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10.1371/journal.pntd.0005833 | Candidate gene polymorphisms study between human African trypanosomiasis clinical phenotypes in Guinea | Human African trypanosomiasis (HAT), a lethal disease induced by Trypanosoma brucei gambiense, has a range of clinical outcomes in its human host in West Africa: an acute form progressing rapidly to second stage, spontaneous self-cure and individuals able to regulate parasitaemia at very low levels, have all been repor... | Human African Trypanosomiasis (HAT) known as sleeping sickness is a lethal neglected disease in West and Central Africa, caused by the parasite Trypanosoma brucei gambiense that is transmitted by tsetse flies Glossina palpalis gambiensis. The disease has long been considered to be invariably fatal, but field studies sh... | Human African trypanosomiasis (HAT) known as sleeping sickness is a neglected disease of sub-Saharan Africa caused by two sub-species of trypanosomes, Trypanosoma brucei (T. b.) gambiense (in West and Central Africa) and T. b. rhodesiense (in East and South Africa), with T. b. gambiense causing > 95% of all cases [1]. ... |
10.1371/journal.pntd.0006739 | Bacterial community composition in the salivary glands of triatomines (Hemiptera: Reduviidae) | Chagas disease is caused by the parasite Trypanosoma cruzi and is transmitted through triatomines (Hemiptera: Reduviidae). In the last year, many studies of triatomine gut microbiota have outlined its potential role in modulating vector competence. However, little is known about the microbiota present in the salivary g... | Chagas disease is caused by the parasite Trypanosoma cruzi and is transmitted through triatomines (Hemiptera: Reduviidae). It is estimated that over 10 000 people die every year from clinical manifestations of Chagas disease, and more than 25 million people risk acquiring the disease per year. Vector control remains th... | In the last few years, multiple studies have focused on understanding the role of microbiota in vector competence, due to the ability of microbiota to acquire, maintain and modulate of pathogens transmission [1, 2]. Bacterial communities can establish different interactions with insects, such as commensal, mutual or pa... |
10.1371/journal.pgen.1008086 | A RID-like putative cytosine methyltransferase homologue controls sexual development in the fungus Podospora anserina | DNA methyltransferases are ubiquitous enzymes conserved in bacteria, plants and opisthokonta. These enzymes, which methylate cytosines, are involved in numerous biological processes, notably development. In mammals and higher plants, methylation patterns established and maintained by the cytosine DNA methyltransferases... | Sexual reproduction is considered to be essential for long-term persistence of eukaryotic species. Sexual reproduction is controlled by strict mechanisms governing which haploids can fuse (mating) and which developmental paths the resulting zygote will follow. In mammals, differential genomic DNA methylation patterns o... | A covalently modified DNA base, the 5-methylcytosine (5-meC) is common in genomes of organisms as diverse as bacteria, fungi, plants and animals. In eukaryotes, when present, this epigenetic modification is associated with down-regulation of gene expression and suppression of transposon activity [1]. Patterns of cytosi... |
10.1371/journal.pntd.0005523 | Soil-transmitted helminth infection, loss of education and cognitive impairment in school-aged children: A systematic review and meta-analysis | Evidence of an adverse influence of soil transmitted helminth (STH) infections on cognitive function and educational loss is equivocal. Prior meta-analyses have focused on randomized controlled trials only and have not sufficiently explored the potential for disparate influence of STH infection by cognitive domain. We ... | Previous systematic reviews of the effect of STH infection on cognitive and educational performance were either inconclusive or found little to no evidence of associated benefit. Lack of consensus in prior reviews and their narrow emphasis on randomized controlled trials prompted this comprehensive assessment of whethe... | Soil-transmitted helminthiases (STH) include infections with roundworm (Ascaris lumbricoides), whipworm (Trichuris trichiura) and hookworm (Ancylostoma duodenale and Necator americanus). STH infection affects one third of the world’s population [1, 2]. Primarily due to poverty, poor personal hygiene, frequent outdoor e... |
10.1371/journal.pcbi.1002416 | Mitochondrial Variability as a Source of Extrinsic Cellular Noise | We present a study investigating the role of mitochondrial variability in generating noise in eukaryotic cells. Noise in cellular physiology plays an important role in many fundamental cellular processes, including transcription, translation, stem cell differentiation and response to medication, but the specific random... | Cellular variability has been found to play a major role in diverse and important phenomena, including stem cell differentiation and drug resistance, but the sources of this variability have yet to be satisfactorily explained. We propose a mechanism, supported by a substantial number of recent and new experiments, by w... | Stochastic influences significantly affect a multitude of processes in cellular biology [1]–[5]. Understanding the sources of this randomness within and between cells is a central current challenge in quantitative biology. Noise has been found to affect processes including stem cell fate decisions [6], bet-hedging in b... |
10.1371/journal.pgen.1002063 | A Deficiency of Ceramide Biosynthesis Causes Cerebellar Purkinje Cell Neurodegeneration and Lipofuscin Accumulation | Sphingolipids, lipids with a common sphingoid base (also termed long chain base) backbone, play essential cellular structural and signaling functions. Alterations of sphingolipid levels have been implicated in many diseases, including neurodegenerative disorders. However, it remains largely unclear whether sphingolipid... | Lipids play many essential cellular roles as structural components of biological membranes or signaling molecules. Alterations of lipids have been observed in the brains of patients with neurodegenerative diseases. However, whether these changes can cause neurodegeneration or otherwise influence the pathology of these ... | A hallmark of aging and many neurodegenerative disorders is the neuronal accumulation of storage materials. These deposits include lipofuscin that contain undigested membranes and defective proteins [1], and/or membrane-free aggregates of misfolded proteins [2]. While the pathological roles of these accrued substances ... |
10.1371/journal.ppat.1004740 | Characterization of CD8+ T Cell Differentiation following SIVΔnef Vaccination by Transcription Factor Expression Profiling | The onset of protective immunity against pathogenic SIV challenge in SIVΔnef-vaccinated macaques is delayed for 15-20 weeks, a process that is related to qualitative changes in CD8+ T cell responses induced by SIVΔnef. As a novel approach to characterize cell differentiation following vaccination, we used multi-target ... | The live attenuated vaccine SIVΔnef can induce robust CD8+ T cell- mediated protection against infection with pathogenic SIV in macaques. Thus, there is substantial interest in characterizing these immune responses to inform HIV vaccine design. Animals challenged at 15–20 weeks post vaccination exhibit robust protectio... | Vaccination of rhesus macaques with SIVΔnef can induce robust immune responses and can protect the majority of vaccinated animals from challenge with wild-type SIV virus strains [1–3]. To date, SIVΔnef is the most efficacious of all vaccine strategies analyzed in the macaque model. Although safety concerns preclude the... |
10.1371/journal.pcbi.1002249 | Second Order Dimensionality Reduction Using Minimum and Maximum Mutual Information Models | Conventional methods used to characterize multidimensional neural feature selectivity, such as spike-triggered covariance (STC) or maximally informative dimensions (MID), are limited to Gaussian stimuli or are only able to identify a small number of features due to the curse of dimensionality. To overcome these issues,... | Neurons are capable of simultaneously encoding information about multiple features of sensory stimuli in their spikes. The dimensionality reduction methods that currently exist to extract those relevant features are either biased for non-Gaussian stimuli or fall victim to the curse of dimensionality. In this paper we i... | In recent years it has become apparent that many types of sensory neurons simultaneously encode information about more than one stimulus feature in their spiking activity. Examples can be found across a wide variety of modalities, including the visual [1]–[12], auditory [13], olfactory [14], somatosensory [15] and mech... |
10.1371/journal.pbio.0060074 | Modelling within-Host Spatiotemporal Dynamics of Invasive Bacterial Disease | Mechanistic determinants of bacterial growth, death, and spread within mammalian hosts
cannot be fully resolved studying a single bacterial population. They are also currently
poorly understood. Here, we report on the application of sophisticated experimental
approaches to map spatiotempor... | Global patterns and mechanistic determinants of bacterial spread in mammalian organisms
are difficult to obtain through numerical and topographical mapping of a single
bacterial population. Appreciation of the true pathogenetic events during infections
needs to be based on the unders... | Central to a complete understanding of any disease is the ability to integrate information
from different scales into a coherent model that fully explains the disease process
[1]. One challenge
that remains is how to move from our ever more detailed understanding of cellular and
molecu... |
10.1371/journal.pntd.0007141 | Association of rodent-borne Leptospira spp. with urban environments in Malaysian Borneo | Although leptospirosis is traditionally considered a disease of rural, agricultural and flooded environments, Leptospira spp. are found in a range of habitats and infect numerous host species, with rodents among the most significant reservoirs and vectors. To explore the local ecology of Leptospira spp. in a city exper... | Leptospirosis is a significant zoonotic disease that is found in a range of environments worldwide, most notably tropical regions prone to flooding. The bacterial agents of this disease, Leptospira spp., are most often associated with rodents, including species frequently found in urban areas. In cities, rodent populat... | Leptospirosis is the most widespread zoonotic disease globally, with over a million cases of severe disease and around 60,000 deaths reported annually [1]. Occurring in a wide variety of environmental settings, and with the greatest impact on public health in tropical and subtropical regions, it is a significantly unde... |
10.1371/journal.pgen.1004480 | Functional EF-Hands in Neuronal Calcium Sensor GCAP2 Determine Its Phosphorylation State and Subcellular Distribution In Vivo, and Are Essential for Photoreceptor Cell Integrity | The neuronal calcium sensor proteins GCAPs (guanylate cyclase activating proteins) switch between Ca2+-free and Ca2+-bound conformational states and confer calcium sensitivity to guanylate cyclase at retinal photoreceptor cells. They play a fundamental role in light adaptation by coupling the rate of cGMP synthesis to ... | Visual perception is initiated at retinal photoreceptor cells, where light activates an enzymatic cascade that reduces free cGMP. As cGMP drops, cGMP-channels close and reduce the inward current –including Ca2+ influx– so that photoreceptors hyperpolarize and emit a signal. As the light extinguishes, cGMP levels are re... | Guanylate-cyclase activating proteins (GCAPs) belong to the neuronal calcium sensor (NCS) family of proteins that display limited similarity to calmodulin. They confer Ca2+-sensitivity to guanylate-cyclase (Ret-GC) activity in retinal photoreceptor cells. GCAP1 and GCAP2 constitute the major species in mammals [1]–[3].... |
10.1371/journal.ppat.1006532 | Salmonella enterica serovar-specific transcriptional reprogramming of infected cells | Despite their high degree of genomic similarity, different Salmonella enterica serovars are often associated with very different clinical presentations. In humans, for example, the typhoidal S. enterica serovar Typhi causes typhoid fever, a life-threatening systemic disease. In contrast, the non-typhoidal S. enterica s... | Salmonella Typhimurium and Salmonella Typhi are associated with very different clinical presentations. While S. Typhimurium causes self-limiting gastroenteritis (i. e. “food poisoning”), S. Typhi causes typhoid fever, a systemic, life-threatening disease. The bases for these major differences are not fully understood b... | Salmonella enterica encompasses multiple serovars that are associated with distinct pathogenic features and host specificities [1, 2]. Salmonella enterica serovar Typhi (S. Typhi), for example, is the cause of typhoid fever, a systemic disease of humans that leads to an estimated 200,000 deaths worldwide [3–6]. In cont... |
10.1371/journal.pgen.1003082 | Comparison of Mitochondrial Mutation Spectra in Ageing Human Colonic Epithelium and Disease: Absence of Evidence for Purifying Selection in Somatic Mitochondrial DNA Point Mutations | Human ageing has been predicted to be caused by the accumulation of molecular damage in cells and tissues. Somatic mitochondrial DNA (mtDNA) mutations have been documented in a number of ageing tissues and have been shown to be associated with cellular mitochondrial dysfunction. It is unknown whether there are selectiv... | Mitochondrial DNA encodes essential components of the mitochondrial respiratory chain and is strictly maternally inherited, making it vulnerable to the accumulation of deleterious mutations. To avoid this, mtDNA is subjected to a bottleneck phenomenon whereby only a small number of mtDNA molecules are passed on to the ... | Ageing is a stochastic process commonly defined as the progressive decline in the condition of an organism which is accompanied by a reduction in fertility and an increasing risk of death [1]. Ageing is unlikely to be genetically programmed as evolution theory suggests that nature would not select for a process which i... |
10.1371/journal.pntd.0004970 | Snowball Vs. House-to-House Technique for Measuring Annual Incidence of Kala-azar in the Higher Endemic Blocks of Bihar, India: A Comparison | Visceral Leishmaniasis, commonly known as kala-azar, is widely prevalent in Bihar. The National Kala-azar Control Program has applied house-to-house survey approach several times for estimating Kala-azar incidence in the past. However, this approach includes huge logistics and operational cost, as occurrence of kala-az... | Visceral Leishmaniasis, commonly known as kala-azar, is one of the major health concerns for Bihar state in India. Time to time estimation of kala-azar incidence plays a pivotal role in defining and evaluating control strategies under National Kala-azar Elimination programme. The house-to-house survey approach, adopted... | Visceral Leishmaniasis (VL), also known as Kala-azar, is a major cause of morbidity and mortality and of tremendous public health importance in India, Bangladesh and Nepal affecting the poorest population groups, primarily in rural areas. With an estimated 200 million people at risk, India, Nepal and Bangladesh harbour... |
10.1371/journal.pntd.0003437 | Source Tracking Mycobacterium ulcerans Infections in the Ashanti Region, Ghana | Although several studies have associated Mycobacterium ulcerans (MU) infection, Buruli ulcer (BU), with slow moving water bodies, there is still no definite mode of transmission. Ecological and transmission studies suggest Variable Number Tandem Repeat (VNTR) typing as a useful tool to differentiate MU strains from oth... | Buruli ulcer is a skin disease, which is endemic in over thirty countries, mostly in West Africa, with affected populations being largely rural. The causative organism, Mycobacterium ulcerans (MU), is an environmental mycobacterium and although transmission is unclear, frequent exposure to these MU-contaminated environ... | Buruli ulcer (BU) is a necrotizing skin disease which has been reported in over thirty countries. The most endemic countries include Ghana, Togo, Cote d’Ivoire and Benin with affected populations significantly being rural [1]. Mycobacterium ulcerans (MU), the causative agent of BU is an environmental mycobacteria. The ... |
10.1371/journal.pntd.0002969 | A Novel Live-Attenuated Vaccine Candidate for Mayaro Fever | Mayaro virus (MAYV) is an emerging, mosquito-borne alphavirus that causes a dengue-like illness in many regions of South America, and which has the potential to urbanize. Because no specific treatment or vaccine is available for MAYV infection, we capitalized on an IRES-based approach to develop a live-attenuated MAYV ... | Mayaro virus (MAYV) is a mosquito-borne alphavirus that causes severe and sometimes chronic arthralgia in persons in South America, where it circulates in forest habitats. It is widely neglected because it is typically mistaken for dengue due to the overlap in the clinical signs and symptoms, and the lack of laboratory... | Mayaro virus (MAYV) is an important and growing human health concern in the neotropics. First isolated in Mayaro county, Trinidad in 1954, cases of Mayaro fever (MAY) have since been reported in 9 different countries in northern South America [1]. In addition, serological surveys suggest that MAYV has expanded into the... |
10.1371/journal.ppat.1004177 | Widespread Sequence Variations in VAMP1 across Vertebrates Suggest a Potential Selective Pressure from Botulinum Neurotoxins | Botulinum neurotoxins (BoNT/A-G), the most potent toxins known, act by cleaving three SNARE proteins required for synaptic vesicle exocytosis. Previous studies on BoNTs have generally utilized the major SNARE homologues expressed in brain (VAMP2, syntaxin 1, and SNAP-25). However, BoNTs target peripheral motor neurons ... | Botulinum neurotoxins (BoNTs) target peripheral motor neurons and act by cleaving SNARE proteins, which are essential for neurotransmitter release from nerve terminals. SNARE proteins occur in multiple homologues and it has been difficult to determine which one is the physiologically relevant toxin target in motor nerv... | Botulinum neurotoxins (BoNTs) are a family of protein toxins produced by diverse species of Clostridia, a genus of anaerobic spore-forming bacteria [1], [2]. These toxins paralyze humans and animals by blocking neurotransmitter release primarily from motor nerve terminals, causing death when respiratory muscles are par... |
10.1371/journal.ppat.1000383 | Identification of Proteins Targeted by the Thioredoxin Superfamily in Plasmodium falciparum | The malarial parasite Plasmodium falciparum possesses a functional thioredoxin and glutathione system comprising the dithiol-containing redox proteins thioredoxin (Trx) and glutaredoxin (Grx), as well as plasmoredoxin (Plrx), which is exclusively found in Plasmodium species. All three proteins belong to the thioredoxin... | Protection from oxidative stress and efficient redox regulation are essential for malarial parasites which have to grow and multiply rapidly in various environments. As shown by glucose-6 phosphate dehydrogenase deficiency, a genetic variation protecting from malaria, the parasite–host cell unit is very susceptible to ... | The malarial parasite Plasmodium falciparum (Pf) possesses two major functional redox systems: The thioredoxin system [1],[2] comprising NADPH, thioredoxin reductase, thioredoxin (Trx) [2],[3], and thioredoxin-dependent peroxiredoxins [4]–[8], and a glutathione system comprising NADPH, glutathione reductase [9], glutat... |
10.1371/journal.pbio.1002412 | Separable Roles for a Caenorhabditis elegans RMI1 Homolog in Promoting and Antagonizing Meiotic Crossovers Ensure Faithful Chromosome Inheritance | During the first meiotic division, crossovers (COs) between homologous chromosomes ensure their correct segregation. COs are produced by homologous recombination (HR)-mediated repair of programmed DNA double strand breaks (DSBs). As more DSBs are induced than COs, mechanisms are required to establish a regulated number... | During meiosis, faithful separation of chromosomes into gametes is essential for fertility and healthy progeny. During the first meiotic division, crossovers (CO) between parental homologs ensure their correct segregation. Programmed DNA double strand breaks (DSBs) and resection steps generate single-stranded overhangs... | During meiosis, the accurate segregation of chromosomes relies on the formation of crossovers (COs) and sister chromatid cohesion [1]. COs are produced by homologous recombination (HR)-mediated repair of programmed DNA double strand breaks (DSBs). In Caenorhabditis elegans, the holocentric chromosome pairs usually unde... |
10.1371/journal.pgen.1003357 | Pax6 Regulates Gene Expression in the Vertebrate Lens through miR-204 | During development, tissue-specific transcription factors regulate both protein-coding and non-coding genes to control differentiation. Recent studies have established a dual role for the transcription factor Pax6 as both an activator and repressor of gene expression in the eye, central nervous system, and pancreas. Ho... | The transcription factor Pax6 is reiteratively employed in space and time for the establishment of progenitor pools and the differentiation of neuronal and non-neuronal lineages of the CNS, pancreas, and eye. Execution of these diverse developmental programs depends on simultaneous activation and repression of gene net... | Lineage-specific transcription factors (TFs) such as Pax6 direct the development of multiple tissues through the regulation of gene networks that execute discrete developmental programs. Pax6 is essential for normal development of the central nervous system (CNS), pancreas, olfactory system and eye (reviewed in [1], [2... |
10.1371/journal.pgen.1004862 | Altered Ca2+ Kinetics Associated with α-Actinin-3 Deficiency May Explain Positive Selection for ACTN3 Null Allele in Human Evolution | Over 1.5 billion people lack the skeletal muscle fast-twitch fibre protein α-actinin-3 due to homozygosity for a common null polymorphism (R577X) in the ACTN3 gene. α-Actinin-3 deficiency is detrimental to sprint performance in elite athletes and beneficial to endurance activities. In the human genome, it is very diffi... | α-Actinin-3 is a protein found inside the muscles of most people around the world. It is encoded by a gene called ACTN3, popularly known as “the gene for speed.” In 1.5 billion people, a certain variation in the genetic sequence of their ACTN3 gene causes their muscles to produce no α-actinin-3 protein at all. These pe... | The sarcomeric α-actinins, α-actinin-2 and -3, are highly homologous actin-binding proteins localised to the Z-discs of skeletal muscle fibres, where they cross-link the actin filaments of adjoining sarcomeres and interact with a host of metabolic and signalling proteins. α-Actinin-2 is present in all muscle fibre type... |
10.1371/journal.ppat.1003010 | Histone H1 Plays a Role in Heterochromatin Formation and VSG Expression Site Silencing in Trypanosoma brucei | The African sleeping sickness parasite Trypanosoma brucei evades the host immune system through antigenic variation of its variant surface glycoprotein (VSG) coat. Although the T. brucei genome contains ∼1500 VSGs, only one VSG is expressed at a time from one of about 15 subtelomeric VSG expression sites (ESs). For ant... | Trypanosoma brucei causes African sleeping sickness, endemic to sub-Saharan Africa. Bloodstream form T. brucei is covered with a dense coat of variant surface glycoprotein (VSG). Only one VSG is expressed at a time out of a vast repertoire of ∼1500 VSGs. The active VSG is transcribed in a telomeric VSG expression site ... | The African trypanosome Trypanosoma brucei is a unicellular parasite causing African sleeping sickness, which is transmitted by tsetse flies in sub-Saharan Africa. As an extracellular parasite of the mammalian bloodstream, T. brucei has evolved a sophisticated strategy to antigenically vary its major surface coat prote... |
10.1371/journal.pbio.1001238 | USP8 Promotes Smoothened Signaling by Preventing Its Ubiquitination and Changing Its Subcellular Localization | The seven transmembrane protein Smoothened (Smo) is a critical component of the Hedgehog (Hh) signaling pathway and is regulated by phosphorylation, dimerization, and cell-surface accumulation upon Hh stimulation. However, it is not clear how Hh regulates Smo accumulation on the cell surface or how Hh regulates the int... | The Hedgehog (Hh) signaling pathway is well known for its role in directing processes such as cell growth, proliferation, and differentiation during embryogenesis. The signal initiated by Hh binding to its receptor, Patched, is transduced by another protein called Smoothened (Smo), which moves from membranes inside the... | Hedgehog (Hh) proteins function as morphogens and play critical roles in pattern formation and cell growth control. Hh signaling has also been implicated in tissue repair and stem cell maintenance [1]. Malfunction of Hh signaling causes birth defects as well as several types of cancer [2],[3]. The Hh signal is transduc... |
10.1371/journal.pcbi.1000154 | A Feature-Based Approach to Modeling Protein–DNA Interactions | Transcription factor (TF) binding to its DNA target site is a fundamental regulatory interaction. The most common model used to represent TF binding specificities is a position specific scoring matrix (PSSM), which assumes independence between binding positions. However, in many cases, this simplifying assumption does ... | Transcription factor (TF) protein binding to its DNA target sequences is a fundamental physical interaction underlying gene regulation. Characterizing the binding specificities of TFs is essential for deducing which genes are regulated by which TFs. Recently, several high-throughput methods that measure sequences enric... | Precise control of gene expression lies at the heart of nearly all biological processes. An important layer in such control is the regulation of transcription. This regulation is preformed by a network of interactions between transcription factor proteins (TFs) and the DNA of the genes they regulate. To understand the ... |
10.1371/journal.pgen.1000131 | E1 Ubiquitin-Activating Enzyme UBA-1 Plays Multiple Roles throughout C. elegans Development | Poly-ubiquitination of target proteins typically marks them for destruction via the proteasome and provides an essential mechanism for the dynamic control of protein levels. The E1 ubiquitin-activating enzyme lies at the apex of the ubiquitination cascade, and its activity is necessary for all subsequent steps in the r... | Proteins that control an organism's development must first be turned on at the proper time and place, and then turned off when they are no longer needed. One of the “off” signals occurs through the attachment of a small protein, known as ubiquitin, to the target protein, which typically leads to the destruction of the ... | Post-translational modification of proteins performs a critical role in regulating protein activity, and ubiquitin-mediated proteolysis has emerged as the key player in the control of protein turnover. Ubiquitin, a highly conserved small protein, is covalently attached to a target protein through an enzymatic cascade, ... |
10.1371/journal.pgen.1005510 | Integration of Genome-Wide SNP Data and Gene-Expression Profiles Reveals Six Novel Loci and Regulatory Mechanisms for Amino Acids and Acylcarnitines in Whole Blood | Profiling amino acids and acylcarnitines in whole blood spots is a powerful tool in the laboratory diagnosis of several inborn errors of metabolism. Emerging data suggests that altered blood levels of amino acids and acylcarnitines are also associated with common metabolic diseases in adults. Thus, the identification o... | Human metabolite levels differ between individuals due to environmental and genetic factors. In the present work, we analyzed whole blood levels of amino acids and acylcarnitines, reflecting disease relevant metabolic pathways, in a cohort of 2,107 individuals. We then performed a genome wide association analysis to di... | High-throughput metabolomics experiments using mass spectrometry platforms are becoming an integral part of clinical and systems biology research. Profiling of amino acids and acylcarnitine species in dried whole blood samples of newborns is used worldwide in neonatal screening programs to identify rare inborn errors o... |
10.1371/journal.ppat.1003810 | Semen CD4+ T Cells and Macrophages Are Productively Infected at All Stages of SIV infection in Macaques | The mucosal events of HIV transmission have been extensively studied, but the role of infected cells present in the genital and rectal secretions, and in the semen, in particular, remains a matter of debate. As a prerequisite to a thorough in vivo investigation of the early transmission events through infected cells, w... | Human Immunodeficiency Virus infection is predominantly transmitted by mucosal exposure, after sexual intercourse. Although substantial progresses have been recently achieved in our understanding of the mechanisms of HIV mucosal transmission, many questions remain. Semen is one of the major sources for HIV which contai... | More than 33 million people are currently living with HIV/AIDS worldwide. Almost 80% of new infections occur through sexual intercourse. Semen is thus one of the major factors in HIV transmission. Most studies on HIV sexual transmission have focused on the role of cell-free particles, and the underlying mechanisms of t... |
10.1371/journal.pgen.1000362 | Adaptations to Submarine Hydrothermal Environments Exemplified by the Genome of Nautilia profundicola | Submarine hydrothermal vents are model systems for the Archaean Earth environment, and some sites maintain conditions that may have favored the formation and evolution of cellular life. Vents are typified by rapid fluctuations in temperature and redox potential that impose a strong selective pressure on resident microb... | Extreme environments, such as deep-sea hydrothermal vents, found 2,500 meters below the ocean surface, support large macrofaunal communities via microbially mediated carbon fixation processes using chemicals (chemoautotrophy) rather than light (photoautotrophy). The genome of one such model chemoautotrophic microbe, N.... | Food webs at deep-sea hydrothermal vents are based on microbial primary productivity fueled by chemical reactions rather than light. Microorganisms that thrive in these environments must adapt to fluctuations in temperature and redox conditions, ranging from the hot, sulfidic, heavy metal-laden plume at the vent outlet... |
10.1371/journal.ppat.1001164 | The Spread of Tomato Yellow Leaf Curl Virus from the Middle East to the World | The ongoing global spread of Tomato yellow leaf curl virus (TYLCV; Genus Begomovirus, Family Geminiviridae) represents a serious looming threat to tomato production in all temperate parts of the world. Whereas determining where and when TYLCV movements have occurred could help curtail its spread and prevent future move... | Tomato yellow leaf curl virus (TYLCV) poses a serious threat to tomato production throughout the temperate regions of the world. Our analysis, using a suite of bioinformatic tools applied to all publically available TYLCV genome sequences, suggests that the virus probably arose somewhere in the Middle East between the ... | Tomato yellow leaf curl disease (TYLCD) is one of the most devastating emerging diseases of tomato in the warm and temperate regions of the world. It is caused by a complex of at least six virus species in the Begomovirus genus of the Family Geminiviridae [1], [2]. Tomato yellow leaf curl virus (TYLCV) is the most wide... |
10.1371/journal.pcbi.1002551 | Protein Scaffolds Can Enhance the Bistability of Multisite Phosphorylation Systems | The phosphorylation of a substrate at multiple sites is a common protein modification that can give rise to important structural and electrostatic changes. Scaffold proteins can enhance protein phosphorylation by facilitating an interaction between a protein kinase enzyme and its target substrate. In this work we consi... | The modification of a protein at multiple sites can result in a number of interesting behaviors at the cellular level, such as all-or-none responses to an external input, or two different stable cellular states in otherwise identical environments. Such behaviors can aid in many different forms of cellular decision-maki... | Protein phosphorylation is a ubiquitous form of post-translational modification [1]. Since covalently-bound phosphate groups are strongly hydrophilic and negatively charged, they can activate or inhibit a protein by changing its conformation or the way it interacts with other proteins [2], [3]. Phosphorylation is a key... |
10.1371/journal.pgen.1004608 | The Actomyosin Machinery Is Required for Drosophila Retinal Lumen Formation | Multicellular tubes consist of polarized cells wrapped around a central lumen and are essential structures underlying many developmental and physiological functions. In Drosophila compound eyes, each ommatidium forms a luminal matrix, the inter-rhabdomeral space, to shape and separate the key phototransduction organell... | Biological tubes are integral units of tissues and organs such as lung, kidney, and the cardiovascular system. The fundamental design of tubes involves a central lumen wrapped by a sheet of cells. To function properly, the tubes require a precise genetic control over their creation, the diametric growth and maintenance... | Multicellular tubes are fundamental structures required for the transport of gases, liquids, or cells and are necessary for the generation and function of tissues and organs such as lung, kidney, blood vessels, neural tubes, and mammary gland. The main feature of a tubular network is a luminal space lined by apical mem... |
10.1371/journal.ppat.1006866 | Intracellular trafficking of begomoviruses in the midgut cells of their insect vector | Begomoviruses are exclusively transmitted by whiteflies in a persistent circulative manner and cause considerable economic losses to crop production worldwide. Previous studies have shown that begomoviruses accumulate in vesicle-like structures in whitefly midgut cells and that clathrin-mediated endocytosis is responsi... | Many plant viruses are vectored by insects in a persistent circulative manner. In this process, the transport of virus from the gut lumen into the hemolymph of the vector is an important step. Identification of vector components involved in this transport process could lead to new strategies to combat virus spread. Her... | Insects transmit the majority of plant viruses [1–3]. The process of virus transmission by an insect vector varies based on how the virus is acquired, retained, and inoculated into plants. Some plant viruses, such as members of the genera Caulimovirus, Cucumovirus and Potyvirus, are transmitted in a non-circulative man... |
10.1371/journal.pgen.1002298 | Identification, Replication, and Fine-Mapping of Loci Associated with Adult Height in Individuals of African Ancestry | Adult height is a classic polygenic trait of high heritability (h2 ∼0.8). More than 180 single nucleotide polymorphisms (SNPs), identified mostly in populations of European descent, are associated with height. These variants convey modest effects and explain ∼10% of the variance in height. Discovery efforts in other po... | Adult height is an ideal phenotype to improve our understanding of the genetic architecture of complex diseases and traits: it is easily measured and usually available in large cohorts, relatively stable, and mostly influenced by genetics (narrow-sense heritability of height h2∼0.8). Genome-wide association (GWA) studi... | Adult height is a classic polygenic trait of high heritability (h2∼0.8) [1], [2]. A recent large meta-analysis of genome-wide association (GWA) results for height, which included data from >180,000 individuals of European descent, identified 180 loci that associate with variation in height [3]. The most significantly a... |
10.1371/journal.ppat.1003378 | The SNARE Protein Syp71 Is Essential for Turnip Mosaic Virus Infection by Mediating Fusion of Virus-Induced Vesicles with Chloroplasts | All positive-strand RNA viruses induce the biogenesis of cytoplasmic membrane-bound virus factories for viral genome multiplication. We have previously demonstrated that upon plant potyvirus infection, the potyviral 6K2 integral membrane protein induces the formation of ER-derived replication vesicles that subsequently... | Potyviruses constitute the largest group of known plant viruses which includes many agriculturally important viruses. Like all other positive-strand RNA viruses, potyviruses induce the cytoplasmic membranous-bound virus factory for viral genome multiplication. But the mechanism by which such a factory is formed and ass... | The host endomembrane system directly contributes to the formation of virus-induced membrane-bound virus factory for positive-strand RNA virus replication [1], [2]. Depending on the virus, membranes from distinct cellular organelles such as the endoplasmic reticulum (ER), chloroplast, mitochondrion, endosome, and perox... |
10.1371/journal.pcbi.0030023 | Mechanochemical Coupling in the Myosin Motor Domain. II. Analysis of Critical Residues | An important challenge in the analysis of mechanochemical coupling in molecular motors is to identify residues that dictate the tight coupling between the chemical site and distant structural rearrangements. In this work, a systematic attempt is made to tackle this issue for the conventional myosin. By judiciously comb... | Molecular motors are inherently allosteric in nature because the small structural changes associated with the chemistry in the active site are propagated over a long distance and amplified into much larger conformational transitions. A fundamental challenge for understanding such processes concerns the identification o... | Large-scale conformational transitions driven by a distant chemical event, such as ligand binding, is the hallmark of many allosteric systems [1]. Although allostery is historically defined for multisubunit systems [2,3], many of which have a considerable degree of symmetry [4], it is increasingly recognized that coord... |
10.1371/journal.ppat.1005123 | The Dual Role of an ESCRT-0 Component HGS in HBV Transcription and Naked Capsid Secretion | The Endosomal Sorting Complex Required for Transport (ESCRT) is an important cellular machinery for the sorting and trafficking of ubiquitinated cargos. It is also known that ESCRT is required for the egress of a number of viruses. To investigate the relationship between ESCRT and hepatitis B virus (HBV), we conducted ... | Hepatitis B virus (HBV) is an important human pathogen. Chronic infection with HBV can lead to cirrhosis and liver cancer. While HBV infection is treatable, it remains a challenge to eradicate the virus in patients. HBV can produce various particles with different sizes and morphologies. Virions are complete particles ... | Hepatitis B virus is a leading cause of chronic liver diseases and more than 240 million people are infected worldwide. Persistent infection with HBV can cause severe liver injury, cirrhosis, and the development of hepatocellular carcinoma (HCC) [1]. Though the HBV vaccination program has been successful in recent deca... |
10.1371/journal.pcbi.1007133 | Per-sample immunoglobulin germline inference from B cell receptor deep sequencing data | The collection of immunoglobulin genes in an individual’s germline, which gives rise to B cell receptors via recombination, is known to vary significantly across individuals. In humans, for example, each individual has only a fraction of the several hundred known V alleles. Furthermore, the currently-accepted set of kn... | Antibodies are an important component of the adaptive immune system, which itself determines our response to both pathogens and vaccines. They are produced by B cells through somatic recombination of germline DNA, which results in a vast diversity of antigen binding affinities across the B cell repertoire. We typically... | The heavy and light chain B cell receptor (BCR) loci arise from a random recombination of germline V, D, and J genes. Repeated across many B cells, this generates the vast diversity of naive BCRs that is integral to the adaptive immune system. As an additional source of population-wide variation, there is significant v... |
10.1371/journal.pcbi.1002990 | In-silico Assessment of Protein-Protein Electron Transfer. A Case Study: Cytochrome c Peroxidase – Cytochrome c | The fast development of software and hardware is notably helping in closing the gap between macroscopic and microscopic data. Using a novel theoretical strategy combining molecular dynamics simulations, conformational clustering, ab-initio quantum mechanics and electronic coupling calculations, we show how computationa... | We have developed a protocol capable of describing long-range electron transfer mechanisms at an atomic detailed level. We demonstrate the maturity of the computational techniques in obtaining a quantitative view of the Cytochrome c Peroxidase/Cytochrome c electron transfer process, known to be a significant challenge.... | Electron transfer (ET) is a fundamental reaction in biochemistry [1], [2]. Its comprehensive elucidation is crucial for the understanding of biological function and the design of synthetic energy transduction systems. In this matter, the question of how intermediary medium controls the electron transfer process between... |
10.1371/journal.pgen.1004262 | FAK Acts as a Suppressor of RTK-MAP Kinase Signalling in Drosophila melanogaster Epithelia and Human Cancer Cells | Receptor Tyrosine Kinases (RTKs) and Focal Adhesion Kinase (FAK) regulate multiple signalling pathways, including mitogen-activated protein (MAP) kinase pathway. FAK interacts with several RTKs but little is known about how FAK regulates their downstream signalling. Here we investigated how FAK regulates signalling res... | Due to their deregulation in cancer and their potential to be inhibited by small chemical compounds, tyrosine kinases are among the most important targets under consideration for cancer therapeutics. One such oncogenic tyrosine kinase is FAK, which is known to regulate cellular signalling downstream of Integrins and Re... | Research in model organisms can provide important insights on the effects of oncogenic pathways in different in vivo environments [1], [2]. Particularly, Drosophila melanogaster has made numerous contributions to cancer biology, e.g. by identifying components of several signalling pathways such as the Hippo [3] and RTK... |
10.1371/journal.ppat.1004082 | HIV and HCV Activate the Inflammasome in Monocytes and Macrophages via Endosomal Toll-Like Receptors without Induction of Type 1 Interferon | Innate immune sensing of viral infection results in type I interferon (IFN) production and inflammasome activation. Type I IFNs, primarily IFN-α and IFN-β, are produced by all cell types upon virus infection and promote an antiviral state in surrounding cells by inducing the expression of IFN-stimulated genes. Type I I... | Pathogens are detected by the immune system in multiple ways that initiate responses to control infection. Two systems of first line defense against viruses are 1) the production of Type I interferons and 2) production of the cytokines IL-1β and IL-18 by the inflammasome. Type I interferons promote an antiviral state i... | Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are RNA viruses capable of causing chronic infection, with an estimated 35 million [1] and 170 million [2] people infected worldwide, respectively. The innate immune response to these viruses generates an antiviral state that alters downstream adaptive immu... |
10.1371/journal.pntd.0006690 | Trypanosoma brucei triggers a marked immune response in male reproductive organs | African trypanosomiasis is caused by the protozoan parasite Trypanosoma brucei, transmitted between mammals by the bite of a tsetse. It has been recently shown that parasites accumulate in large numbers in various organs and tissues, including the mouse testis. Whether parasites are protected from the immune system in ... | The protozoan parasite Trypanosoma brucei is the causative agent of African trypanosomiasis in humans (sleeping sickness) and animals (nagana). In male animals, natural infection is commonly associated with decreased fertility but the causes for this condition remain poorly understood. Interestingly, in mouse experimen... | Human African Trypanosomiasis (HAT), also known as sleeping sickness, is caused by the protozoan parasite Trypanosoma brucei [1]. HAT evolves through different clinical stages and often leads to death if left untreated. It is broadly characterized by an early/hemolymphatic stage and a late/encephalic stage. There are t... |
10.1371/journal.pntd.0002393 | Infection of Domestic Dogs in Peru by Zoonotic Bartonella Species: A Cross-Sectional Prevalence Study of 219 Asymptomatic Dogs | Bartonella species are emerging infectious organisms transmitted by arthropods capable of causing long-lasting infection in mammalian hosts. Among over 30 species described from four continents to date, 15 are known to infect humans, with eight of these capable of infecting dogs as well. B. bacilliformis is the only sp... | Bartonella are bacteria transmitted by fleas, ticks, sandflies and other insects capable of infecting humans, domestic animals, livestock and wildlife, including marine mammals. In humans, they cause diseases such as trench fever, cat scratch disease, endocarditis, fever of unknown origin and have been recently associa... | Bartonella species are gram-negative bacteria associated with an increasing array of disease manifestations in humans and animals. They are small, obligate intracellular organisms that adhere and invade erythrocytes and endothelial cells of mammalian hosts, causing long lasting bacteremia [1], [2]. These zoonotic organ... |
10.1371/journal.pntd.0004335 | Mycobacterium leprae-Infected Macrophages Preferentially Primed Regulatory T Cell Responses and Was Associated with Lepromatous Leprosy | The persistence of Mycobacterium leprae (M. leprae) infection is largely dependent on the types of host immune responses being induced. Macrophage, a crucial modulator of innate and adaptive immune responses, could be directly infected by M. leprae. We therefore postulated that M. leprae-infected macrophages might have... | Macrophages play critical roles in modulating Mycobacterium leprae (M. leprae) infection. In this study, we investigated the immune status of macrophages stimulated with live M. leprae or killed M. leprae. We found that live M. leprae-infected macrophages polarized toward the regulatory M2-type, preferentially primed T... | The ability of an intracellular pathogen to establish a productive infection relies on its ability to evade cytotoxic T cell-mediated clearance of infected cells. In the case of Mycobacterium leprae (M. leprae), an obligate intracellular pathogen that is dependent on the host fatty acid metabolism for microbial lipid s... |
10.1371/journal.ppat.1004348 | Rabies Virus Hijacks and Accelerates the p75NTR Retrograde Axonal Transport Machinery | Rabies virus (RABV) is a neurotropic virus that depends on long distance axonal transport in order to reach the central nervous system (CNS). The strategy RABV uses to hijack the cellular transport machinery is still not clear. It is thought that RABV interacts with membrane receptors in order to internalize and exploi... | Rabies virus (RABV) is a neurotropic virus that depends on long distance axonal transport in order to reach the central nervous system (CNS). The strategy RABV uses to hijack the cellular transport machinery is unknown. Here we use live cell imaging to track RABV entry at nerve terminals and study its retrograde transp... | Rabies virus (RABV) is a neurotropic negative-strand RNA virus of the Lyssavirus genus, belonging to the Rhabdoviridae family. It is transmitted mostly via bites of diseased animals and causes a fatal infection of the nervous system in both animals and humans. A key step in RABV pathogenesis is rapid transfer to the Ce... |
10.1371/journal.pcbi.1000866 | Mechanism of MicroRNA-Target Interaction: Molecular Dynamics Simulations and Thermodynamics Analysis | MicroRNAs (miRNAs) are endogenously produced ∼21-nt riboregulators that associate with Argonaute (Ago) proteins to direct mRNA cleavage or repress the translation of complementary RNAs. Capturing the molecular mechanisms of miRNA interacting with its target will not only reinforce the understanding of underlying RNA in... | One of the biggest surprises at the beginning of the ‘post-genome era’ was the discovery of numerous genes encoding microRNAs. The number of microRNA genes is estimated to be nearly 1% of that of protein-coding genes, which were found in genomes of such diverse organisms as Caenorhabditis elegans, Drosophila melanogast... | As single-stranded RNA molecules of ∼21–23 nucleotide (nt) RNAs, microRNAs (miRNAs) post-transcriptionally regulate the eukaryotic gene expression by reducing the protein yield from specific target mRNAs, which function is crucial for control of a multitude of critical processes in both plant and animal cells [1], [2].... |
10.1371/journal.pgen.1003233 | Comparative Genome Structure, Secondary Metabolite, and Effector Coding Capacity across Cochliobolus Pathogens | The genomes of five Cochliobolus heterostrophus strains, two Cochliobolus sativus strains, three additional Cochliobolus species (Cochliobolus victoriae, Cochliobolus carbonum, Cochliobolus miyabeanus), and closely related Setosphaeria turcica were sequenced at the Joint Genome Institute (JGI). The datasets were used t... | The filamentous ascomycete genus Cochliobolus includes highly aggressive necrotrophic and hemibiotrophic pathogens with particular specificity to their host plants, often associated with production of host selective toxins (HST) that allow necrotrophs to trigger host cell death. Hemibiotrophs must keep their hosts aliv... | The filamentous ascomycete genus Cochliobolus (anamorph Bipolaris/Curvularia) is comprised of more than forty closely related, often highly aggressive, pathogenic species with particular specificity to their host plants. All members of the genus known to cause serious crop diseases fall in a tight phylogenetic group su... |
10.1371/journal.pgen.1002523 | Association of a Functional Variant in the Wnt Co-Receptor LRP6 with Early Onset Ileal Crohn's Disease | Ileal Crohn's Disease (CD), a chronic small intestinal inflammatory disorder, is characterized by reduced levels of the antimicrobial peptides DEFA5 (HD-5) and DEFA6 (HD-6). Both of these α-defensins are exclusively produced in Paneth cells (PCs) at small intestinal crypt bases. Different ileal CD–associated genes incl... | Crohn's Disease (CD) is to date incurable and is characterized by severe, reoccurring inflammations that can affect different intestinal locations. The complicated and multifactorial pathogenesis is not completely understood but involves disturbed epithelial barriers and immune reactions against the commensal flora in ... | Ileal Crohn's disease (CD) belongs to the group of inflammatory bowel diseases characterized by chronic intestinal inflammation, ulceration and consequent diarrhoea [1]. Both, environmental and inherited factors contribute to the disease risk [2], [3] and different genetic backgrounds likely explain variability in dise... |
10.1371/journal.pgen.1004402 | Mosaic Epigenetic Dysregulation of Ectodermal Cells in Autism Spectrum Disorder | DNA mutational events are increasingly being identified in autism spectrum disorder (ASD), but the potential additional role of dysregulation of the epigenome in the pathogenesis of the condition remains unclear. The epigenome is of interest as a possible mediator of environmental effects during development, encoding a... | Older mothers have a higher than expected risk of having a child with an autism spectrum disorder (ASD). The reason for this increased risk is unknown. The eggs of older mothers are more prone to abnormalities of chromosome numbers, suggesting this as one possible mechanism of the increased ASD risk. Age is also associ... | Progress in understanding the genetic basis of ASD has been substantial in recent years, with the development of microarray technologies allowing the identification of copy number variants associated with the disorder [1] and massively-parallel sequencing focused on protein-coding exons allowing insights into smaller m... |
10.1371/journal.pntd.0004478 | Prevalence of River Epilepsy in the Orientale Province in the Democratic Republic of the Congo | An increased prevalence of epilepsy has been reported in many onchocerciasis endemic areas.
To determine the prevalence and distribution of epilepsy in an onchocerciasis endemic region in the Democratic Republic of the Congo (DRC).
An epilepsy prevalence study was carried out in 2014, in two localities of the Bas-Uélé ... | An increased prevalence of epilepsy has been reported in many onchocerciasis (river blindness) endemic areas. In 2014, an epilepsy prevalence study was conducted in Dingila and Titule, two localities within the onchocerciasis endemic Orientale province of the Democratic Republic of Congo, both within the Bas-Uélé distr... | An association between onchocerciasis and epilepsy was suspected as early as the 1930’s in Mexico [1] and later reports were published showing clustering of epilepsy in several African onchocerciasis foci [2–7]. Ecological studies carried out in onchocerciasis endemic areas in West, Central and East Africa found a stro... |
10.1371/journal.pcbi.1002082 | The Dynamical Mechanism of Auto-Inhibition of AMP-Activated Protein Kinase | We use a novel normal mode analysis of an elastic network model drawn from configurations generated during microsecond all-atom molecular dynamics simulations to analyze the mechanism of auto-inhibition of AMP-activated protein kinase (AMPK). A recent X-ray and mutagenesis experiment (Chen, et al Nature 2009, 459, 1146... | AMP-activated protein kinase (AMPK) maintains the balance between ATP production and energy consumption in eukaryotic cells by responding to the rise of intracellular AMP. We report on a novel method that uses normal mode analysis of an elastic network model drawn from microsecond all-atom molecular dynamics simulation... | AMP-activated protein kinase (AMPK) is a highly conserved enzyme in eukaryotic cells that regulates cellular and whole-body energy homeostasis by phosphorylating a wide variety of substrates [1], [2], [3], [4]. The homolog of AMPK in yeast [5], [6], sucrose non-fermenting 1 (SNF1), has been widely used as a model syste... |
10.1371/journal.pgen.1002847 | A General G1/S-Phase Cell-Cycle Control Module in the Flowering Plant Arabidopsis thaliana | The decision to replicate its DNA is of crucial importance for every cell and, in many organisms, is decisive for the progression through the entire cell cycle. A comparison of animals versus yeast has shown that, although most of the involved cell-cycle regulators are divergent in both clades, they fulfill a similar r... | In order to grow, multicellular organisms need to multiply their cells. Cell proliferation is achieved through a complex order of events called the cell cycle, during which the nuclear DNA is duplicated and subsequently distributed to the newly forming daughter cells. The decision to replicate the nuclear DNA is in man... | Understanding the mechanisms of plant growth and differentiation is an important task, given the global biomass of land plants with approximately 600 billion tons of carbon [1]. Although cell proliferation is a main determinant of growth, relatively little is known about cell-cycle regulation in plants in comparison to... |
10.1371/journal.pgen.1002600 | Critical Evaluation of Imprinted Gene Expression by RNA–Seq: A New Perspective | In contrast to existing estimates of approximately 200 murine imprinted genes, recent work based on transcriptome sequencing uncovered parent-of-origin allelic effects at more than 1,300 loci in the developing brain and two adult brain regions, including hundreds present in only males or females. Our independent replic... | Typically both copies of mammalian genes are expressed, but in some cases, “imprinting” restricts expression to the maternal or paternal copy. Having two copies of each gene is considered advantageous since in enables compensation when one does not function properly. Why imprinting evolved and its utility to each sex i... | Why diploid organisms would forgo the safety-net of a redundant genome and preferentially express one allele in a parent-of-origin dependent manner has been a matter of debate since the discovery of imprinted transcription. Our understanding of this issue as well as the range of processes affected by imprinting is depe... |
10.1371/journal.pbio.0060204 | Direct Estimation of the Mitochondrial DNA Mutation Rate in Drosophila melanogaster | Mitochondrial DNA (mtDNA) variants are widely used in evolutionary genetics as markers for population history and to estimate divergence times among taxa. Inferences of species history are generally based on phylogenetic comparisons, which assume that molecular evolution is clock-like. Between-species comparisons have ... | Mitochondria are the energy-producing organelles of the cell, and they contain genetic information encoded on their own genome. Because rates of mutation for mitochondrial genomes are believed to be much higher than those in nuclear DNA, mitochondrial genetic differences between and within species are particularly usef... | Mitochondrial genetic variation between populations and species is widely used in dating evolutionary events and population movements [1]. These studies exploit several features of the mitochondrial genome, including its simple organization, lack of recombination, maternal mode of inheritance in many species, and, in a... |
10.1371/journal.pgen.1004187 | DNA Dynamics during Early Double-Strand Break Processing Revealed by Non-Intrusive Imaging of Living Cells | Chromosome breakage is a major threat to genome integrity. The most accurate way to repair DNA double strand breaks (DSB) is homologous recombination (HR) with an intact copy of the broken locus. Mobility of the broken DNA has been seen to increase during the search for a donor copy. Observing chromosome dynamics durin... | When chromosomes break, cells must repair them to avoid becoming abnormal, cancerous or dead. The most accurate repair mechanism is based on homologous recombination (HR), in which single strands generated next to the break seek an intact replica which is copied into the broken site. Changes in chromosome dynamics duri... | DNA double strand breaks (DSB) are a major threat to chromosome integrity and cell survival. Cells meet it by launching repair programs consisting of the enzymatic restoration of the DNA and of appropriate chromatin remodelling and checkpoint activation. The exposed DNA ends are protected by the Ku70-Ku80 complex (Ku c... |
10.1371/journal.pgen.1006994 | Ribosomal DNA copy number amplification and loss in human cancers is linked to tumor genetic context, nucleolus activity, and proliferation | Ribosomal RNAs (rRNAs) are transcribed from two multicopy DNA arrays: the 5S ribosomal DNA (rDNA) array residing in a single human autosome and the 45S rDNA array residing in five human autosomes. The arrays are among the most variable segments of the genome, exhibit concerted copy number variation (cCNV), encode essen... | The 45S and 5S ribosomal DNA (rDNA) arrays contain hundreds of rDNA copies, with substantial variability across individuals in human populations. Although physically unlinked, the arrays also exhibit joint variation across individual genotypes. However, whether this co-variation in copy number (CN) is universally obser... | The ribosomal DNA (rDNA) arrays give origin to the nucleolus, the nuclear organelle that is the site of ribosomal RNA (rRNA) transcription and ribosome biogenesis [1]. The rRNAs constitute the vast majority of cellular RNAs and are encoded from two kinds of tandemly repeated ribosomal DNA (rDNA) arrays [2–5]. The 45S r... |
10.1371/journal.pgen.1002180 | Replication and Explorations of High-Order Epistasis Using a Large Advanced Intercross Line Pedigree | Dissection of the genetic architecture of complex traits persists as a major challenge in biology; despite considerable efforts, much remains unclear including the role and importance of genetic interactions. This study provides empirical evidence for a strong and persistent contribution of both second- and third-order... | This study provides evidence for a strong and persistent contribution of epistatic interactions to the selection response in two chicken lines subjected to 50 generations of divergent selection for 8-week body weight. We show that the genetic architecture of the trait involves genetic interactions of both second- and t... | The regulation of most biological traits is complex and results from the action and interaction of multiple genes and environmental factors. Phenotypic variability within populations resulting from polymorphisms in the genes regulating these traits is the key to evolutionary change of the phenotypes over time, resultin... |
10.1371/journal.ppat.1007964 | Members of chitin synthase family in Metarhizium acridum differentially affect fungal growth, stress tolerances, cell wall integrity and virulence | Chitin is an important component of the fungal cell wall with a family of chitin synthases mediating its synthesis. Here, we report on the genetic characterization of the full suite of seven chitin synthases (MaChsI-VII) identified in the insect pathogenic fungus, Metarhizium acridum. Aberrant distribution of chitin wa... | The fungal cell wall is a dynamic and flexible organelle that modulates the interaction of the pathogen with its host and acts as a critical recognition and evasion interface with host defenses. Chitin is a hallmark constituent of the fungal cell wall and all fungi contain multiple chitin synthase (Chs) genes. However,... | The fungal cell wall is a dynamic and flexible organelle that modulates the interaction of the organism with its environment and, in the case of pathogens, acts as a critical recognition and evasion interface with host defenses [1]. Chitin, a homopolymer of β-(1/4)–linked N-acetylglucosamine, is a basic component of th... |
10.1371/journal.pgen.1007388 | Specific detection of fission yeast primary septum reveals septum and cleavage furrow ingression during early anaphase independent of mitosis completion | It is widely accepted in eukaryotes that the cleavage furrow only initiates after mitosis completion. In fission yeast, cytokinesis requires the synthesis of a septum tightly coupled to cleavage furrow ingression. The current cytokinesis model establishes that simultaneous septation and furrow ingression only initiate ... | Fission yeast cytokinesis requires the invagination of the equatorial plasma membrane (cleavage furrow ingression) coupled to the synthesis of a special wall structure named septum (septation). Despite Cdk1 kinase is inactivated in early anaphase, it is believed that cleavage furrow ingression and septation onset requi... | The division of a cell into two genetically identical daughter cells requires the accurate coordination of events such as the entry into mitosis, chromosome segregation, and cytokinesis. Thus, precise timing of the late mitotic events is critical for faithful chromosome segregation and genome integrity. The events occu... |
10.1371/journal.pgen.1004796 | Inversion of the Chromosomal Region between Two Mating Type Loci Switches the Mating Type in Hansenula polymorpha | Yeast mating type is determined by the genotype at the mating type locus (MAT). In homothallic (self-fertile) Saccharomycotina such as Saccharomyces cerevisiae and Kluveromyces lactis, high-efficiency switching between a and α mating types enables mating. Two silent mating type cassettes, in addition to an active MAT l... | The mating system of Saccharomycotina has evolved from the ancestral heterothallic system as seen in Yarrowia lipolytica to homothallism as seen in Saccharomyces cerevisiae. The acquisition of silent cassettes was an important step towards homothallism. However, some Saccharomycotina species that diverged from the comm... | Many yeast species have a sexual cycle as well as an asexual proliferation cycle. Sexual reproduction in yeast is initiated by the recognition of a mating partner and cell fusion, followed by nuclear fusion to form diploid cells that undergo meiosis and produce haploid progeny. In most ascomycetous yeast, cell-cell rec... |
10.1371/journal.pgen.1000020 | Identification of Genetic and Chemical Modulators of Zebrafish Mechanosensory Hair Cell Death | Inner ear sensory hair cell death is observed in the majority of hearing and balance disorders, affecting the health of more than 600 million people worldwide. While normal aging is the single greatest contributor, exposure to environmental toxins and therapeutic drugs such as aminoglycoside antibiotics and antineoplas... | Loss of sensory hair cells in the inner ear is observed in the majority of hearing and balance disorders, affecting the health of more than 600 million people worldwide. Exposure to environmental toxins and certain pharmaceutical drugs such as aminoglycoside antibiotics and some cancer chemotherapy agents account for m... | Hearing loss and vestibular dysfunction are among the most common disorders requiring medical attention. Globally, over a third of older adults suffer from these conditions. Studies of both laboratory animals and humans reveal tremendous variation in hearing loss due to ageing as well as exogenous challenges such as ot... |
10.1371/journal.ppat.1005401 | Differential Toxicity of Antibodies to the Prion Protein | Antibodies against the prion protein PrPC can antagonize prion replication and neuroinvasion, and therefore hold promise as possible therapeutics against prion diseases. However, the safety profile of such antibodies is controversial. It was originally reported that the monoclonal antibody D13 exhibits strong target-re... | The human prion disease, Creutzfeldt-Jakob disease (CJD), is a progressive neurodegenerative syndrome. Although far less prevalent, CJD shows many molecular and clinical similarities to Alzheimer's disease, such as the buildup of protein aggregates in the brain and the absence of effective treatments. Many attempts at ... | Active and passive immunotherapy that foster the clearance of pathological aggregates represent potential therapeutic strategies against diseases caused by the inappropriate aggregation of proteins [1]. While considerable effort has been devoted to the immunotherapy of Alzheimer's disease with antibodies against the Aβ... |
10.1371/journal.pcbi.1004878 | Oscillations via Spike-Timing Dependent Plasticity in a Feed-Forward Model | Neuronal oscillatory activity has been reported in relation to a wide range of cognitive processes including the encoding of external stimuli, attention, and learning. Although the specific role of these oscillations has yet to be determined, it is clear that neuronal oscillations are abundant in the central nervous sy... | Oscillatory activity in the brain has been described in relation to many cognitive states and tasks, including the encoding of external stimuli, attention, learning and consolidation of memory. However, without tuning of synaptic weights with the preferred phase of firing the oscillatory signal may not be able to propa... | It is generally believed that synaptic plasticity is the basis for learning and memory. According to Hebb's rule [1], which is considered the foundation for current views on learning and memory, the interaction strength between two neurons that are co-activated potentiates. This rule has been extended to the temporal d... |
10.1371/journal.ppat.1007628 | NDRG1 facilitates the replication and persistence of Kaposi’s sarcoma-associated herpesvirus by interacting with the DNA polymerase clamp PCNA | Kaposi’s sarcoma-associated herpesvirus (KSHV) latently infects host cells and establishes lifelong persistence as an extra-chromosomal episome in the nucleus. To persist in proliferating cells, the viral genome typically replicates once per cell cycle and is distributed into daughter cells. This process involves host ... | KSHV latently infects cells and establishes lifelong persistence, but the underlying mechanisms of this process has not been fully elucidated. Here, we find a novel host protein NDRG1 is highly up-regulated by KSHV infection and the viral protein LANA is essential in this process. NDRG1 is a multiple functional protein... | Kaposi’s sarcoma-associated herpesvirus (KSHV), a human oncogenic DNA gammaherpesvirus, is known for its causal association with human cancers, including endothelial-derived Kaposi’s sarcoma (KS), a B cell malignancy named primary effusion lymphoma (PEL), and a plasmablastic form of the B lymphoproliferative disorder n... |
10.1371/journal.pntd.0005976 | Chikungunya virus dissemination from the midgut of Aedes aegypti is associated with temporal basal lamina degradation during bloodmeal digestion | In the mosquito, the midgut epithelium is the initial tissue to become infected with an arthropod-borne virus (arbovirus) that has been acquired from a vertebrate host along with a viremic bloodmeal. Following its replication in midgut epithelial cells, the virus needs to exit the midgut and infect secondary tissues in... | The biological nature of the midgut escape barrier in insects for arthropod-borne viruses has been a mystery for decades. Here we show that the basal lamina (BL) surrounding the mosquito midgut acts as a barrier for chikungunya virus, an alphavirus, which has emerged in the New World hemisphere around three years ago. ... | Aedes aegypti is the primary vector for important human pathogenic arboviruses such as dengue virus (Flaviviridae; Flavivirus; DENV1-4), chikungunya virus (Togaviridae; Alphavirus; CHIKV), and Zika virus (Flaviviridae; Flavivirus; ZIKV) [1,2]. Following acquisition of a viremic bloodmeal from a human, viruses such as C... |
10.1371/journal.pgen.1008143 | Biallelic HEPHL1 variants impair ferroxidase activity and cause an abnormal hair phenotype | Maintenance of the correct redox status of iron is functionally important for critical biological processes. Multicopper ferroxidases play an important role in oxidizing ferrous iron, released from the cells, into ferric iron, which is subsequently distributed by transferrin. Two well-characterized ferroxidases, cerulo... | Multi-copper ferroxidases play a critical role in maintaining iron homeostasis in humans. Two well-characterized ferroxidases, ceruloplasmin and hephaestin, facilitate iron transport in different tissues by oxidizing ferrous iron to the ferric form, which is subsequently carried by transferrin. Hephaestin like 1 (HEPHL... | Iron is an essential trace element and constituent of important cellular proteins that include hemoglobin, myoglobin, flavoproteins, cytochromes and various non-heme enzymes. Transfer of electrons via oxidation–reduction (redox) reactions results in the conversion of iron between its ferrous [Fe (II)] and ferric [Fe (I... |
10.1371/journal.pgen.1000761 | Regulators of AWC-Mediated Olfactory Plasticity in Caenorhabditis elegans | While most sensory neurons will adapt to prolonged stimulation by down-regulating their responsiveness to the signal, it is not clear which events initiate long-lasting sensory adaptation. Likewise, we are just beginning to understand how the physiology of the adapted cell is altered. Caenorhabditis elegans is inherent... | Caenorhabditis elegans is capable of sensing a variety of attractive volatile compounds. These odors are the worm's “best guesses” as to how to track down food. Employing calculated approximations underlies a foraging strategy that is open to failure. When C. elegans track an odor which proves unrewarding, they must mo... | Olfactory adaptation may subserve a food-seeking strategy in C. elegans. Since the sources of many odors that are inherently attractive to C. elegans do not, in fact, provide a source of nutrition, the worm may have to discriminate between rewarding and unrewarding stimuli by adapting to nutritionally profitless odors.... |
10.1371/journal.pntd.0005036 | Validation and Application of a Commercial Quantitative Real-Time Reverse Transcriptase-PCR Assay in Investigation of a Large Dengue Virus Outbreak in Southern Taiwan | Accurate, rapid, and early diagnosis of dengue virus (DENV) infections is essential for optimal clinical care. Here, we evaluated the efficacy of the quantitative real-time PCR (qRT-PCR)-LightMix dengue virus EC kit for DENV detection using samples from a dengue outbreak in Taiwan in 2015.
Sera from patients with suspe... | The LightMix dengue virus EC qRT-PCR assay is effective for early diagnosis of DENV infection. High viral loads during primary infection in elderly patients may comprise a positive predictor for severe illness, and may contribute to high mortality rates.
| Dengue virus (DENV) is a member of the viral genus Flavivirus (family Flaviviridae) that is transmitted by mosquitos, causing endemic and epidemic outbreaks in tropical and subtropical areas. It is estimated that approximately 390 million people are infected with DENV globally each year, resulting in disease manifestat... |
10.1371/journal.pgen.1002406 | A Comprehensive Analysis of Shared Loci between Systemic Lupus Erythematosus (SLE) and Sixteen Autoimmune Diseases Reveals Limited Genetic Overlap | In spite of the well-known clustering of multiple autoimmune disorders in families, analyses of specific shared genes and polymorphisms between systemic lupus erythematosus (SLE) and other autoimmune diseases (ADs) have been limited. Therefore, we comprehensively tested autoimmune variants for association with SLE, aim... | It is well known that multiple autoimmune disorders cluster in families. However, all of the genetic variants that explain this clustering have not been discovered, and the specific genetic variants shared between systemic lupus erythematosus (SLE) and other autoimmune diseases (ADs) are not known. In order to better u... | Systemic lupus erythematosus (SLE [MIM 152700]) is a chronic and severe systemic autoimmune disease characterized by the production of high titers of autoantibodies directed against native DNA and other cellular constituents. It is a prototypic autoimmune disease with heterogeneous clinical manifestations that may invo... |
10.1371/journal.ppat.1002302 | Trafficking of Hepatitis C Virus Core Protein during Virus Particle Assembly | Hepatitis C virus (HCV) core protein is directed to the surface of lipid droplets (LD), a step that is essential for infectious virus production. However, the process by which core is recruited from LD into nascent virus particles is not well understood. To investigate the kinetics of core trafficking, we developed met... | Hepatitis C virus (HCV) infects almost 200 million people worldwide, causing both acute and chronic liver disease. Although some antiviral treatments exist, they are not fully effective against all HCV genotypes and have serious side effects. In order to develop more effective treatment strategies, a better understandi... | Hepatitis C virus (HCV) is a major cause of acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. HCV is an enveloped, positive-strand RNA virus classified with the Family Flaviviridae [1]. The viral genome encodes an open reading frame of ≈3011 codons that is translated as a single polyprotein, which i... |
10.1371/journal.pbio.2005536 | The noisy basis of morphogenesis: Mechanisms and mechanics of cell sheet folding inferred from developmental variability | Variability is emerging as an integral part of development. It is therefore imperative to ask how to access the information contained in this variability. Yet most studies of development average their observations and, discarding the variability, seek to derive models, biological or physical, that explain these average... | Biological noise is unavoidable in—and even necessary for—development. Here, we ask whether this variability can teach us something about the process that underlies it. We show how to access the information hidden in the variability in an analysis of the variability of cell sheet folding in the green alga Volvox globat... | ‘The phenomena are always the same, and this is what matters to us, but their variations, for the greater or for the lesser, are beyond count.’ Thus opined Xavier Bichat in the account of his investigations into life and death [1] and thereby spelt out how, to the present day, questions in developmental biology and cel... |
10.1371/journal.pgen.1006246 | Competing for Iron: Duplication and Amplification of the isd Locus in Staphylococcus lugdunensis HKU09-01 Provides a Competitive Advantage to Overcome Nutritional Limitation | Staphylococcus lugdunensis is a coagulase negative bacterial pathogen that is particularly associated with severe cases of infectious endocarditis. Unique amongst the coagulase-negative staphylococci, S. lugdunensis harbors an iron regulated surface determinant locus (isd). This locus facilitates the acquisition of hem... | Sometimes changing environmental conditions force bacteria to boost protein expression above the level that can be achieved by transcriptional or translational control. Gene duplication and amplification (GDA) represents a simple and effective means to augment protein expression and is frequently associated with the de... | Bacterial pathogens possess a tremendous ability to adapt to changing environmental conditions. This is especially noticeable within the hospital setting where strong artificial selective pressures such as antibiotics and disinfectants drive the evolution of pathogens to develop resistance to these agents. In contrast,... |
10.1371/journal.pgen.1005308 | The SMC Loader Scc2 Promotes ncRNA Biogenesis and Translational Fidelity | The Scc2-Scc4 complex is essential for loading the cohesin complex onto DNA. Cohesin has important roles in chromosome segregation, DSB repair, and chromosome condensation. Here we report that Scc2 is important for gene expression in budding yeast. Scc2 and the transcriptional regulator Paf1 collaborate to promote the ... | The structure of chromosomes contributes to the production of RNAs. Chromosome structure is maintained in part by an evolutionarily conserved group of proteins known as structural maintenance of chromosomes proteins. These proteins are loaded onto chromosomes by a second evolutionarily conserved protein complex known a... | Cohesion between sister chromatids generates the force that holds sister chromatids together until the onset of anaphase [1]. Cohesion is generated by cohesin, an evolutionarily conserved multi-subunit protein complex consisting of four core subunits: Smc1, Smc3, the α-kleisin subunit Mcd1/Scc1/Rad21, and the HEAT repe... |
10.1371/journal.pcbi.1005098 | Population Density Modulates Drug Inhibition and Gives Rise to Potential Bistability of Treatment Outcomes for Bacterial Infections | The inoculum effect (IE) is an increase in the minimum inhibitory concentration (MIC) of an antibiotic as a function of the initial size of a microbial population. The IE has been observed in a wide range of bacteria, implying that antibiotic efficacy may depend on population density. Such density dependence could have... | The pace of antibiotic discovery has rapidly slowed in the last few decades, creating an urgent need to reevaluate and optimize therapies based on current drugs. In this work, we combine quantitative laboratory experiments on bacterial populations with mathematical models of antimicrobial therapies to demonstrate that ... | The inhibitory effects of antibiotics often decrease with increasing density of the starting microbial population, a phenomenon known as the inoculum effect [1]. While the IE is commonly attributed to enzymatic degradation of the drug [2, 3]—with the classical example being the degradation of β-lactams by a β-lactamase... |
10.1371/journal.ppat.1002282 | A Wide Extent of Inter-Strain Diversity in Virulent and Vaccine Strains of Alphaherpesviruses | Alphaherpesviruses are widespread in the human population, and include herpes simplex virus 1 (HSV-1) and 2, and varicella zoster virus (VZV). These viral pathogens cause epithelial lesions, and then infect the nervous system to cause lifelong latency, reactivation, and spread. A related veterinary herpesvirus, pseudor... | Alphaherpesviruses such as herpes simplex virus (HSV) are ubiquitous in the human population. HSV causes oral and genital lesions, and has co-morbidities in acquisition and spread of human immunodeficiency virus (HIV). The lack of a vaccine for HSV hinders medical progress for both of these infections. A related veteri... | Alphaherpesviruses are widespread in the human population, with herpes simplex virus 1 (HSV1) and 2 causing oral and genital lesions, respectively, while varicella zoster virus (VZV) causes chicken pox and shingles [1]–[3]. In the agricultural industry, a related veterinary alphaherpesvirus, pseudorabies virus (PRV), c... |
10.1371/journal.pbio.1000621 | Hydrogen Peroxide Promotes Injury-Induced Peripheral Sensory Axon Regeneration in the Zebrafish Skin | Functional recovery from cutaneous injury requires not only the healing and regeneration of skin cells but also reinnervation of the skin by somatosensory peripheral axon endings. To investigate how sensory axon regeneration and wound healing are coordinated, we amputated the caudal fins of zebrafish larvae and imaged ... | Touch-sensing neurons project axonal processes that branch extensively within the outer layers of skin to detect touch stimuli. Recovering from skin injuries thus requires not only repair of damaged skin tissue but also regeneration of the sensory axons innervating it. To study whether skin wound healing is coordinated... | Successful wound repair and regeneration requires coordination between the various cell types that make up the injured tissue. For example, following injuries that damage both epidermis and sensory endings, wounded epidermis promotes the regeneration of nerve fibers [1],[2]. Conversely, complete epidermal wound healing... |
10.1371/journal.pntd.0006285 | Prospective evaluation of accuracy and clinical utility of the Dual Path Platform (DPP) assay for the point-of-care diagnosis of leptospirosis in hospitalized patients | Early detection of leptospirosis with field-ready diagnostics may improve clinical management and mitigate outbreaks. We previously validated the point-of-care Dual Path Platform (DPP) for leptospirosis with sera in the laboratory. This prospective study compares the diagnostic accuracy and clinical utility of the DPP ... | The reliable, portable, point-of-care DPP assay effectively discriminates case status for patients presenting to hospital with acute febrile syndromes consistent with classic leptospirosis. Diagnostic accuracy of the finger stick DPP using the initial acute-phase specimen at the bedside is similar to serum DPP and IgM-... | Leptospirosis is an important global cause of acute fever and a leading cause of morbidity among zoonotic diseases [1]. Annually, more than 1 million cases and 50,000 deaths occur worldwide [2], and disease burden is estimated at 2.9 million disability adjusted life years (DALYs) [3]. Approximately 5–10% of symptomatic... |
10.1371/journal.pgen.1008287 | Functionalization of CD36 cardiovascular disease and expression associated variants by interdisciplinary high throughput analysis | CD36 is a platelet membrane glycoprotein whose engagement with oxidized low-density lipoprotein (oxLDL) results in platelet activation. The CD36 gene has been associated with platelet count, platelet volume, as well as lipid levels and CVD risk by genome-wide association studies. Platelet CD36 expression levels have be... | Platelets are anucleate cells that are best known as regulators of vascular hemostasis and thrombosis but also play important roles in cancer, angiogenesis, and inflammation. CD36 is a platelet surface marker that can activate platelet in response to oxidized low density lipoprotein (oxLDL). CD36 has been associated wi... | Cardiovascular disease (CVD) remains the number one cause of death globally [1]. Myocardial infarctions (MI) are acute events in CVD which are frequently the proximal causes of death or severe disability which are the result of platelet-rich thrombi [2]. Genome wide association studies (GWASs) have identified numerous ... |
10.1371/journal.pntd.0003820 | Ex Vivo Host and Parasite Response to Antileishmanial Drugs and Immunomodulators | Therapeutic response in infectious disease involves host as well as microbial determinants. Because the immune and inflammatory response to Leishmania (Viannia) species defines the outcome of infection and efficacy of treatment, immunomodulation is considered a promising therapeutic strategy. However, since Leishmania ... | Host determinants of the response to infection have increasingly been recognized as therapeutically relevant targets. Despite the pathogenesis of dermal leishmaniasis being mediated by the immune and inflammatory response, in vitro anti-leishmanial drug screening has been based on antimicrobial effect without considera... | The outcome of treatment of leishmaniasis and other infectious diseases is multi-factorial involving host as well as microbial determinants; yet evaluation of antimicrobial drug susceptibility is limited to assessment of drug effects on microbial pathogens and toxicity. However, the efficacy of antimicrobial treatment ... |
10.1371/journal.pcbi.1000512 | Transcriptional Profiling of the Dose Response: A More Powerful Approach for Characterizing Drug Activities | The dose response curve is the gold standard for measuring the effect of a drug treatment, but is rarely used in genomic scale transcriptional profiling due to perceived obstacles of cost and analysis. One barrier to examining transcriptional dose responses is that existing methods for microarray data analysis can iden... | Transcriptional profiling is arguably the most powerful hypothesis-free method for investigating biological effects of drugs—so why do the experiments typically use outmoded single-dose designs? Such single-dose experiments will co-mingle effects that can occur with different potency (e.g., effects on the known target ... | The necessity of dose information in interpreting drug effects has been recognized since the 16th century, when Paracelsus observed: “All things are poison, and nothing is without poison: the dose alone makes a thing not poison” [1]. Today, dose-response models are routinely used to evaluate drug effects in biochemical... |
10.1371/journal.pntd.0004407 | Use of a Chagas Urine Nanoparticle Test (Chunap) to Correlate with Parasitemia Levels in T. cruzi/HIV Co-infected Patients | Early diagnosis of reactivated Chagas disease in HIV patients could be lifesaving. In Latin America, the diagnosis is made by microscopical detection of the T. cruzi parasite in the blood; a diagnostic test that lacks sensitivity. This study evaluates if levels of T. cruzi antigens in urine, determined by Chunap (Chaga... | Reactivation of Chagas disease in people living with HIV is a serious clinical condition that is associated with high mortality. Hence, early diagnosis and treatment can be lifesaving. Although there are not well accepted criteria to identify patients at risk of reactivation, parasitemia levels are usually considered a... | Chagas disease, caused by the protozoan Trypanosoma cruzi, affects an estimated 7.8 million people in the Americas [1]. Similar to HIV infection, Chagas disease is most prevalent in the adult population [2]. Massive rural-to-urban migration throughout has brought many cases of chronic Chagas disease into the city where... |
10.1371/journal.pntd.0005017 | DNA Microarray Platform for Detection and Surveillance of Viruses Transmitted by Small Mammals and Arthropods | Viruses transmitted by small mammals and arthropods serve as global threats to humans. Most emergent and re-emergent viral agents are transmitted by these groups; therefore, the development of high-throughput screening methods for the detection and surveillance of such viruses is of great interest. In this study, we de... | Viruses transmitted by small mammals and blood-feeding insects represent global threats to humans. Most emergent viral agents are transmitted by these groups; therefore, the development of methods for the detection and surveillance of such viruses is of great interest. Here, we describe a DNA microchip platform (SMAvir... | Human activity is responsible for global environmental and climate changes, which can negatively impact human health. Uncontrolled urbanization, deforestation, large-scale agriculture, road construction, dam building, and rapid expansion of global trade and air travel are important factors that have been associated wit... |
10.1371/journal.ppat.1002845 | Identification and Targeting of an Interaction between a Tyrosine Motif within Hepatitis C Virus Core Protein and AP2M1 Essential for Viral Assembly | Novel therapies are urgently needed against hepatitis C virus infection (HCV), a major global health problem. The current model of infectious virus production suggests that HCV virions are assembled on or near the surface of lipid droplets, acquire their envelope at the ER, and egress through the secretory pathway. The... | Novel antiviral strategies are needed to combat the HCV pandemic. Understanding viral-host determinants involved in mediating assembly is critical for the development of drugs targeting this stage of the HCV life cycle. We identified a conserved heretofore unrecognized tyrosine motif within core, which is homologous to... | HCV is a major cause of liver disease, estimated to infect 170 million people worldwide [1]. Although combining interferon-ribavirin-based regimens with HCV protease or polymerase inhibitors improves response rates, resistance and toxicity continue to pose major challenges [2]. A “cocktail” of drugs, each targeting an ... |
10.1371/journal.ppat.1005008 | Expression of the Blood-Group-Related Gene B4galnt2 Alters Susceptibility to Salmonella Infection | Glycans play important roles in host-microbe interactions. Tissue-specific expression patterns of the blood group glycosyltransferase β-1,4-N-acetylgalactosaminyltransferase 2 (B4galnt2) are variable in wild mouse populations, and loss of B4galnt2 expression is associated with altered intestinal microbiota. We hypothes... | Human blood groups are among the oldest known genetic polymorphisms. It has been proposed that blood group variation is a byproduct of pathogen-driven selection, including in the gastrointestinal tract where blood-group-related genes are often variably expressed. The B4galnt2 gene is responsible for the synthesis of th... | The luminal surface of the intestinal mucosa is covered by distinct layers of highly glycosylated mucus that form a physical barrier between the intestinal microbial community and the host’s tissues. In addition to their important roles in host metabolism and signaling, glycans are known to contribute to the compositio... |
10.1371/journal.pbio.2004921 | Molecular mechanism of the tree shrew’s insensitivity to spiciness | Spicy foods elicit a pungent or hot and painful sensation that repels almost all mammals. Here, we observe that the tree shrew (Tupaia belangeri chinensis), which possesses a close relationship with primates and can directly and actively consume spicy plants. Our genomic and functional analyses reveal that a single poi... | Most mammals cannot tolerate the pungent sensation, such as that evoked by eating chili peppers. Here, we show that unexpectedly, the tree shrew, a mammal closely related to primates, can consume pungent plants. We determined that this tolerance is caused by an amino acid change in the tree shrew’s transient receptor p... | Many plants contain pungent chemicals that deter animals from consuming them. Particularly, the genus Capsicum encompasses 22 wild species and produces a capsaicinoid called capsaicin, which is a pungent substance [1,2]. One of these species, the chili pepper, is a low shrub with capsaicin-containing fruits that are re... |
10.1371/journal.pgen.1007749 | Genome-wide CRISPR-dCas9 screens in E. coli identify essential genes and phage host factors | High-throughput genetic screens are powerful methods to identify genes linked to a given phenotype. The catalytic null mutant of the Cas9 RNA-guided nuclease (dCas9) can be conveniently used to silence genes of interest in a method also known as CRISPRi. Here, we report a genome-wide CRISPR-dCas9 screen using a startin... | Over the past few years, CRISPR-Cas technologies have emerged as powerful tools to edit genomes and modulate gene expression. They have been applied to perform high-throughput genetic screens with the purpose to understand the function of genes in a systematic manner, but the application of these screens to bacteria ha... | The technological applications of RNA-guided nucleases derived from the Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) prokaryotic immune system [1–3] represents a true paradigm shift in our ability to manipulate cells at the genetic level [4]. In particular, the Cas9 nuclease from type II systems ca... |
10.1371/journal.pcbi.1001100 | Effect of Promoter Architecture on the Cell-to-Cell Variability in Gene Expression | According to recent experimental evidence, promoter architecture, defined by the number, strength and regulatory role of the operators that control transcription, plays a major role in determining the level of cell-to-cell variability in gene expression. These quantitative experiments call for a corresponding modeling ... | Stochastic chemical kinetics provides a framework for modeling gene regulation at the single-cell level. Using this framework, we systematically investigate the effect of promoter architecture, that is, the number, quality and position of transcription factor binding sites, on cell-to-cell variability in transcription ... | A fundamental property of all living organisms is their ability to gather information about their environment and adjust their internal physiological state in response to environmental conditions. This property, shared by all organisms, includes the ability of single-cells to respond to changes in their environment by ... |
10.1371/journal.ppat.1003008 | Whole Genome Sequencing Reveals Local Transmission Patterns of Mycobacterium bovis in Sympatric Cattle and Badger Populations | Whole genome sequencing (WGS) technology holds great promise as a tool for the forensic epidemiology of bacterial pathogens. It is likely to be particularly useful for studying the transmission dynamics of an observed epidemic involving a largely unsampled ‘reservoir’ host, as for bovine tuberculosis (bTB) in British a... | Whole genome sequencing (WGS) offers the potential for unprecedented insight into infectious diseases spread at the individual-to-individual level. However, this potential can be compromised when a poorly sampled ‘reservoir’ population contributes to transmission, as strong biases in the obtained data are inevitable. T... | The application of whole genome sequencing (WGS) technology to infectious bacterial diseases has resulted in unprecedented advances in our ability to resolve epidemic data at the global scale [1], [2], provided new insights into within-host replication processes [3], and been used to corroborate the importance of exhau... |
10.1371/journal.pcbi.1000503 | Eradication of Chronic Myeloid Leukemia Stem Cells: A Novel Mathematical Model Predicts No Therapeutic Benefit of Adding G-CSF to Imatinib | Imatinib mesylate induces complete cytogenetic responses in patients with chronic myeloid leukemia (CML), yet many patients have detectable BCR-ABL transcripts in peripheral blood even after prolonged therapy. Bone marrow studies have shown that this residual disease resides within the stem cell compartment. Quiescence... | Imatinib mesylate (Gleevec) is currently the standard treatment for chronic myeloid leukemia (CML) and elicits a large reduction in leukemic cell burden in most patients. However, strong evidence suggests that imatinib does not cure the disease; approximately 20% of patients relapse within three years, and discontinuat... | The existence of cancer stem cells, a rare subpopulation of cancer cells responsible for tumor initiation and maintenance, was first postulated in the 1960s [1]. In leukemia in particular, increasing evidence suggests that leukemic stem cells are the only cells within the tumor capable of propagating the disease [2]–[6... |
10.1371/journal.pbio.2005066 | Spore-autonomous fluorescent protein expression identifies meiotic chromosome mis-segregation as the principal cause of hybrid sterility in yeast | Genome-wide sequence divergence between populations can cause hybrid sterility through the action of the anti-recombination system, which rejects crossover repair of double strand breaks between nonidentical sequences. Because crossovers are necessary to ensure proper segregation of homologous chromosomes during meiosi... | Different species are kept genetically separated from each other by reproductive isolation, which can result in the production of sterile hybrids. Despite the central role of reproductive isolation in evolutionary biology, the mechanisms underlying hybrid sterility remain controversial. We focus on one potential cause:... | Separate species are often reproductively isolated by intrinsic postzygotic mechanisms. The diverged genomes from two different parental populations may not interact properly when combined in a hybrid, resulting in reduced fertility, reduced viability, or both [1]. Errors during gamete production, particularly problems... |
10.1371/journal.pbio.1000600 | Exceptional Diversity, Maintenance of Polymorphism, and Recent Directional Selection on the APL1 Malaria Resistance Genes of Anopheles gambiae | The three-gene APL1 locus encodes essential components of the mosquito immune defense against malaria parasites. APL1 was originally identified because it lies within a mapped QTL conferring the vector mosquito Anopheles gambiae natural resistance to the human malaria parasite, Plasmodium falciparum, and APL1 genes hav... | Immune defense genes are sometimes highly variable in host populations, reflecting selective pressure to combat diverse pathogens. In other instances, where there are only a few dominant pathogens, natural selection may favor only one or a few defense alleles. Here, we show that both adaptive strategies can occur in th... | Approximately 250 million human malaria cases are reported annually, most of them occurring in sub-Saharan Africa [1]. The vast majority of these are caused by the malaria parasite Plasmodium falciparum, vectored by the mosquito Anopheles gambiae [2]. However, many wild A. gambiae are genetically resistant to P. falcip... |
10.1371/journal.pntd.0007633 | Characterization of Entamoeba histolytica adenosine 5′-phosphosulfate (APS) kinase; validation as a target and provision of leads for the development of new drugs against amoebiasis | Amoebiasis, caused by Entamoeba histolytica infection, is a global public health problem. However, available drugs to treat amoebiasis are currently limited, and no effective vaccine exists. Therefore, development of new preventive measures against amoebiasis is urgently needed.
Here, to develop new drugs against amoeb... | Amoebiasis is a parasitic disease caused by Entamoeba histolytica that is an important health problem worldwide because of high morbidity and mortality rates. However, clinical options are inadequate; therefore, developing new preventive measures, such as anti-amoebic drugs, is urgently needed. In general, for the deve... | Amoebiasis, a parasitic disease, causes high morbidity and mortality; approximately 50 million cases of disease and 40,000–70,000 deaths annually [1]. Typical symptoms of this disease include diarrhea, dysentery, fever, and abdominal pains, which are diagnosed as intestinal manifestations. Patients sometimes develop ex... |
10.1371/journal.pbio.1002188 | The BEACH Domain Protein SPIRRIG Is Essential for Arabidopsis Salt Stress Tolerance and Functions as a Regulator of Transcript Stabilization and Localization | Members of the highly conserved class of BEACH domain containing proteins (BDCPs) have been established as broad facilitators of protein–protein interactions and membrane dynamics in the context of human diseases like albinism, bleeding diathesis, impaired cellular immunity, cancer predisposition, and neurological dysf... | BEACH (beige and Chediak Higashi) domain containing proteins (BDCPs) are a highly conserved protein family in eukaryotes. BDCPs are known to be important for membrane dynamics such as vesicle transport, membrane fission and fusion events, and autophagy. Here we describe a new, membrane-independent molecular function of... | BEACH (beige and Chediak Higashi) domain containing proteins (BDCPs) represent a highly conserved protein family in eukaryotes [1,2]. Initially, the BEACH domain was described as a protein motif in the human lysosomal trafficking regulator protein (LYST). Mutations in LYST cause the autosomal recessive human Chediak Hi... |
10.1371/journal.ppat.1004113 | Structural Basis for the Ubiquitin-Linkage Specificity and deISGylating Activity of SARS-CoV Papain-Like Protease | Severe acute respiratory syndrome coronavirus (SARS-CoV) encodes a papain-like protease (PLpro) with both deubiquitinating (DUB) and deISGylating activities that are proposed to counteract the post-translational modification of signaling molecules that activate the innate immune response. Here we examine the structural... | All coronaviruses such as the SARS virus and the recently identified Middle East Respiratory Syndrome (MERS) virus encode in their genomes at least one papain-like protease (PLpro) enzyme that has two distinct functions in viral pathogenesis. The first function is to process the viral polyprotein into individual protei... | Ubiquitin (Ub), a 76-amino-acid protein, is the building block for a set of versatile, post-translational modifications that regulate a number of cellular pathways, including many processes associated with combating viral infection [1]. Through the action of activating and conjugating enzymes, the C-terminus of ubiquit... |
10.1371/journal.pgen.1005878 | An Energy-Independent Pro-longevity Function of Triacylglycerol in Yeast | Intracellular triacylglycerol (TAG) is a ubiquitous energy storage lipid also involved in lipid homeostasis and signaling. Comparatively, little is known about TAG’s role in other cellular functions. Here we show a pro-longevity function of TAG in the budding yeast Saccharomyces cerevisiae. In yeast strains derived fro... | Triacylglycerol (TAG) is a ubiquitous lipid species well-known for its roles in storing surplus energy, providing insulation, and maintaining cellular lipid homeostasis. Here we present evidence for a novel pro-longevity function of TAG in the budding yeast, a model organism for aging research. Yeast cells that are gen... | Lipid is essential for all life forms on earth. Polar lipids, most notably phospholipids, are the primary components of biological membranes, whereas neutral lipids such as triacylglycerols (TAG; or triglycerides, TG), are long believed to store excessive energy and to provide thermal and physical insulation for animal... |
10.1371/journal.pcbi.1005842 | Electrical stimulus artifact cancellation and neural spike detection on large multi-electrode arrays | Simultaneous electrical stimulation and recording using multi-electrode arrays can provide a valuable technique for studying circuit connectivity and engineering neural interfaces. However, interpreting these measurements is challenging because the spike sorting process (identifying and segregating action potentials ar... | Simultaneous electrical stimulation and recording using multi-electrode arrays can provide a valuable technique for studying circuit connectivity and engineering neural interfaces. However, interpreting these recordings is challenging because the spike sorting process (identifying and segregating action potentials aris... | Simultaneous electrical stimulation and recording with multi-electrode arrays (MEAs) serves at least two important purposes for investigating neural circuits and for neural engineering. First, it enables the probing of neural circuits, leading to improved understanding of circuit anatomy and function [1–6]. Second, it ... |
10.1371/journal.ppat.1001038 | The N-Terminal Domain of the Arenavirus L Protein Is an RNA Endonuclease Essential in mRNA Transcription | Arenaviridae synthesize viral mRNAs using short capped primers presumably acquired from cellular transcripts by a ‘cap-snatching’ mechanism. Here, we report the crystal structure and functional characterization of the N-terminal 196 residues (NL1) of the L protein from the prototypic arenavirus: lymphocytic choriomenin... | The Arenaviridae virus family includes several life-threatening human pathogens that cause meningitis or hemorrhagic fever. These RNA viruses replicate and transcribe their genome using an RNA synthesis machinery for which no structural data currently exist. They synthesize viral mRNAs using short capped primers presum... | The Arenaviridae family includes 22 viral species into a single genus Arenavirus, with new species awaiting classification [1], [2]. They cause chronic and asymptomatic infections in rodents, and occasional transmission to man may result in life-threatening meningitis and/or hemorrhagic fever. Lymphocytic choriomeningi... |
10.1371/journal.pntd.0003318 | A Novel Psittacine Adenovirus Identified During an Outbreak of Avian Chlamydiosis and Human Psittacosis: Zoonosis Associated with Virus-Bacterium Coinfection in Birds | Chlamydophila psittaci is found worldwide, but is particularly common among psittacine birds in tropical and subtropical regions. While investigating a human psittacosis outbreak that was associated with avian chlamydiosis in Hong Kong, we identified a novel adenovirus in epidemiologically linked Mealy Parrots, which w... | Chlamydophila psittaci is a bacterial pathogen which can cause avian chlamydiosis and human psittacosis. Although C. psittaci is frequently detected in birds from the tropical and subtropical regions, large outbreaks of human infections rarely occur. During the investigation of a human psittacosis outbreak that was ass... | About 70% of microbial agents causing outbreaks of emerging infectious diseases in humans originate directly from animals [1]. Among respiratory virus infections, the influenza A viruses H5N1 and H7N9 from avian species, and the severe acute respiratory syndrome coronavirus from bats have caused large epidemics [1]–[3]... |
10.1371/journal.pgen.1007964 | Two isoforms of the RAC-specific guanine nucleotide exchange factor TIAM2 act oppositely on transmission ratio distortion by the mouse t-haplotype | Transmission ratio distortion (TRD) by the mouse t-haplotype, a variant region on chromosome 17, is a well-studied model of non-Mendelian inheritance. It is characterized by the high transmission ratio (up to 99%) of the t-haplotype from t/+ males to their offspring. TRD is achieved by the exquisite ability of the resp... | Exceptions to Gregor Mendel’s rules of inheritance have attracted geneticists over many decades. One of the best-studied cases in mammals is the extremely high transmission rate (up to 99%) of a chromosomal variant in mouse, called the t-haplotype, from t/+ heterozygous males to their offspring. Previous studies have r... | According to Mendel’s rules, diploid organisms transmit the two alleles of a gene located on the homologous chromosomes at an equal ratio to their offspring. However, exceptions to “fair” transmission of genetic material to the next generation have been observed in most domains of life, and one of the most illustrative... |
10.1371/journal.pcbi.1006319 | Modeling subjective relevance in schizophrenia and its relation to aberrant salience | In schizophrenia, increased aberrant salience to irrelevant events and reduced learning of relevant information may relate to an underlying deficit in relevance detection. So far, subjective estimates of relevance have not been probed in schizophrenia patients. The mechanisms underlying belief formation about relevance... | Schizophrenia patients display deficits in the appropriate attribution of meaningfulness to stimuli; such as aberrantly increased processing of irrelevant and insufficient processing of relevant information. We aimed to investigate the subjective nature of relevance detection and its deficit in schizophrenia and develo... | Reduced differentiation between relevance and irrelevance, a disruption of salience attribution, is the key component of the aberrant salience hypothesis of psychosis [1–3]. According to this theoretical framework, neurobiological noise in terms of increased striatal dopamine turnover may cause the subjective experienc... |
10.1371/journal.pmed.1002698 | Healthy volunteers' perceptions of risk in US Phase I clinical trials: A mixed-methods study | There is limited research on healthy volunteers’ perceptions of the risks of Phase I clinical trials. In order to contribute empirically to long-standing ethical concerns about healthy volunteers’ involvement in drug development, it is crucial to assess how these participants understand trial risks. The objectives of t... | The purpose of this study was to better understand how healthy volunteers perceive the risks of enrolling in Phase I clinical trials. These trials offer healthy volunteers no direct medical benefit for their participation, but participants are financially compensated.
Ethical concerns regarding undue inducement—or that... | Healthy volunteers are recruited using financial incentives to participate in Phase I clinical trials to evaluate the safety and tolerability of investigational drugs. These trials are generally considered quite safe [1], which justifies the enrollment of healthy participants who cannot personally benefit medically fro... |
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