysis and specifies its shape. PG hydrolases play essential roles in remodeling this three-dimensional network during growth and d... | Bacterial growth and division require the synthesis and remodeling of the cell wall exoskeleton. To prevent lethal breaches in this protective layer, peptidoglycan (PG) hydrolases that remodel the cell wall must be carefully regulated but the mechanisms underlying this control remain poorly understood. The noncanonical... | Most bacteria are encased within a cell wall exoskeleton composed of the heteropolymer peptidoglycan (PG). This macromolecule is assembled from long glycan strands cross-linked together by attached peptides, generating a continuous three-dimensional meshwork that encapsulates the cytoplasmic membrane, specifies cell sh... |
10.1371/journal.pcbi.1005153 | Structural Identifiability of Dynamic Systems Biology Models | A powerful way of gaining insight into biological systems is by creating a nonlinear differential equation model, which usually contains many unknown parameters. Such a model is called structurally identifiable if it is possible to determine the values of its parameters from measurements of the model outputs. Structura... | Advances in computing power have facilitated the development of increasingly larger dynamic models of biological processes, which usually have many unknown parameters. Often times, such models contain parameters that are structurally unidentifiable, i.e., they cannot be uniquely determined from experiments. Any paramet... | Mathematical modelling has become a fundamental tool in present day biology [1], and system identification is one of the key tasks of this process [2]. Building a dynamic model usually requires establishing the values of some unknown parameters, which raises the issue of parameter identifiability [3]. A model is struct... |
10.1371/journal.pgen.1007532 | A genome-wide association study identifies a susceptibility locus for biliary atresia on 2p16.1 within the gene EFEMP1 | Biliary atresia (BA) is a rare pediatric cholangiopathy characterized by fibrosclerosing obliteration of the extrahepatic bile ducts, leading to cholestasis, fibrosis, cirrhosis, and eventual liver failure. The etiology of BA remains unknown, although environmental, inflammatory, infectious, and genetic risk factors ha... | The etiology of biliary atresia (BA) is unknown and likely complex. Environmental, infectious, and genetic risk factors have all been proposed, and the leading hypothesis in the field is that a combination of these factors is responsible for disease manifestation. To identify susceptibility loci for BA, we performed a ... | Biliary atresia (BA; OMIM 210500) is a progressive, necro-inflammatory disease, affecting the extra- and intrahepatic biliary system, leading to bile flow obstruction, cholestasis, and jaundice in infants [1–3]. If left untreated, the condition progresses to hepatic fibrosis, cirrhosis, liver failure, and eventual deat... |
10.1371/journal.pntd.0000297 | The Potential Impact of Density Dependent Fecundity on the Use of the Faecal Egg Count Reduction Test for Detecting Drug Resistance in Human Hookworms | Current efforts to control human soil-transmitted helminth (STH) infections involve the periodic mass treatment of people, particularly children, in all endemic areas, using benzimidazole and imidothiazole drugs. Given the fact that high levels of resistance have developed to these same drugs in roundworms of livestock... | Current efforts to control soil-transmitted helminth (STH) infections in humans in endemic countries involve the mass administration of drugs. The use of these same drugs for many years to control livestock nematodes has resulted in the emergence of significant levels of resistance. Hence, there is a need to manage the... | Soil transmitted helminth (STH) infections (Ascaris lumbricoides, Trichuris trichiura, and the hookworms Necator americanus and Ancylostoma duodenale) contribute significantly to morbidity in humans in endemic countries. The major means of controlling these infections is by the periodic administration of anthelmintic d... |
10.1371/journal.pgen.1004503 | Recombination in the Human Pseudoautosomal Region PAR1 | The pseudoautosomal region (PAR) is a short region of homology between the mammalian X and Y chromosomes, which has undergone rapid evolution. A crossover in the PAR is essential for the proper disjunction of X and Y chromosomes in male meiosis, and PAR deletion results in male sterility. This leads the human PAR with ... | Recombination is a fundamental biological process, which shuffles genes between pairs of chromosomes during the production of eggs and sperm. After shuffling, the chromosomes consist of alternating sequences of genes from each parent, where the switches are the result of ‘crossovers’. Recombination is essential for egg... | Pseudoautosomal regions (PARs) are segments of sequence homology between the X and Y (or Z and W) chromosomes, which are otherwise non-homologous. Uniquely, PARs are inherited in the same manner as autosomes, while also being partially linked with X-specific and Y-specific loci. They have a critical role in the success... |
10.1371/journal.pbio.0050234 | Deletion of Ultraconserved Elements Yields Viable Mice | Ultraconserved elements have been suggested to retain extended perfect sequence identity between the human, mouse, and rat genomes due to essential functional properties. To investigate the necessities of these elements in vivo, we removed four noncoding ultraconserved elements (ranging in length from 222 to 731 base p... | It is widely believed that the most evolutionarily conserved DNA sequences in the human genome have been preserved because of their functional importance and that their removal would thus have a devastating effect on the organism. To ascertain this we removed from the mouse genome four ultraconserved elements—sequences... | Evolutionary conservation has become a powerful means for identifying functionally important genomic sequences [1,2]. Ultraconserved elements have been defined as a group of extremely conserved sequences that show 100% identity over 200 bp or greater between the human, mouse, and rat genomes [3]. This category of extre... |
10.1371/journal.ppat.1001110 | Cellular Entry of Ebola Virus Involves Uptake by a Macropinocytosis-Like Mechanism and Subsequent Trafficking through Early and Late Endosomes | Zaire ebolavirus (ZEBOV), a highly pathogenic zoonotic virus, poses serious public health, ecological and potential bioterrorism threats. Currently no specific therapy or vaccine is available. Virus entry is an attractive target for therapeutic intervention. However, current knowledge of the ZEBOV entry mechanism is li... | Filoviruses, including Zaire ebolavirus (ZEBOV), are among the most pathogenic viruses known. Our understanding of how these viruses enter into host cells is very limited. A deeper understanding of this process would enable the design of better targeted antiviral therapies. This study defines in detail, key steps of ZE... | Zaire ebolavirus (ZEBOV, Genbank:AF086833), a member of the family Filoviridae, genus Filovirus, causes a highly fatal hemorrhagic fever in humans and non-human primates. Over the past three decades numerous human outbreaks have occurred in Central Africa involving hundreds of cases with fatality rates ranging from 50–... |
10.1371/journal.pcbi.1006458 | Assessment of mutation probabilities of KRAS G12 missense mutants and their long-timescale dynamics by atomistic molecular simulations and Markov state modeling | A mutated KRAS protein is frequently observed in human cancers. Traditionally, the oncogenic properties of KRAS missense mutants at position 12 (G12X) have been considered as equal. Here, by assessing the probabilities of occurrence of all KRAS G12X mutations and KRAS dynamics we show that this assumption does not hold... | The oncogene KRAS is frequently mutated in various cancers. When the amino acid glycine 12 is mutated, KRAS protein acquires oncogenic properties that result in tumor cell-growth and cancer progression. These mutations prevail especially in the pancreatic ductal adenocarcinoma, which is a cancer with an exceptionally d... | The small GTPase protein KRAS is a signal-transducing protein, which binds GDP in its inactive state and GTP in its active state [1]. The gene KRAS is frequently mutated in various human cancers. The mutation is most often, in about 86% of the cases [2], found at G12. In fact, every missense mutation at G12 (G12X) is o... |
10.1371/journal.pbio.0060158 | Neuronal Correlates of the Set-Size Effect in Monkey Lateral Intraparietal Area | It has long been known that the brain is limited in the amount of sensory information that it can process at any given time. A well-known form of capacity limitation in vision is the set-size effect, whereby the time needed to find a target increases in the presence of distractors. The set-size effect implies that inpu... | It is well known that the brain is limited in the amount of sensory information that it can process at any given time. During an everyday task such as finding an object in a cluttered environment (known as visual search), observers take longer to find a target as the number of distractors increases. This well-known phe... | It has long been known that the visual system is limited in its ability to process multiple simultaneous inputs. Psychophysical evidence for visual capacity limitations comes from the observation that irrelevant distractors impair the ability to detect or discriminate a task-relevant target. Distractor interference is ... |
10.1371/journal.pcbi.1005825 | Insight into glucocorticoid receptor signalling through interactome model analysis | Glucocorticoid hormones (GCs) are used to treat a variety of diseases because of their potent anti-inflammatory effect and their ability to induce apoptosis in lymphoid malignancies through the glucocorticoid receptor (GR). Despite ongoing research, high glucocorticoid efficacy and widespread usage in medicine, resista... | Here we present modelling of the glucocorticoid receptor (GR) signalling network. The GR is the effector for a class of drugs known as corticosteroids, which are widely used in medicine for their anti-inflammatory effects and ability to induce apoptosis in leukaemic cells. However, side effects, treatment-related toxic... | Glucocorticoids (GCs) steroid hormones released from the adrenal cortex as part of the stress response play an important role in a variety of bodily processes such as inflammation, immunity, and numerous metabolic processes [1–3]. Their varied effects allow for their clinical application in numerous diseases, particula... |
10.1371/journal.pcbi.1000579 | A High-Throughput Screening Approach to Discovering Good Forms of Biologically Inspired Visual Representation | While many models of biological object recognition share a common set of “broad-stroke” properties, the performance of any one model depends strongly on the choice of parameters in a particular instantiation of that model—e.g., the number of units per layer, the size of pooling kernels, exponents in normalization opera... | One of the primary obstacles to understanding the computational underpinnings of biological vision is its sheer scale—the visual system is a massively parallel computer, comprised of billions of elements. While this scale has historically been beyond the reach of even the fastest super-computing systems, recent advance... | The study of biological vision and the creation of artificial vision systems are naturally intertwined—exploration of the neuronal substrates of visual processing provides clues and inspiration for artificial systems, and artificial systems, in turn, serve as important generators of new ideas and working hypotheses. Th... |
10.1371/journal.pbio.0050072 | Modification of a Hydrophobic Layer by a Point Mutation in Syntaxin 1A Regulates the Rate of Synaptic Vesicle Fusion | Both constitutive secretion and Ca2+-regulated exocytosis require the assembly of the soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) complexes. At present, little is known about how the SNARE complexes mediating these two distinct pathways differ in structure. Using the Drosophila neuromu... | Most living cells constantly renew their membrane compositions and frequently communicate with neighboring cells by delivering cargo molecules from small vesicles. A key step in cargo delivery requires the fusion of the vesicle membrane with the target membrane mediated by SNARE proteins. In most cellular compartments,... | Soluble N-ethylmaleimide–sensitive factor (NSF) attachment protein receptor (SNARE) proteins are thought to mediate vesicle fusion in all eukaryotes [1–4]. In nerve terminals, there are two target-SNAREs (t-SNAREs, also called Q-SNAREs), syntaxin 1A and synaptosome-associated protein-25 kDa (SNAP-25) on the plasma memb... |
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