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10.1371/journal.pntd.0003441 | Type 3 Secretion System Cluster 3 Is a Critical Virulence Determinant for Lung-Specific Melioidosis | Burkholderia pseudomallei, the bacterial agent of melioidosis, causes disease through inhalation of infectious particles, and is classified as a Tier 1 Select Agent. Optical diagnostic imaging has demonstrated that murine respiratory disease models are subject to significant upper respiratory tract (URT) colonization. ... | Respiratory melioidosis is a lethal disease presentation of the bacterium Burkholderia pseudomallei, which is found in tropical regions worldwide. Respiratory melioidosis has also been highlighted as a concern in the biodefense community given the potential for weaponization of B. pseudomallei. This study demonstrates ... | Burkholderia pseudomallei is the Tier 1 Select Agent bacterial pathogen responsible for the disease melioidosis. B. pseudomallei is found in moist tropical soils worldwide, but has been long characterized to be endemic to Southeast Asia and northern Australia [1]. Naturally acquired disease typically involves percutane... |
10.1371/journal.pntd.0005846 | Strong interferon-gamma mediated cellular immunity to scrub typhus demonstrated using a novel whole cell antigen ELISpot assay in rhesus macaques and humans | Scrub typhus is a febrile infection caused by the obligate intracellular bacterium Orientia tsutsugamushi, which causes significant morbidity and mortality across the Asia-Pacific region. The control of this vector-borne disease is challenging due to humans being dead-end hosts, vertical maintenance of the pathogen in ... | Scrub typhus is a disease caused by bacteria that invade cells in our immune system and blood vessels. It is transmitted by mites and is treatable with antibiotics. Unfortunately diagnosis is difficult and requires techniques that are not easily accessible everywhere. Currently, there is no scrub typhus vaccine availab... | Scrub typhus is a zoonotic illness caused by the intracellular bacterium Orientia tsutsugamushi which is endemic mainly across the Asia-Pacific region [1]. The pathogen is transmitted by the bite of larval Trombiculid mites known as chiggers [2, 3]. Scrub typhus is a febrile illness with a wide spectrum of disease seve... |
10.1371/journal.pntd.0005311 | Identification of BALB/c Immune Markers Correlated with a Partial Protection to Leishmania infantum after Vaccination with a Rationally Designed Multi-epitope Cysteine Protease A Peptide-Based Nanovaccine | Through their increased potential to be engaged and processed by dendritic cells (DCs), nanovaccines consisting of Poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with both antigenic moieties and adjuvants are attractive candidates for triggering specific defense mechanisms against intracellular pat... | Leishmaniases are a wide spectrum of parasite diseases caused by different species of the genus Leishmania. Among them, visceral leishmaniasis is the most severe form of the disease affecting millions of people worldwide. Currently chemotherapeutic agents are highly toxic and suffer from extensive drug resistance. Howe... | Leishmaniasis is an infectious diseases complex caused by protozoan parasites of the genus Leishmania. According to epidemiological data, visceral leishmaniasis (VL) is the second most common parasitic cause of death among tropical infections and is prevalent in 47 countries with about 200 million people at risk and an... |
10.1371/journal.pgen.1008417 | European Roma groups show complex West Eurasian admixture footprints and a common South Asian genetic origin | The Roma population is the largest transnational ethnic minority in Europe, characterized by a linguistic, cultural and historical heterogeneity. Comparative linguistics and genetic studies have placed the origin of European Roma in the Northwest of India. After their migration across Persia, they entered into the Balk... | Human demographic processes and admixture events leave traceable footprints in the genomes of the populations and they can modulate the genetic architecture of complex diseases. Here, we aim to study the Roma people, an admixed population with a particular demographic history recognized as the largest ethnic minority i... | The diaspora of the Roma people, also known with the misnomer of Gypsies, is a not-well documented human movement, which is characterized by recent dispersals and multiple founder events. The Roma population is recognized as the largest transnational ethnic minority in Europe, with an estimated population of up to 10 m... |
10.1371/journal.pgen.1007842 | RNA-on-X 1 and 2 in Drosophila melanogaster fulfill separate functions in dosage compensation | In Drosophila melanogaster, the male-specific lethal (MSL) complex plays a key role in dosage compensation by stimulating expression of male X-chromosome genes. It consists of MSL proteins and two long noncoding RNAs, roX1 and roX2, that are required for spreading of the complex on the chromosome and are redundant in t... | In humans and fruit flies, females and males have different sets of sex chromosomes. This causes gene dosage differences that must be compensated for by adjusting the expression of most genes located on the X-chromosome. Long non-coding RNAs are central in this compensation and in fruit flies this is mediated by two no... | In eukaryotic genomes several long non-coding RNAs (lncRNAs) are associated with chromatin and involved in gene expression regulation, but the mechanisms involved are largely unknown. In both mammals and fruit flies, they are required to specifically identify and mark X-chromosomes for dosage compensation, a mechanism ... |
10.1371/journal.pgen.1003257 | The [PSI+] Prion Exists as a Dynamic Cloud of Variants | [PSI+] is an amyloid-based prion of Sup35p, a subunit of the translation termination factor. Prion “strains” or “variants” are amyloids with different conformations of a single protein sequence, conferring different phenotypes, but each relatively faithfully propagated. Wild Saccharomyces cerevisiae isolates have SUP35... | The [PSI+] prion (infectious protein) of yeast is a self-propagating amyloid (filamentous protein polymer) of the Sup35 protein, a subunit of the translation termination factor. A single protein can form many biologically distinct prions, called prion variants. Wild yeast strains have three groups of Sup35 sequences (p... | Prions in yeast are a new form of gene, composed of proteins instead of nucleic acids [1]. As such, their inheritance, mutation and segregation are not expected to follow the same rules as the majority DNA/RNA genes. The [PSI+] prion was first recognized as a non-chromosomal genetic element enhancing the read-thru of t... |
10.1371/journal.pcbi.1002222 | Coupled Information Diffusion–Pest Dynamics Models Predict Delayed Benefits of Farmer Cooperation in Pest Management Programs | Worldwide, the theory and practice of agricultural extension system have been dominated for almost half a century by Rogers' “diffusion of innovation theory”. In particular, the success of integrated pest management (IPM) extension programs depends on the effectiveness of IPM information diffusion from trained farmers ... | Food security of millions of people in the third world has faced a growing number of challenges in recent years including risks associated with emergent agricultural pests. Worldwide, the promotion of integrated pest management practices has been heavily promoted through participative methodologies relying on farmer co... | In view of the growing number of challenges related to controlling agricultural pests, the promotion of Integrated Pest Management practices (IPM; a range of methods used for responsible pest control) has a larger place than ever on the international policy agenda [1], [2]. The participation of local communities and ot... |
10.1371/journal.ppat.1006313 | Predicting HIV-1 transmission and antibody neutralization efficacy in vivo from stoichiometric parameters | The potential of broadly neutralizing antibodies targeting the HIV-1 envelope trimer to prevent HIV-1 transmission has opened new avenues for therapies and vaccines. However, their implementation remains challenging and would profit from a deepened mechanistic understanding of HIV-antibody interactions and the mucosal ... | Successful solicitation of the potential of neutralizing antibodies for HIV-1 prevention will require a deepened understanding of HIV-1 transmission and antibody neutralization. In this study, we experimentally determined molecular parameters of the HIV-1-antibody interaction, and subsequently used this knowledge to de... | Recent years have seen tremendous success in the isolation and characterization of broadly neutralizing antibodies (bnAbs) from selected HIV-1 infected patients. By binding to the HIV-1 envelope glycoprotein trimer (Env), bnAbs succeed to neutralize a majority of circulating HIV-1 strains. It is assumed that the elicit... |
10.1371/journal.pcbi.1001082 | Loss of Genetic Redundancy in Reductive Genome Evolution | Biological systems evolved to be functionally robust in uncertain environments, but also highly adaptable. Such robustness is partly achieved by genetic redundancy, where the failure of a specific component through mutation or environmental challenge can be compensated by duplicate components capable of performing, to ... | Bacteria have found many niches in which to live, and one of them is inside eukaryotic cells. These intracellular bacteria include endosymbionts like Buchnera aphidicola, which provides its host, an aphid, with essential amino acids, as well as many pathogenic bacteria such as Mycobacterium leprae and Rickettsia prowaz... | Living organisms evolved to be functional in frequently harsh and variable environments, buffering internal molecular noise, genetic variation and unpredictable environmental fluctuations. Such ability is termed robustness [1]. One common source of robustness is genetic redundancy, in which one or more genes can perfor... |
10.1371/journal.ppat.1006823 | Importin α1 is required for nuclear import of herpes simplex virus proteins and capsid assembly in fibroblasts and neurons | Herpesviruses are large DNA viruses which depend on many nuclear functions, and therefore on host transport factors to ensure specific nuclear import of viral and host components. While some import cargoes bind directly to certain transport factors, most recruit importin β1 via importin α. We identified importin α1 in ... | Nuclear pore complexes are highly selective gateways that penetrate the nuclear envelope for bidirectional trafficking between the cytoplasm and the nucleoplasm. Viral and host cargoes have to engage specific transport factors to achieve active nuclear import and export. Like many human and animal DNA viruses, herpesvi... | Herpesviruses such as herpes simplex virus (HSV), human cytomegalovirus or Epstein-Barr virus cause human diseases ranging from minor ailments to life threatening acute infections, blindness or cancers, particularly in immunocompromised patients. They are complex DNA viruses that depend on many nuclear functions; e.g. ... |
10.1371/journal.ppat.1002098 | A Role for the Chemokine RANTES in Regulating CD8 T Cell Responses during Chronic Viral Infection | RANTES (CCL5) is a chemokine expressed by many hematopoietic and non-hematopoietic cell types that plays an important role in homing and migration of effector and memory T cells during acute infections. The RANTES receptor, CCR5, is a major target of anti-HIV drugs based on blocking viral entry. However, defects in RAN... | Chemokines are small proteins that attract cells and play complex roles in coordinating immune responses. RANTES is one such chemokine that attracts many different cell types. The receptor for RANTES, CCR5, is also a coreceptor for HIV and drugs blocking the RANTES∶CCR5 pathway are in clinical use to treat HIV-infected... | During many chronic infections, virus spreads rapidly from the site of initial infection to distal tissues. T cells, on the other hand, must first become activated in the LNs and spleen and then gain the ability to migrate to infected organs. Chemokines play a key role in orchestrating all stages of this T cell respons... |
10.1371/journal.pgen.1007369 | mTOR signaling regulates central and peripheral circadian clock function | The circadian clock coordinates physiology and metabolism. mTOR (mammalian/mechanistic target of rapamycin) is a major intracellular sensor that integrates nutrient and energy status to regulate protein synthesis, metabolism, and cell growth. Previous studies have identified a key role for mTOR in regulating photic ent... | The circadian clock coordinates daily physiology and metabolism in animals. There has been considerable interest in identifying mechanisms that link metabolic signals to circadian time keeping. mTOR (mammalian/mechanistic target of rapamycin) is a major intracellular sensor that integrates nutrient and energy status to... | The circadian clock regulates the sleep/wake cycle and all associated cellular, metabolic and physiological processes in animals. Disruption of the circadian system is associated with a variety of disease states, including sleep disorders, metabolic syndromes, and cardiovascular diseases[1–3]. In mammals, the central c... |
10.1371/journal.pbio.1001490 | Parallel Evolutionary Dynamics of Adaptive Diversification in Escherichia coli | The causes and mechanisms of evolutionary diversification are central issues in biology. Geographic isolation is the traditional explanation for diversification, but recent theoretical and empirical studies have shown that frequency-dependent selection can drive diversification without isolation and that adaptive diver... | The causes and mechanisms of evolutionary diversification are central issues in biology. There is well-established theory that predicts that adaptive diversification can arise because of ecological interactions between individuals, such as competition or predation, but there are no empirical examples in which this proc... | The causes and mechanisms of diversification are central issues in evolutionary biology. Explanations that involve the splitting of an ancestral population into geographically or otherwise isolated populations (allopatric diversification) have historically been favored because of theoretical difficulties with sympatric... |
10.1371/journal.pgen.1000085 | Systematic Identification of Genes that Regulate Neuronal Wiring in the Drosophila Visual System | Forward genetic screens in model organisms are an attractive means to identify those genes involved in any complex biological process, including neural circuit assembly. Although mutagenesis screens are readily performed to saturation, gene identification rarely is, being limited by the considerable effort generally re... | In the nervous system, every neuronal process should know where to grow and when to establish contacts to the next-order neurons. During development, it is known that neural circuit formation is primarily determined by the genes. To identify these genes, we focused on the Drosophila visual circuitry as a model system, ... | The adult visual system of Drosophila melanogaster is a powerful genetic model for exploring the molecular and cellular mechanisms involved in axon growth, guidance, and synaptic specificity [1]. The adult retina consists of some 800 ommatidia, each containing 8 photoreceptor cells (R1–R8) that form topographic connect... |
10.1371/journal.pcbi.1003380 | Time Scales in Epigenetic Dynamics and Phenotypic Heterogeneity of Embryonic Stem Cells | A remarkable feature of the self-renewing population of embryonic stem cells (ESCs) is their phenotypic heterogeneity: Nanog and other marker proteins of ESCs show large cell-to-cell variation in their expression level, which should significantly influence the differentiation process of individual cells. The molecular ... | Embryonic stem cells (ESCs) can proliferate indefinitely by keeping pluripotency, i.e., the ability to differentiate into any cell-lineage. ESCs, therefore, have been the focus of intense biological and medical interests. A remarkable feature of ESCs is their phenotypic heterogeneity: ESCs show large cell-to-cell fluct... | Embryonic stem cells (ESCs) are pluripotent having the ability to differentiate into a variety of lineages, while in suitable culture conditions they proliferate indefinitely by maintaining pluripotency. These self-renewing ESCs are distinguished by the marker proteins including Sox2, Oct4 and Nanog (SON) [1]–[4]. SON ... |
10.1371/journal.pcbi.1005538 | Uncovering direct and indirect molecular determinants of chromatin loops using a computational integrative approach | Chromosomal organization in 3D plays a central role in regulating cell-type specific transcriptional and DNA replication timing programs. Yet it remains unclear to what extent the resulting long-range contacts depend on specific molecular drivers. Here we propose a model that comprehensively assesses the influence on c... | Chromosomal DNA is tightly packed in three dimensions (3D) such that a 2-meter long human genome can fit into a microscopic nucleus. Recent studies have revealed that such packing of DNA is not random but instead structured into functional DNA loops. Those loops are essential to numerous key processes in the cell, such... | Chromosomal DNA is tightly packed in three dimensions (3D) such that a 2-meter long human genome can fit into a nucleus of approximately 10 microns in diameter [1]. Such 3D structure of chromosome has recently been explored by chromosome conformation capture combined with high-throughput sequencing technique (Hi-C) at ... |
10.1371/journal.pgen.1006766 | Polymorphisms in the yeast galactose sensor underlie a natural continuum of nutrient-decision phenotypes | In nature, microbes often need to "decide" which of several available nutrients to utilize, a choice that depends on a cell’s inherent preference and external nutrient levels. While natural environments can have mixtures of different nutrients, phenotypic variation in microbes’ decisions of which nutrient to utilize is... | In nature, microbes often need to decide which of many potential nutrients to consume. This decision making process is complex, involving both intracellular constraints and the organism’s perception of the environment. To begin to mimic the complexity of natural environments, we grew cells in mixtures of two sugars, gl... | The nutrient composition of natural environments can fluctuate and organisms must induce metabolic pathways that allow them to utilize the available nutrients [1–3]. Recent studies have found that closely related microbes vary in both the types of nutrients they can utilize and the efficiency at which they do so [4,5].... |
10.1371/journal.pcbi.1003110 | A Design Principle of Group-level Decision Making in Cell Populations | Populations of cells often switch states as a group to cope with environmental changes such as nutrient availability and cell density. Although the gene circuits that underlie the switches are well understood at the level of single cells, the ways in which such circuits work in concert among many cells to support group... | Although the genetic circuits underlying state switching at the single-cell level are well understood, how such circuits work in concert among many cells to support the population-level switching of cellular behaviors is not fully explored. Experiments using microbial signaling systems show that group-level changes in ... | Cells often switch their state autonomously, either individually or as a group [1]–[3]. The cell-autonomous switch is exemplified by the classical molecular switch in Bacteriophage Lambda: the cI and cro genes mutually repress one another and thus operate as a genetic toggle switch between the lytic and lysogenic cycle... |
10.1371/journal.ppat.1000914 | Mouse Senile Amyloid Fibrils Deposited in Skeletal Muscle Exhibit Amyloidosis-Enhancing Activity | Amyloidosis describes a group of protein folding diseases in which amyloid proteins are abnormally deposited in organs and/or tissues as fine fibrils. Mouse senile amyloidosis is a disorder in which apolipoprotein A-II (apoA-II) deposits as amyloid fibrils (AApoAII) and can be transmitted from one animal to another bot... | “Amyloidosis”, a group of protein folding diseases characterized by deposition of fine fibrils in tissues, is a common disorder of protein metabolism and can be acquired, inherited and/or age-associated. Recently, prion-like transmission has been found in various amyloidoses. AApoAII amyloid fibrils in mouse senile amy... | Amyloidosis refers to a group of protein folding disorders. Various proteins that are harmless and soluble under normal physiological conditions can undergo marked conformational changes and subsequent self-assembly outside of the cell into highly stable, insoluble amyloid fibrils with a high content of ß-sheet structu... |
10.1371/journal.ppat.1000947 | Coexpression of PD-1, 2B4, CD160 and KLRG1 on Exhausted HCV-Specific CD8+ T Cells Is Linked to Antigen Recognition and T Cell Differentiation | Exhausted CD8+ T cell responses during chronic viral infections are defined by a complex expression pattern of inhibitory receptors. However, very little information is currently available about the coexpression patterns of these receptors on human virus-specific CD8+ T cells and their correlation with antiviral functi... | About 170 million people are infected with hepatitis C virus (HCV), which may cause severe liver disease and liver cancer. Upon acute infection, only about 30% of patients are able to eliminate the virus spontaneously while about 70% of patients develop chronic infection. It is known that a successful immune response a... | Virus-specific CD8+ T cells play a central role in the outcome of HCV infection. Indeed, several human and animal studies have shown associations between strong and multispecific T cell responses and viral clearance [1]. During chronic HCV infection, viral escape and an impairment of HCV-specific CD8+ T cell antiviral ... |
10.1371/journal.ppat.1000527 | Production of Superoxide Anions by Keratinocytes Initiates P. acnes-Induced Inflammation of the Skin | Acne vulgaris is a chronic inflammatory disorder of the sebaceous follicles. Propionibacterium acnes (P. acnes), a gram-positive anareobic bacterium, plays a critical role in the development of these inflammatory lesions. This study aimed at determining whether reactive oxygen species (ROS) are produced by keratinocyte... | Acne vulgaris is a chronic inflammatory disorder of the sebaceous follicles. It is the most common skin disease, affecting up to 80% of individuals at some point between the ages of 11 and 30 years. Propionibacterium acnes (P. acnes) plays a role in the development of inflammatory acne lesions, but whether it causes in... | Acne vulgaris is a chronic inflammatory disorder of the sebaceous follicles. Acne is the most common skin disease, estimated to affect up to 80% of individuals at some point between the ages of 11 and 30 years. Despite its common occurrence, the pathogenesis of acne is not fully understood. Excessive shedding of epithe... |
10.1371/journal.ppat.1006937 | The interferon-stimulated gene product oligoadenylate synthetase-like protein enhances replication of Kaposi’s sarcoma-associated herpesvirus (KSHV) and interacts with the KSHV ORF20 protein | Kaposi’s sarcoma-associated herpesvirus (KSHV) is one of the few oncogenic human viruses known to date. Its large genome encodes more than 85 proteins and includes both unique viral proteins as well as proteins conserved amongst herpesviruses. KSHV ORF20 is a member of the herpesviral core UL24 family, but the function... | The herpesviruses are a family of large double-stranded DNA viruses that cause a variety of illnesses from chicken pox to cancer. Kaposi’s sarcoma-associated herpesvirus (KSHV) is a cancer-causing herpesvirus and can lead to development of Kaposi’s sarcoma, a major form of cancer in HIV-positive patients. As for all he... | The oncogenic human herpesvirus 8, also known as Kaposi’s sarcoma-associated herpesvirus (KSHV), belongs to the Gammaherpesvirinae subfamily of the Herpesviridae [1]. KSHV is the etiological agent of multiple malignancies, including Kaposi’s sarcoma, which is a common form of cancer in HIV-infected individuals [2], and... |
10.1371/journal.pgen.1003461 | The Histone Demethylase Jarid1b Ensures Faithful Mouse Development by Protecting Developmental Genes from Aberrant H3K4me3 | Embryonic development is tightly regulated by transcription factors and chromatin-associated proteins. H3K4me3 is associated with active transcription and H3K27me3 with gene repression, while the combination of both keeps genes required for development in a plastic state. Here we show that deletion of the H3K4me2/3 his... | Histone modifications are involved in transcriptional regulation and thus affect cellular identity, differentiation, and development. We study the histone demethylase Jarid1b (Kdm5b/Plu1), as it has been reported to be highly expressed in several human cancers and therefore might present a novel target for anti-cancer ... | Embryonic development is characterized by a coordinated program of proliferation and differentiation that is tightly regulated by transcription factors and chromatin-associated proteins. As embryonic cells differentiate, certain genes are activated while others are repressed, resulting in a unique pattern of gene expre... |
10.1371/journal.pcbi.1004974 | The Role of Adaptation in Bacterial Speed Races | Evolution of biological sensory systems is driven by the need for efficient responses to environmental stimuli. A paradigm among prokaryotes is the chemotaxis system, which allows bacteria to navigate gradients of chemoattractants by biasing their run-and-tumble motion. A notable feature of chemotaxis is adaptation: af... | Biological sensory pathways are presumed to evolve for the processing of environmental information, yet quantitative evidence is scant. Chemotaxis allows bacteria to sense chemical gradients but their ecological distribution, e.g. whether natural gradients sensed by E. coli change slowly or rapidly in space and time, i... | A major example of adaptation in transduction pathways is bacterial chemotaxis, where saturating stimuli are followed by a precise recovery of the cell’s pre-stimulus tumbling frequency [1, 2]. The recovery is achieved by an integral feedback control [3], which is molecularly mediated by the methylation of chemorecepto... |
10.1371/journal.pcbi.0030106 | A Survey of Genomic Properties for the Detection of Regulatory Polymorphisms | Advances in the computational identification of functional noncoding polymorphisms will aid in cataloging novel determinants of health and identifying genetic variants that explain human evolution. To date, however, the development and evaluation of such techniques has been limited by the availability of known regulato... | Computational techniques are used in biology to prioritize DNA sequence variants (or polymorphisms) that may be responsible for population diversity and the manifestation of species-specific traits. Predominantly, they have been used to predict the class of polymorphisms that alter protein function through allele-speci... | Our ability to identify the molecular mechanisms responsible for specific genetic traits within our population will be enhanced by our imminent ability to decipher each individual's genome. This is evident from recent advances in sequencing and genotyping technologies, which allow an increasing number of variants to be... |
10.1371/journal.pgen.1002144 | Rare and Common Regulatory Variation in Population-Scale Sequenced Human Genomes | Population-scale genome sequencing allows the characterization of functional effects of a broad spectrum of genetic variants underlying human phenotypic variation. Here, we investigate the influence of rare and common genetic variants on gene expression patterns, using variants identified from sequencing data from the ... | The recent availability of almost fully sequenced human genomes by the 1000 genomes project allows the direct study of genetic variants that influence levels of gene expression in the cell. In this study, we explore the effect of rare and common variants on levels of gene expression. We show that the availability of a ... | Deeper characterization of genetic variation is becoming increasingly available with advances in DNA sequencing technology [1]–[5]. This improves our ability to pinpoint protein-coding variants which disrupt protein structure, and has already begun to provide insight into the genetic basis of disease with unknown etiol... |
10.1371/journal.pgen.1004586 | The Vip1 Inositol Polyphosphate Kinase Family Regulates Polarized Growth and Modulates the Microtubule Cytoskeleton in Fungi | Microtubules (MTs) are pivotal for numerous eukaryotic processes ranging from cellular morphogenesis, chromosome segregation to intracellular transport. Execution of these tasks requires intricate regulation of MT dynamics. Here, we identify a new regulator of the Schizosaccharomyces pombe MT cytoskeleton: Asp1, a memb... | Fungi are an extremely successful and diverse group of organisms ranging from the small single-celled yeasts to the indefinitely growing filamentous fungi. Polarized growth, where growth is restricted to defined regions, leads to the specific cell shape of yeast cells, as well as the very long hyphae of filamentous fun... | Cell polarization can be viewed as the generation and upkeep of a defined cellular organization. The readout of cell polarization in fungal systems is polarized growth resulting in a specific cell shape and size. This ranges from the 14 µm long cylindrical Schizosaccharomyces pombe fission yeast cell, which maintains i... |
10.1371/journal.pbio.2005258 | The brown algal mode of tip growth: Keeping stress under control | Tip growth has been studied in pollen tubes, root hairs, and fungal and oomycete hyphae and is the most widely distributed unidirectional growth process on the planet. It ensures spatial colonization, nutrient predation, fertilization, and symbiosis with growth speeds of up to 800 μm h−1. Although turgor-driven growth ... | Tip growth is known in organisms with filament-like structures, such as fungi (e.g., hyphae), plants (e.g., root hairs, moss protonemata), and algae (e.g., filamentous thalli). The driving force for growth in these organisms is the difference in osmotic pressure (turgor) between the inside of the cell and the external ... | The prostrate filaments of the alga Ectocarpus develop via tip growth [28]. Prior to identifying the underlying mechanisms, a series of additional biophysical information was collected. The cell wall dye calcofluor-white was used in pulse-chase experiments to measure the growing region more precisely. The stain was loc... |
10.1371/journal.pcbi.1005938 | Across-subjects classification of stimulus modality from human MEG high frequency activity | Single-trial analyses have the potential to uncover meaningful brain dynamics that are obscured when averaging across trials. However, low signal-to-noise ratio (SNR) can impede the use of single-trial analyses and decoding methods. In this study, we investigate the applicability of a single-trial approach to decode st... | Averaging brain activity across trials is a powerful way to increase signal-to-noise ratio in MEG data. This approach, however, potentially obscures meaningful brain dynamics that unfold on the single-trial level. Single-trial analyses have been successfully applied to time domain or low frequency oscillatory activity;... | Since the first reports of cortical gamma band activity [1, 2], these high frequency responses have been linked to a plethora of brain processes and mental tasks, for example visual perception and processing [3–6], auditory perception [7, 8] or memory [9–12]. Although numerous theories about the origin and function of ... |
10.1371/journal.pcbi.1003079 | A Two-Stage Cascade Model of BOLD Responses in Human Visual Cortex | Visual neuroscientists have discovered fundamental properties of neural representation through careful analysis of responses to controlled stimuli. Typically, different properties are studied and modeled separately. To integrate our knowledge, it is necessary to build general models that begin with an input image and p... | Much has been learned about how stimuli are represented in the visual system from measuring responses to carefully designed stimuli. Typically, different studies focus on different types of stimuli. Making sense of the large array of findings requires integrated models that explain responses to a wide range of stimuli.... | Studies of visual cortex typically measure responses to a narrow set of stimuli designed to investigate a particular phenomenon. For example, a study might use sinusoidal gratings varying in contrast to study contrast response functions [1], [2], another study might use silhouettes to study shape tuning [3], [4], and y... |
10.1371/journal.ppat.1004496 | The Plasmodesmal Protein PDLP1 Localises to Haustoria-Associated Membranes during Downy Mildew Infection and Regulates Callose Deposition | The downy mildew pathogen Hyaloperonospora arabidopsidis (Hpa) is a filamentous oomycete that invades plant cells via sophisticated but poorly understood structures called haustoria. Haustoria are separated from the host cell cytoplasm and surrounded by an extrahaustorial membrane (EHM) of unknown origin. In some inter... | Haustoria are specialised invasive structures that project from fungal or oomycete hyphae into host plant cells during infection, acting as sites for molecular exchange between host and pathogen. Haustoria are targets of plant defence responses, including the deposition of membranes and polysaccharides in an encasement... | Eukaryotic filamentous pathogens such as rusts, powdery mildew fungi, and oomycetes including Arabidopsis downy mildew Hyaloperanospora arabidopsidis (Hpa) and Phytophthora spp., form specialized feeding structures in host cells called haustoria. Haustoria are unicellular protrusions from hyphae and function as the sit... |
10.1371/journal.pcbi.1004698 | Optimal Information Representation and Criticality in an Adaptive Sensory Recurrent Neuronal Network | Recurrent connections play an important role in cortical function, yet their exact contribution to the network computation remains unknown. The principles guiding the long-term evolution of these connections are poorly understood as well. Therefore, gaining insight into their computational role and into the mechanism s... | The recurrent interactions among cortical neurons shape the representation of incoming information but the principles governing their evolution are yet unclear. We investigate the computational role of recurrent connections in the context of sensory processing. Specifically, we study a neuronal network model in which t... | The anatomical abundance of lateral interactions [1, 2] between neurons of the local cerebral circuit (referred in this text as recurrent connections) suggest they play a fundamental role in cortical function. Indirect physiological evidence of their involvement in memory [3, 4], sensory processing [5] and in other bra... |
10.1371/journal.pgen.1007003 | Genomics-enabled analysis of the emergent disease cotton bacterial blight | Cotton bacterial blight (CBB), an important disease of (Gossypium hirsutum) in the early 20th century, had been controlled by resistant germplasm for over half a century. Recently, CBB re-emerged as an agronomic problem in the United States. Here, we report analysis of cotton variety planting statistics that indicate a... | Cotton bacterial blight (CBB), caused by Xanthomonas citri pv. malvacearum (Xcm), significantly limited cotton yields in the early 20th century but has been controlled by classical resistance genes for more than 50 years. In 2011, the pathogen re-emerged with a vengeance. In this study, we compare diverse pathogen isol... | Upland cotton (Gossypium hirsutum L.) is the world’s leading natural fiber crop. Cotton is commercially grown in over 84 countries, and in the United States, is responsible for $74 billion annually [1, 2]. Numerous foliar diseases affect cotton throughout the world’s cotton growing regions. Historically, one of the mos... |
10.1371/journal.ppat.0040022 | Inhibition of IκB Kinase by Vaccinia Virus Virulence Factor B14 | The IκB kinase (IKK) complex is a key regulator of signal transduction pathways leading to the induction of NF-κB-dependent gene expression and production of pro-inflammatory cytokines. It therefore represents a major target for the development of anti-inflammatory therapeutic drugs and may be targeted by pathogens see... | Vaccinia virus (VACV) is the live vaccine used to eradicate smallpox and is also the most intensively studied poxvirus. Like many poxviruses, VACV produces a wide variety of proteins that inhibit parts of the host response to infection. Consequently, the virus can escape destruction by the immune system and be passed o... | Nuclear factor-κB (NF-κB) is critical for the innate and adaptive immune responses to infection. Various stimuli, such as the pro-inflammatory cytokines interleukin (IL)-1 and tumour necrosis factor (TNF), activate signaling pathways leading to NF-κB-dependent gene expression [1,2]. Several of these signaling pathways ... |
10.1371/journal.pgen.1004827 | The IKAROS Interaction with a Complex Including Chromatin Remodeling and Transcription Elongation Activities Is Required for Hematopoiesis | IKAROS is a critical regulator of hematopoietic cell fate and its dynamic expression pattern is required for proper hematopoiesis. In collaboration with the Nucleosome Remodeling and Deacetylase (NuRD) complex, it promotes gene repression and activation. It remains to be clarified how IKAROS can support transcription a... | Perturbation of the expression level of IKAROS, a transcription factor critical during hematopoiesis, is associated with malignant transformation in mice and humans. The importance of IKAROS expression levels for the control of target-gene regulation was addressed in hematopoietic progenitor cells. The collaboration be... | The tumor suppressor IKAROS is a transcription factor critical for hematopoietic multi-lineage priming, cell fate and lineage determination [1]–[5]. Mice homozygote for the Ikaros null mutation (IkNULL) display severe defects in lymphocyte development and function, and develop leukemias and lymphomas with complete pene... |
10.1371/journal.pcbi.1003641 | A Signature of Attractor Dynamics in the CA3 Region of the Hippocampus | The notion of attractor networks is the leading hypothesis for how associative memories are stored and recalled. A defining anatomical feature of such networks is excitatory recurrent connections. These “attract” the firing pattern of the network to a stored pattern, even when the external input is incomplete (pattern ... | A type of neural network called an “attractor network” is thought to underlie memory associations. Importantly, when such a network is presented with part of a memory, the network activity is attracted to the complete memory. However, it has been difficult to obtain clear experimental evidence for such attractor networ... | Theoretical work has shown how networks with excitatory recurrent connections can function as an associative memory [1]–[4]. Specifically, Hebbian plasticity at the synapses of recurrent connections leads to the association of the elements of a memory. Information stored in this way can be recalled given external input... |
10.1371/journal.pbio.0050293 | A sex-ratio Meiotic Drive System in Drosophila simulans. II: An X-linked Distorter | The evolution of heteromorphic sex chromosomes creates a genetic condition favoring the invasion of sex-ratio meiotic drive elements, resulting in the biased transmission of one sex chromosome over the other, in violation of Mendel's first law. The molecular mechanisms of sex-ratio meiotic drive may therefore help us t... | Mendel's first law of genetics states that two alleles of a heterozygote are transmitted to the next generation at an equal ratio. The cornerstone of population genetics, this law states that the evolutionary fate of genetic variants is solely governed by their contribution to the good of their carriers. However, meiot... | Sex chromosomes are believed to evolve from a pair of autosomes [1–3]. An incipient Y chromosome, like an autosome, is largely euchromatic and free to recombine, except for a small region determining sex, as exemplified by species such as the papaya plant [4] and the medaka and stickleback fish [5,6]. On an evolutionar... |
10.1371/journal.pgen.1001353 | Incorporating Biological Pathways via a Markov Random Field Model in Genome-Wide Association Studies | Genome-wide association studies (GWAS) examine a large number of markers across the genome to identify associations between genetic variants and disease. Most published studies examine only single markers, which may be less informative than considering multiple markers and multiple genes jointly because genes may inter... | Statistical methods used in most GWAS are based on the analysis of single markers. Prior biological information about markers, genes, and pathways is not commonly incorporated in the detection of associated disease loci. Recently a number of methods have been developed to incorporate such information, and it has been s... | In genome-wide association studies (GWAS) researchers examine a large number of markers across the genome in many individuals to identify associations between genetic variants and disease, or to prioritize markers for follow up studies. However, most of the times the signals from individual markers are weak and the sam... |
10.1371/journal.pntd.0003776 | Minimizing the Risk of Disease Transmission in Emergency Settings: Novel In Situ Physico-Chemical Disinfection of Pathogen-Laden Hospital Wastewaters | The operation of a health care facility, such as a cholera or Ebola treatment center in an emergency setting, results in the production of pathogen-laden wastewaters that may potentially lead to onward transmission of the disease. The research presented here evaluated the design and operation of a novel treatment syste... | When an outbreak of infectious disease occurs in a low-resource setting, the rapid construction of emergency healthcare facilities may significantly reduce mortality. The facilities also result in the generation of large volumes of highly contaminated fecal waste that represents a potential basis for further disease tr... | Outbreaks of specific infectious diseases that may potentially be transmitted by human excreta, including cholera, Ebola and hepatitis A and E present a challenge to existing WASH (water, sanitation and hygiene) practices and a greater focus on practical in situ disinfection of human waste may offer an effective first ... |
10.1371/journal.pgen.1007296 | The TIE1 transcriptional repressor controls shoot branching by directly repressing BRANCHED1 in Arabidopsis | Shoot branching is a major determinant of plant architecture and is regulated by both endogenous and environmental factors. BRANCHED1 (BRC1) is a central local regulator that integrates signals controlling shoot branching. So far, the regulation of BRC1 activity at the protein level is still largely unknown. In this st... | Shoot branching is a key factor that not only affects plant survival but also determines food productivity in crop species. BRANCHED1 (BRC1) integrates internal and external signals to determine shoot branching. However, the regulation of BRC1 at the protein level remains elusive. We found that TIE1 (TCP interactor con... | Shoot branching greatly affects plant architecture, one of the most important agronomic traits. The manipulation of shoot branching patterns is an efficient way to promote and manage crop production [1]. Shoot branching is a developmental process with a high plasticity and tightly regulated by diverse endogenous and en... |
10.1371/journal.pntd.0007532 | Clinical and histopathologic features of canine tegumentary leishmaniasis and the molecular characterization of Leishmania braziliensis in dogs | Cutaneous leishmaniasis (CL), caused by Leishmania braziliensis, is the most important presentation of tegumentary leishmaniasis (TL) in Latin American. While the role of dogs as reservoirs of Leishmania infantum, and the clinic features of canine visceral leishmanisis are well described, little is known about the impo... | Cutaneous Leishmaniasis (CL) is the major clinical forms of tegumentary leishmaniasis. More than 1 million of people develop cutaneous leishmaniasis worldwide and Leishmania braziliensis is the main causal agent of the disease in Latin American. Wild and domestic animals play an important role in the maintenance of the... | Leishmaniasis is an antropozoonosis caused by the protozoa of the genus Leishmania, which is transmitted to humans by infected sandflies. Leishmaniasis is classified as visceral leishmaniasis (VL) and tegumentary leishmaniasis (TL). Approximately 20 Leishmania species may cause human disease. In the New World, VL is ca... |
10.1371/journal.pntd.0001993 | Field Evaluation and Impact on Clinical Management of a Rapid Diagnostic Kit That Detects Dengue NS1, IgM and IgG | Dengue diagnosis is complex and until recently only specialized laboratories were able to definitively confirm dengue infection. Rapid tests are now available commercially making biological diagnosis possible in the field. The aim of this study was to evaluate a combined dengue rapid test for the detection of NS1 and I... | Dengue is a potentially life-threatening viral disease. Symptoms are often not specific hence the importance to confirm the diagnosis during the early stage of the disease. Nevertheless, until recently only specialized laboratories were able to confirm dengue diagnosis. The discovery of the NS1 protein as a marker of i... | The World Health Organization estimates that 50 million dengue infections occur annually and approximately 2.5 billion people live in area at high risk of infection. These areas are located in tropical and sub-tropical regions in South East Asia, Africa, Eastern Mediterranean, Western Pacific, Central and South America... |
10.1371/journal.ppat.1004449 | Identification of the Microsporidian Encephalitozoon cuniculi as a New Target of the IFNγ-Inducible IRG Resistance System | The IRG system of IFNγ-inducible GTPases constitutes a powerful resistance mechanism in mice against Toxoplasma gondii and two Chlamydia strains but not against many other bacteria and protozoa. Why only T. gondii and Chlamydia? We hypothesized that unusual features of the entry mechanisms and intracellular replicative... | For some time we have studied an intracellular resistance system essential for mice to survive infection with the intracellular protozoan, Toxoplasma gondii, that is based on a family of proteins, immunity-related GTPases or IRG proteins. Immediately after the parasite enters a cell, IRG proteins accumulate on the memb... | The IFNγ-inducible, immunity-related GTPases (IRG proteins) are a family of proteins essential for innate resistance of mice against certain intracellular pathogens. Until now, the protozoon Toxoplasma gondii [1], [2], [3], [4], [5] and its very close relative, Neospora caninum [6], [7], as well as two strains of the b... |
10.1371/journal.pgen.1007081 | Orienting the causal relationship between imprecisely measured traits using GWAS summary data | Inference about the causal structure that induces correlations between two traits can be achieved by combining genetic associations with a mediation-based approach, as is done in the causal inference test (CIT). However, we show that measurement error in the phenotypes can lead to the CIT inferring the wrong causal dir... | Understanding the causal relationships between pairs of traits is crucial for unravelling the causes of disease. To this end, results from genome-wide association studies are valuable because if a trait is known to be influenced by a genetic variant then this knowledge can be used to test the trait’s causal influences ... | Observational measures of the human phenome are growing ever more abundant, but using these data to make causal inference is notoriously susceptible to many pitfalls, with basic regression-based techniques unable to distinguish a true causal association from reverse causation or confounding [1–3]. In response to this, ... |
10.1371/journal.ppat.1005710 | The Actin Filament-Binding Protein Coronin Regulates Motility in Plasmodium Sporozoites | Parasites causing malaria need to migrate in order to penetrate tissue barriers and enter host cells. Here we show that the actin filament-binding protein coronin regulates gliding motility in Plasmodium berghei sporozoites, the highly motile forms of a rodent malaria-causing parasite transmitted by mosquitoes. Parasit... | Parasites causing malaria are transmitted by mosquitoes and need to migrate to cross tissue barriers. The form of the parasite transmitted by the mosquito, the so-called sporozoite, needs motility to enter the salivary glands, to migrate within the skin and to enter into blood capillaries and eventually hepatocytes, wh... | Malaria-causing parasites need to actively migrate at several steps in their complex life cycle [1]. Without motility they would fail, for example, to enter red blood cells or to penetrate the mosquito midgut. The stage with the most formidable motility is the sporozoite, which migrates at average speeds exceeding 1 μm... |
10.1371/journal.pcbi.1005307 | Cell Sorting and Noise-Induced Cell Plasticity Coordinate to Sharpen Boundaries between Gene Expression Domains | A fundamental question in biology is how sharp boundaries of gene expression form precisely in spite of biological variation/noise. Numerous mechanisms position gene expression domains across fields of cells (e.g. morphogens), but how these domains are refined remains unclear. In some cases, domain boundaries sharpen t... | In many developing systems, chemical gradients control the formation of segmental domains of gene expression, specifying distinct domains that go on to form different tissues and structures, in a concentration-dependent manner. These gradients are noisy however, raising the question of how sharply delineated boundaries... | The specification of segmental domains of gene expression is a fundamental aspect of animal development and a critical first step in bilaterian body plan organization [1, 2]. Within these domains, differential gene expression determines the functional properties of cells. For example, alternating domains of pair rule g... |
10.1371/journal.pbio.1000439 | Structural and Biochemical Characterization of the Human Cyclophilin Family of Peptidyl-Prolyl Isomerases | Peptidyl-prolyl isomerases catalyze the conversion between cis and trans isomers of proline. The cyclophilin family of peptidyl-prolyl isomerases is well known for being the target of the immunosuppressive drug cyclosporin, used to combat organ transplant rejection. There is great interest in both the substrate specifi... | Cyclophilins are proteins that catalyze the isomerization of prolines, interconverting this structurally important amino acid between cis and trans isomers. Although there are 17 cyclophilins in the human genome, the function of most cyclophilin isoforms is unknown. At least some members of this protein family are of i... | Cyclophilins are peptidyl-prolyl isomerases (PPIases: EC 5.2.1.8) and are characterized by their ability to catalyze the interconversion of cis and trans isomers of proline [1]. Cyclophilins and the structurally unrelated FK506 binding proteins were initially described as the in vivo receptors for the natural products ... |
10.1371/journal.ppat.1006865 | Conditional mutagenesis in vivo reveals cell type- and infection stage-specific requirements for LANA in chronic MHV68 infection | Gammaherpesvirus (GHV) pathogenesis is a complex process that involves productive viral replication, dissemination to tissues that harbor lifelong latent infection, and reactivation from latency back into a productive replication cycle. Traditional loss-of-function mutagenesis approaches in mice using murine gammaherpe... | Gammaherpesviruses (GHVs), including the human pathogens Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus, establish lifelong infections that can lead to cancer. Defining the functions of viral gene products in acute replication and chronic infection is important for understanding how these viruses cause di... | Gammaherpesviruses (GHVs) are large, enveloped, double-strand DNA viruses that include the human pathogens Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV). GHVs establish lifelong, chronic infections in their hosts and are responsible for causing lymphoproliferative disorders (LPD) and cancer ... |
10.1371/journal.pntd.0006728 | Shorter-course treatment for Mycobacterium ulcerans disease with high-dose rifamycins and clofazimine in a mouse model of Buruli ulcer | Starting in 2004, the standard regimen for treatment of Buruli ulcer (BU) recommended by the World Health Organization has been daily treatment for eight weeks with rifampin (RIF) and streptomycin. Based on recent clinical trials, treatment with an all-oral regimen of RIF and clarithromycin (CLR) may be an effective al... | Buruli ulcer, a neglected tropical skin disease caused by Mycobacterium ulcerans, is treatable since 2004 with antibiotics instead of surgery. Treatment with either rifampin plus streptomycin or, more recently, rifampin plus clarithromycin requires taking the drugs daily for 8 weeks. Streptomycin is administered by inj... | Buruli ulcer (BU), or Mycobacterium ulcerans disease, is a necrotizing skin disease driven by production of the immunosuppressive and cytotoxic macrolide-like toxin, mycolactone. Treatment for BU shifted from surgery and skin grafting to antibiotic therapy following pre-clinical and clinical evidence that combination, ... |
10.1371/journal.ppat.1007207 | S‐acylation mediates Mungbean yellow mosaic virus AC4 localization to the plasma membrane and in turns gene silencing suppression | RNA silencing plays a critical role in plant resistance against viruses. To counteract host defense, plant viruses encode viral suppressors of RNA silencing (VSRs) that interfere with the cellular silencing machinery through various mechanisms not always well understood. We examined the role of Mungbean yellow mosaic v... | Plants have developed small RNA (siRNA)-mediated post-transcriptional gene silencing as a defense mechanism against viruses. In response, plant viruses encode viral suppressors of RNA silencing (VSRs) that can interfere with various steps of the silencing pathway. Mungbean yellow mosaic virus (MYMV) is a plant bipartit... | Viruses are obligate intracellular parasites that exploit host machineries to propagate and spread in the host. Their presence and activity deploy diverse plant mechanisms to combat viral infections at both the cellular and the whole-organism levels. Double-stranded (ds)RNA forming during virus replication and self-com... |
10.1371/journal.pgen.1004518 | Requirements for Pseudomonas aeruginosa Acute Burn and Chronic Surgical Wound Infection | Opportunistic infections caused by Pseudomonas aeruginosa can be acute or chronic. While acute infections often spread rapidly and can cause tissue damage and sepsis with high mortality rates, chronic infections can persist for weeks, months, or years in the face of intensive clinical intervention. Remarkably, this div... | Soft tissue infections, such as those in burns, bed sores, and diabetic ulcers, are a significant healthcare and economic burden in the developed and developing world. The opportunistic pathogen P. aeruginosa can cause both acute and chronic infections, and the trajectory of these two types of infections is vastly diff... | Infections caused by opportunistic bacterial pathogens are a primary cause of morbidity and mortality in both the developed and developing world. These infections are often characterized by robust growth of the pathogen in the infection site and increasingly high resistance to antibiotic treatment. The opportunistic pa... |
10.1371/journal.pcbi.1002233 | How Landscape Heterogeneity Frames Optimal Diffusivity in Searching Processes | Theoretical and empirical investigations of search strategies typically have failed to distinguish the distinct roles played by density versus patchiness of resources. It is well known that motility and diffusivity of organisms often increase in environments with low density of resources, but thus far there has been li... | Understanding how animals search for food is crucial for animal ecology. Although much has been learned about the main aspects of the so-called foraging problem, some important questions still remain unanswered. In this work we address the issue of the relevance of heterogeneity in the resources distribution to efficie... | The random search problem has lately received a great deal of attention [1], [2]. This is partly due to its broad interdisciplinary range of applications, which include, e.g., enhanced diffusion of regulatory proteins while “searching” for specific DNA spots [3], [4] and the finding of binding sites on transmembrane pr... |
10.1371/journal.pbio.1000488 | Stochastic E2F Activation and Reconciliation of Phenomenological Cell-Cycle Models | The transition of the mammalian cell from quiescence to proliferation is a highly variable process. Over the last four decades, two lines of apparently contradictory, phenomenological models have been proposed to account for such temporal variability. These include various forms of the transition probability (TP) model... | Mammalian cells enter the division cycle in response to appropriate growth signals. For each cell, the decision to do so is critically dependent on the interplay between environmental cues and the internal state of the cell and is influenced by random fluctuations in cellular processes. Indeed, experimental evidence in... | Cell-to-cell variability in the timing of cell-fate commitment is widely observed in biological settings [1]–[4]. In particular, the variable timing of transition from the quiescent to the proliferative state is a well-documented phenomenon [5]–[8]. In a population of proliferating cells, such variability is reflected ... |
10.1371/journal.pgen.1005879 | 3’UTR Shortening Potentiates MicroRNA-Based Repression of Pro-differentiation Genes in Proliferating Human Cells | Most mammalian genes often feature alternative polyadenylation (APA) sites and hence diverse 3’UTR lengths. Proliferating cells were reported to favor APA sites that result in shorter 3’UTRs. One consequence of such shortening is escape of mRNAs from targeting by microRNAs (miRNAs) whose binding sites are eliminated. S... | MicroRNAs (miRNAs) are regulators of gene expression. Typically they recognize a binding site in genes' sequences and exert a repressive effect. This scheme prescribes a regulatory network that determines which gene is regulated by which miRNA. Yet this is a static sequence-based scheme that might not support dynamic c... | RNA polyadenylation is a pivotal molecular process, which plays important roles in ensuring the stability, nuclear export and efficient translation of mRNA. Cleavage of the mRNA in its 3’ untranslated region (UTR), prior to addition of the poly(A) tail, is instructed by a polyadenylation signal (PAS) [1]. In fact, most... |
10.1371/journal.pgen.1004991 | Interaction between the tRNA-Binding and C-Terminal Domains of Yeast Gcn2 Regulates Kinase Activity In Vivo | The stress-activated protein kinase Gcn2 regulates protein synthesis by phosphorylation of translation initiation factor eIF2α. Gcn2 is activated in amino acid-deprived cells by binding of uncharged tRNA to the regulatory domain related to histidyl-tRNA synthetase, but the molecular mechanism of activation is unclear. ... | The survival of all living organisms depends on their capacity to adapt their gene expression program to variations in the environment. When subjected to various stresses, eukaryotic cells modulate general and gene-specific protein synthesis by phosphorylating the α-subunit of eukaryotic translation initiation factor 2... | Eukaryotic cells harbor stress-activated protein kinases that allow cells to reduce bulk protein synthesis while simultaneously activating the transcription of genes encoding stress management proteins. The target of these kinases is Ser-51 of the α-subunit of translation initiation factor 2 (eIF2α). Phosphorylation of... |
10.1371/journal.pntd.0002142 | The Incidence of Human Cysticercosis in a Rural Community of Eastern Zambia | A community-based longitudinal study was performed in the Eastern Province of Zambia, in which repeated serological samplings were done to determine the incidence of human cysticercosis. Three sampling rounds were carried out at six months intervals. A total of 867 participants presented for all three samplings. All sa... | Human neurocysticercosis is an infection of the central nervous system caused by the larval stage of the pork tapeworm (Taenia solium). The infection occurs mainly in developing countries and is associated with poverty, poor sanitation and free-range pig management. It is estimated to be responsible for 30% of cases of... | Human (neuro) cysticercosis, an infection caused by the metacestode larval stage of the pork tapeworm Taenia solium, is a serious but neglected zoonotic disease and a major public health problem in many developing countries of Latin America, Asia and Africa [1], [2]. Humans are the definitive hosts harbouring the adult... |
10.1371/journal.pntd.0003167 | Genetic Diversity of Brazilian Aedes aegypti: Patterns following an Eradication Program | Aedes aegypti is the most important vector of dengue fever in Brazil, where severe epidemics have recently taken place. Ae. aegypti in Brazil was the subject of an intense eradication program in the 1940s and 50s to control yellow fever. Brazil was the largest country declared free of this mosquito by the Pan-American ... | The mosquito, Aedes aegypti, was historically very important as the major vector of yellow fever, whereas today it is most notorious for being the major transmitter of dengue fever. In the 1940s and 50s, the Pan-American Health Organization organized a campaign to eradicate Ae. aegypti from the New World. They were par... | Dengue fever is a viral disease transmitted by Aedes mosquitoes that occur in tropical and subtropical areas around the world. Due to a widespread distribution, this disease could be more important than malaria in terms of economic impact and morbidity [1]–[4]. It is estimated that more than two billion people (over 40... |
10.1371/journal.pntd.0004965 | DenHunt - A Comprehensive Database of the Intricate Network of Dengue-Human Interactions | Dengue virus (DENV) is a human pathogen and its etiology has been widely established. There are many interactions between DENV and human proteins that have been reported in literature. However, no publicly accessible resource for efficiently retrieving the information is yet available. In this study, we mined all publi... | The ‘Dengue Human Interaction Database’, called DenHunt, available at http://proline.biochem.iisc.ernet.in/DenHunt/ was created to catalog all interactions between dengue viral and human components published in peer-reviewed literature. There are three types of dengue-human molecular interactions in the database: direc... | Dengue, an emerging infectious disease, is presently the most common arboviral disease globally. Approximately 2.5 billion people live in dengue infested regions worldwide and 390 million dengue infections are reported per year [1]. Dengue infection leads to complications ranging from mild dengue fever to more severe d... |
10.1371/journal.pgen.1000357 | Short Telomeres Initiate Telomere Recombination in Primary and Tumor Cells | Human tumors that lack telomerase maintain telomeres by alternative lengthening mechanisms. Tumors can also form in telomerase-deficient mice; however, the genetic mechanism responsible for tumor growth without telomerase is unknown. In yeast, several different recombination pathways maintain telomeres in the absence o... | Telomeres shorten with each cell division and are normally maintained by telomerase. Tumor cells typically up-regulate telomerase to maintain telomeres during rapid growth; however, some tumors lack telomerase and utilize alternative mechanisms to maintain the telomeres. Studies in yeast indicate that recombination con... | Telomere length is maintained by the ribonucleoprotein complex telomerase [1]. However, telomerase expression in humans occurs primarily in early development, germ cells, and in stem cells and is not detected in primary cells [2],[3]. Most human tumor cells have detectable telomerase activity, however some proliferatin... |
10.1371/journal.pgen.1007943 | Marine environmental DNA biomonitoring reveals seasonal patterns in biodiversity and identifies ecosystem responses to anomalous climatic events | Marine ecosystems are changing rapidly as the oceans warm and become more acidic. The physical factors and the changes to ocean chemistry that they drive can all be measured with great precision. Changes in the biological composition of communities in different ocean regions are far more challenging to measure because ... | All environments contain genetic remnants of the life they contain and support. For example, samples collected from the ocean contain biological material such as microscopic organisms, shed cells, excrement and saliva—the DNA from which reveals the surrounding marine biodiversity. Environmental DNA (eDNA) approaches ha... | Changes in ocean temperatures, chemistry and currents are occurring faster now than at any time in human history [1, 2]. These changes will certainly impact the productivity in marine environments that is critical for social and economic wellbeing [3]. These impacts have driven the expansion of global efforts to monito... |
10.1371/journal.pgen.1002203 | B Chromosomes Have a Functional Effect on Female Sex Determination in Lake Victoria Cichlid Fishes | The endemic cichlid fishes in Lake Victoria are a model system for speciation through adaptive radiation. Although the evolution of the sex-determination system may also play a role in speciation, little is known about the sex-determination system of Lake Victoria cichlids. To understand the evolution of the sex-determ... | The diversity of sex chromosomes among animal species is well known, but how these sex chromosomes emerged during evolutionary history remains to be solved. One hypothesis for the origin of sex chromosomes is that a portion of the sex chromosome was derived from B chromosomes. In about 10% of eukaryotes, B chromosomes ... | The species flock of endemic cichlid fishes in Lake Victoria is the largest known example of recent adaptive radiation and has been highlighted as a model system for the genetic study of speciation [1]–[3]. The evolution of the sex-determination system is suggested to drive the speciation of the cichlids because novel ... |
10.1371/journal.pbio.1001645 | The CK2 Kinase Stabilizes CLOCK and Represses Its Activity in the Drosophila Circadian Oscillator | Phosphorylation is a pivotal regulatory mechanism for protein stability and activity in circadian clocks regardless of their evolutionary origin. It determines the speed and strength of molecular oscillations by acting on transcriptional activators and their repressors, which form negative feedback loops. In Drosophila... | The CK2 kinase is an ancient enzyme known to be at the heart of self-sustaining circadian clocks in animals, plants, and fungi. Circadian clocks are responsible for daily circadian rhythms in molecular, physiological, and behavioral processes. Their mechanism relies on transcriptional activators and repressors that con... | Circadian oscillations of gene expression, physiology, and behavior are found in a wide range of organisms. They are governed by temporally regulated feedback loops in which transcription factors activate the expression of their own inhibitors. In the Drosophila circadian oscillator, the CLOCK (CLK) and CYCLE (CYC) bHL... |
10.1371/journal.pgen.1000958 | The Polyproline Site in Hinge 2 Influences the Functional Capacity of Truncated Dystrophins | Mutations in dystrophin can lead to Duchenne muscular dystrophy or the more mild form of the disease, Becker muscular dystrophy. The hinge 3 region in the rod domain of dystrophin is particularly prone to deletion mutations. In-frame deletions of hinge 3 are predicted to lead to BMD, however the severity of disease can... | Dystrophin functions like a large molecular spring between the muscle cytoskeleton and the extracellular matrix in order to protect the membrane from contraction-induced injury. Mutations in dystrophin can lead to a severe muscle wasting disease called Duchenne muscular dystrophy (DMD) in young boys. DMD patients are t... | Duchenne muscular dystrophy (DMD) is a lethal X-linked recessive disease caused by mutations in the 2.2 MB dystrophin gene [1]–[3]. In skeletal muscle, dystrophin provides a flexible connection between the cytoskeleton and the dystrophin-glycoprotein complex at the sarcolemma, myotendinous junction (MTJ) and neuromuscu... |
10.1371/journal.pcbi.1002185 | Transmission Selects for HIV-1 Strains of Intermediate Virulence: A Modelling Approach | Recent data shows that HIV-1 is characterised by variation in viral virulence factors that is heritable between infections, which suggests that viral virulence can be naturally selected at the population level. A trade-off between transmissibility and duration of infection appears to favour viruses of intermediate viru... | Recent studies have suggested that virulence in HIV-1 is partly a characteristic of the virus which is carried from one infection to the next. An infection with intermediate virulence will produce more transmissions during the infectious lifetime because it optimises the trade-off between rate of transmission and durat... | The median time between HIV-1 seroconversion and progression to symptomatic Acquired Immune Deficiency Syndrome (AIDS) is approximately 10 years [1]. However, there is considerable variation in this rate of progression, with substantial proportions of infected individuals progressing to AIDS in less than 5 years, or re... |
10.1371/journal.pgen.1008121 | Chaperonin TRiC/CCT supports mitotic exit and entry into endocycle in Drosophila | Endocycle is a commonly observed cell cycle variant through which cells undergo repeated rounds of genome DNA replication without mitosis. Endocycling cells arise from mitotic cells through a switch of the cell cycle mode, called the mitotic-to-endocycle switch (MES), to initiate cell growth and terminal differentiatio... | Endocycle, a cell cycle variant consisting of DNA replication and Gap phases without a mitotic phase, is widespread in nature. Endocycling cells arise from proliferating cells through a switch of the cell cycle mode called mitotic-to-endocycle switching (MES). While the molecular mechanisms regulating progression of th... | A tightly controlled cell cycle is a fundamental system for survival in every organism. The best-known cell cycle mode is mitotic cell cycle, which is achieved through a sequence of distinct phases including genome DNA synthesis (S), mitotic (M), and intervening Gap (G) phases. Moreover, endocycle, a cell cycle variant... |
10.1371/journal.pntd.0007607 | Cryptosporidium infection in rural Gambian children: Epidemiology and risk factors | Cryptosporidium is a major pathogen associated with diarrheal disease in young children. We studied Cryptosporidium diarrhea in children enrolled in the Global Enteric Multicenter Study (GEMS) in rural Gambia.
We recruited children <5 years of age with moderate-to-severe diarrhea (MSD) for 3 years (2008–2010), and chil... | Cryptosporidium, a protozoan parasite, is one of the most common diarrheal pathogens in young children living in developing countries. We describe the prevalence and risk factors for Cryptosporidium diarrhea in under-five children in The Gambia using data from the Global Enteric Study (GEMS), conducted in seven develop... | Diarrhea is the second leading cause of morbidity and mortality in children less than 5 years old, causing approximately 600,000 annual deaths, mostly in developing countries [1]. Cryptosporidium, a protozoan parasite, is transmitted like other diarrheal pathogens by the fecal-oral route and is more prevalent in patien... |
10.1371/journal.pntd.0000211 | An Analysis of Genetic Diversity and Inbreeding in Wuchereria bancrofti: Implications for the Spread and Detection of Drug Resistance | Estimates of genetic diversity in helminth infections of humans often have to rely on genotyping (immature) parasite transmission stages instead of adult worms. Here we analyse the results of one such study investigating a single polymorphic locus (a change at position 200 of the β-tubulin gene) in microfilariae of the... | During the last decade, there has been a substantial increase in the use of mass drug administration to reduce the disease caused by parasitic worms. With so many people regularly receiving treatment, there is a risk that drug resistance may develop. As a result, the number of studies looking for genetic markers of dru... | In recent years there has been a substantial increase in the use of mass drug administration (MDA) to reduce the morbidity associated with helminth infections of humans [1], increasing the probability that anthelmintic resistance may become a public health concern in the future. One such annual MDA programme is the Glo... |
10.1371/journal.pgen.1004672 | Sensors at Centrosomes Reveal Determinants of Local Separase Activity | Separase is best known for its function in sister chromatid separation at the metaphase-anaphase transition. It also has a role in centriole disengagement in late mitosis/G1. To gain insight into the activity of separase at centrosomes, we developed two separase activity sensors: mCherry-Scc1(142-467)-ΔNLS-eGFP-PACT an... | Centriole disengagement in telophase/G1 is the licensing step for centrosome duplication in the subsequent S phase. Recent data suggest that separase, together with polo-like kinase Plk1, is essential for the centriole disengagement and individual depletion of either separase or Plk1 alone fails to suppress the centrio... | Centrosomes are the main microtubule organizing centers of animal cells that consist of the organizing centrioles and pericentriolar material. Centrosomes, like DNA, duplicate exactly once per cell cycle. From S phase to the end of mitosis centrosomes are composed of a pair of centrioles, the mother and the daughter ce... |
10.1371/journal.pgen.1007940 | The Drosophila fussel gene is required for bitter gustatory neuron differentiation acting within an Rpd3 dependent chromatin modifying complex | Members of the Ski/Sno protein family are classified as proto-oncogenes and act as negative regulators of the TGF-ß/BMP-pathways in vertebrates and invertebrates. A newly identified member of this protein family is fussel (fuss), the Drosophila homologue of the human functional Smad suppressing elements (fussel-15 and ... | Ski/Sno proteins have been discovered as proto-oncogenes transforming chicken fibroblasts into cancer cells. They have been found to be ubiquitously expressed in embryonic and adult tissues and to interfere with TGF-ß/BMP signaling. More recently, a group of proteins has been discovered which belongs to the same protei... | During development, the TGF-ß superfamily plays an important role in cell proliferation, differentiation, apoptosis, cell adhesion, wound healing, bone morphogenesis and cell motility [1]. Accordingly, there are multiple inhibitory factors taking care of proper regulation of TGF-ß pathways. Besides inhibitory Smads and... |
10.1371/journal.ppat.1001044 | The Pneumococcal Serine-Rich Repeat Protein Is an Intra-Species Bacterial Adhesin That Promotes Bacterial Aggregation In Vivo and in Biofilms | The Pneumococcal serine-rich repeat protein (PsrP) is a pathogenicity island encoded adhesin that has been positively correlated with the ability of Streptococcus pneumoniae to cause invasive disease. Previous studies have shown that PsrP mediates bacterial attachment to Keratin 10 (K10) on the surface of lung cells th... | Serine-rich repeat proteins (SRRPs) are a family of surface-expressed proteins found in numerous Gram-positive pathogens, including Staphylococcus aureus, Streptococcus pneumoniae, Group B streptococci, and the oral streptococci that cause infective endocarditis. For all of these bacteria, SRRPs have been demonstrated ... | Streptococcus pneumoniae is a leading cause of otitis media (OM), community-acquired pneumonia, sepsis and meningitis. Primarily a commensal, S. pneumoniae typically colonizes the nasopharynx asymptomatically, however in susceptible individuals such as infants, the elderly, persons who are immunocompromised, and those ... |
10.1371/journal.pcbi.1002939 | A Dynamical Role for Acetylcholine in Synaptic Renormalization | Although sleep is a fundamental behavior observed in virtually all animal species, its functions remain unclear. One leading proposal, known as the synaptic renormalization hypothesis, suggests that sleep is necessary to counteract a global strengthening of synapses that occurs during wakefulness. Evidence for sleep-de... | The function of sleep is one of the greatest mysteries in contemporary neuroscience. Nearly every species of animal requires it, yet we do not know why. One idea, known as the synaptic renormalization hypothesis, suggests that waking results in a global increase in the strengths of connections in the brain, a phenomeno... | Sleep is crucial for normal cognitive function as evidenced by the many cognitive impairments associated with chronic sleep loss [1], [2]. A leading proposal for the function of sleep, called the synaptic renormalization hypothesis, posits that sleep is required to maintain synaptic balance in the brain [3], [4]. Accor... |
10.1371/journal.pgen.1008259 | Attenuating the emergence of anti-fungal drug resistance by harnessing synthetic lethal interactions in a model organism | Drug resistance is a rapidly emerging concern, thus prompting the development of novel therapeutics or combinatorial therapy. Currently, combinatorial therapy targets are based on knowledge of drug mode of action and/or resistance mechanisms, constraining the number of target proteins. Unbiased genome-wide screens coul... | Life threatening infections are an increasing reality. Multi-drug resistant bacteria e.g. MRSA are present in nearly all hospitals, and community acquired TB is often recalcitrant to treatment. Less well known, but causing four to five times more deaths in the UK than MRSA, are fungi in the genus Candida. These are com... | Drug resistance has emerged as a huge problem in many areas of medicine from cancer to infectious diseases [1, 2, 3, 4]. This is leading to the development of novel therapeutic strategies. Multi-target therapies are gaining ground, where combinations of drugs targeting different components of disease networks are deplo... |
10.1371/journal.pgen.1004641 | The Association of the Vanin-1 N131S Variant with Blood Pressure Is Mediated by Endoplasmic Reticulum-Associated Degradation and Loss of Function | High blood pressure (BP) is the most common cardiovascular risk factor worldwide and a major contributor to heart disease and stroke. We previously discovered a BP-associated missense SNP (single nucleotide polymorphism)–rs2272996–in the gene encoding vanin-1, a glycosylphosphatidylinositol (GPI)-anchored membrane pant... | Hypertension (HTN) or high blood pressure (BP) is common worldwide and a major risk factor for cardiovascular disease and all-cause mortality. Identification of genetic variants of consequence for HTN serves as the molecular basis for its treatment. Using admixture mapping analysis of the Family Blood Pressure Program ... | Hypertension (HTN) or high blood pressure (BP) is common in populations worldwide and a major risk factor for cardiovascular disease (CVD) and all-cause mortality [1]. Although it is observed across ethnically diverse populations, the prevalence of HTN in the US varies from 27% in persons of European ancestry to 40% am... |
10.1371/journal.pcbi.1000185 | A Dual Receptor Crosstalk Model of G-Protein-Coupled Signal Transduction | Macrophage cells that are stimulated by two different ligands that bind to G-protein-coupled receptors (GPCRs) usually respond as if the stimulus effects are additive, but for a minority of ligand combinations the response is synergistic. The G-protein-coupled receptor system integrates signaling cues from the environm... | The G protein signal transduction system transmits a wide variety of extracellular signals including light, odors, and hormones, to intracellular effectors in diverse cell types in eukaryotes. G-protein-coupled receptors are involved in many diseases including inflammation, cardiac dysfunction, and diabetes, and are th... | The G-protein-coupled signal transduction system integrates a wide range of intercellular signals and actuates downstream pathways. G-protein-coupled receptors (GPCRs) are composed of seven α-helices that span the plasma membrane, an extracellular domain that is activated by an agonist and an intracellular domain that ... |
10.1371/journal.pbio.1001034 | A Structural and Mutagenic Blueprint for Molecular Recognition of Strychnine and d-Tubocurarine by Different Cys-Loop Receptors | Cys-loop receptors (CLR) are pentameric ligand-gated ion channels that mediate fast excitatory or inhibitory transmission in the nervous system. Strychnine and d-tubocurarine (d-TC) are neurotoxins that have been highly instrumental in decades of research on glycine receptors (GlyR) and nicotinic acetylcholine receptor... | Ligand-gated ion channels play an important role in fast electrochemical signaling in the brain. Cys-loop receptors are a class of pentameric ligand-gated ion channels that are activated by specific neurotransmitters, including acetylcholine (ACh), serotonin (5-HT), glycine (Gly), and γ-aminobutyric acid (GABA). Each t... | Strychnine and d-TC (Figure 1A) are alkaloids from poisonous plants. Strychnine exerts its lethal effects by antagonizing inhibitory glycine receptors (GlyR) in the central nervous system. Intoxication with strychnine causes muscle spasms, convulsions and eventually leads to death by respiratory paralysis. Clinical use... |
10.1371/journal.pmed.1002558 | Maternal age and offspring developmental vulnerability at age five: A population-based cohort study of Australian children | In recent decades, there has been a shift to later childbearing in high-income countries. There is limited large-scale evidence of the relationship between maternal age and child outcomes beyond the perinatal period. The objective of this study is to quantify a child’s risk of developmental vulnerability at age five, a... | There has been a shift towards later childbearing in recent decades; although the perinatal risks are well documented, the consequences on child development are less clear.
Several observational cohort studies have reported that increasing maternal age is associated with better child development outcomes, although the ... | In recent decades, there has been a shift towards later average age at childbearing in high-income countries, underpinned by an increasing proportion of women giving birth at older ages, combined with a reduction in teenage pregnancies [1]. Some of the primary drivers behind this trend have altered the age-related demo... |
10.1371/journal.pgen.1002224 | Cholesterol Metabolism Is Required for Intracellular Hedgehog Signal Transduction In Vivo | We describe the rudolph mouse, a mutant with striking defects in both central nervous system and skeletal development. Rudolph is an allele of the cholesterol biosynthetic enzyme, hydroxysteroid (17-beta) dehydrogenase 7, which is an intriguing finding given the recent implication of oxysterols in mediating intracellul... | The molecules and signaling pathways that regulate growth and patterning of the developing embryo are still being elucidated, and one valuable experimental approach is the use of animal models, such as the mouse. We have identified a recessive mutation in the mouse, rudolph, that causes abnormal forebrain development a... | Hedgehog (Hh) ligands have numerous and fundamental roles in both embryonic development [1], [2] and tumor biology [3]. Mammalian hedgehog proteins bind to the transmembrane receptor Patched (Ptc) and thereby relieve its repression of Smoothened (Smo). Intracellular transduction of Smo activity requires processing of G... |
10.1371/journal.pntd.0003638 | Sensitivity and Specificity of a Novel Classifier for the Early Diagnosis of Dengue | Dengue is the commonest arboviral disease of humans. An early and accurate diagnosis of dengue can support clinical management, surveillance and disease control and is central to achieving the World Health Organisation target of a 50% reduction in dengue case mortality by 2020.
5729 children with fever of <72hrs durati... | Dengue is a very common acute infectious disease in the tropical world. Health care professionals are able to better care for dengue patients if they can make an early diagnosis and make a plan for case management. This current study investigated fever in 5729 children in Vietnam with 3 days or less of fever and identi... | Dengue is an acute, systemic viral infection and a public health problem in the tropical world [1]. The etiological agents of dengue are any of the four dengue viruses (DENV-1-4). In endemic countries it is common for all four DENV serotypes to co-circulate. Late-stage trials of a dengue vaccine with intermediate effic... |
10.1371/journal.ppat.1004974 | A Comprehensive Analysis of Replicating Merkel Cell Polyomavirus Genomes Delineates the Viral Transcription Program and Suggests a Role for mcv-miR-M1 in Episomal Persistence | Merkel cell polyomavirus (MCPyV) is considered the etiological agent of Merkel cell carcinoma and persists asymptomatically in the majority of its healthy hosts. Largely due to the lack of appropriate model systems, the mechanisms of viral replication and MCPyV persistence remain poorly understood. Using a semi-permiss... | MCPyV is a recently discovered human polyomavirus that is likely to cause the majority of cases of Merkel cell carcinoma (MCC), a rare but highly aggressive skin cancer. While much research has been focused on understanding transforming functions of MCPyV gene products, owing to the lack of fully permissive replication... | Merkel cell polyomavirus (MCPyV), first identified in 2008 in tissue from Merkel cell carcinoma (MCC) [1], is the only human polyomavirus considered to be the etiological agent of tumors arising in its natural host. Several lines of evidence, including frequent detection of monoclonally integrated sequences bearing hal... |
10.1371/journal.pcbi.1002149 | Efficacy of Synaptic Inhibition Depends on Multiple, Dynamically Interacting Mechanisms Implicated in Chloride Homeostasis | Chloride homeostasis is a critical determinant of the strength and robustness of inhibition mediated by GABAA receptors (GABAARs). The impact of changes in steady state Cl− gradient is relatively straightforward to understand, but how dynamic interplay between Cl− influx, diffusion, extrusion and interaction with other... | Fast synaptic inhibition relies on chloride current to hyperpolarize the neuron or to prevent depolarization caused by concurrent excitatory input. Both scenarios necessarily involve chloride flux into the cell and, thus, a change in intracellular chloride concentration. The vast majority of models neglect changes in i... | In the central nervous system, fast inhibition is mediated by GABAA and glycine receptor-gated Cl− channels (GABAAR and GlyR). Influx of Cl− through these channels produces outward currents that cause hyperpolarization or prevent depolarization caused by concurrent excitatory input (i.e. shunting) [1], [2]. Hyperpolari... |
10.1371/journal.pgen.1000500 | The Role of Geography in Human Adaptation | Various observations argue for a role of adaptation in recent human evolution, including results from genome-wide studies and analyses of selection signals at candidate genes. Here, we use genome-wide SNP data from the HapMap and CEPH-Human Genome Diversity Panel samples to study the geographic distributions of putativ... | Since the beginning of the study of evolution, people have been fascinated by recent human evolution and adaptation. Despite great progress in our understanding of human history, we still know relatively little about the selection pressures and historical factors that have been important over the past 100,000 years. In... | One of the central problems in evolutionary biology is to understand the genetic and ecological mechanisms that drive adaptation. With the advent of large-scale SNP and DNA sequence data it is now possible to study selection and adaptation at a genome-wide scale. In recent years there has been considerable progress in ... |
10.1371/journal.pgen.1006897 | Altered paracellular cation permeability due to a rare CLDN10B variant causes anhidrosis and kidney damage | Claudins constitute the major component of tight junctions and regulate paracellular permeability of epithelia. Claudin-10 occurs in two major isoforms that form paracellular channels with ion selectivity. We report on two families segregating an autosomal recessive disorder characterized by generalized anhidrosis, sev... | Claudins are tight junction proteins forming paracellular barriers that are critical for normal development and homeostasis. The tissue specific paracellular barrier properties are determined by the protein composition of tight junctions that regulates the permeability of solutes and water between different compartment... | Epithelial and endothelial cells constitute sheets that divide organs into functional compartments. Homeostasis of different organ and body compartments are dependent on epithelial cells and their paracellular barrier that prevents solutes and water from leaking between the cells. The tissue specific paracellular barri... |
10.1371/journal.pbio.2002612 | A multiscale cerebral neurochemical connectome of the rat brain | Understanding the rat neurochemical connectome is fundamental for exploring neuronal information processing. By using advanced data mining, supervised machine learning, and network analysis, this study integrates over 5 decades of neuroanatomical investigations into a multiscale, multilayer neurochemical connectome of ... | The mammalian brain consists of a network of chemically diverse, multiscale, and multilayer neuronal wiring patterns that form the physical infrastructure underlying the processing of motoric, sensory, emotional, and cognitive information. Decades of histological track-tracing studies have generated a set of highly val... | Automatic keyword-based search (1,750 keywords) and manual grey search on electronic databases revealed 124,694 abstracts, titles, or both identified as original publications. Out of these, 4,517 studies were relevant for data mining and data from 1,560 original research articles with 36,464 rats were selected for the ... |
10.1371/journal.ppat.0030030 | Female Inheritance of Malarial lap Genes Is Essential for Mosquito Transmission | Members of the LCCL/lectin adhesive-like protein (LAP) family, a family of six putative secreted proteins with predicted adhesive extracellular domains, have all been detected in the sexual and sporogonic stages of Plasmodium and have previously been predicted to play a role in parasite–mosquito interactions and/or imm... | Malaria parasites are transmitted between human hosts by female mosquitoes. Following fertilization between male and female gametes in the blood meal, zygotes develop into motile ookinetes that, 24 hours later, cross the mosquito midgut epithelium and encyst on the midgut wall. During this development, parasite numbers... | Transmission of the malarial parasite Plasmodium from the vertebrate host to the mosquito vector requires rapid sexual development within the mosquito midgut, which is triggered upon ingestion of male and female gametocytes by the mosquito during a blood meal. Gametocyte activation and gametogenesis occur within 15 min... |
10.1371/journal.pcbi.1006381 | Identification of excitatory-inhibitory links and network topology in large-scale neuronal assemblies from multi-electrode recordings | Functional-effective connectivity and network topology are nowadays key issues for studying brain physiological functions and pathologies. Inferring neuronal connectivity from electrophysiological recordings presents open challenges and unsolved problems. In this work, we present a cross-correlation based method for re... | The balance between excitation and inhibition is fundamental for proper brain functions and for this reason is precisely regulated in adult cortices. Impaired excitation/inhibition balance is often associated with several neurological disorders, such as epilepsy, autism and schizophrenia. However, estimating functional... | Understanding the relationships between structure and function, dynamics and connectivity of neuronal circuits are a challenge of the modern neurosciences, especially as the characterization of neuronal interaction in terms of functional and effective connectivity [1–3] is concerned. Functional connectivity is an obser... |
10.1371/journal.ppat.1001192 | MAP Kinase Phosphatase-2 Plays a Critical Role in Response to Infection by Leishmania mexicana | In this study we generated a novel dual specific phosphatase 4 (DUSP4) deletion mouse using a targeted deletion strategy in order to examine the role of MAP kinase phosphatase-2 (MKP-2) in immune responses. Lipopolysaccharide (LPS) induced a rapid, time and concentration-dependent increase in MKP-2 protein expression i... | In cells of the immune system are switch-on enzymes called kinases which regulate responses to infectious agents such as Leishmania. However, in the same cells there are switch-off enzymes known as phosphatases which function to turn off the kinases once they have done their work. A lot of studies have focussed on the ... | The mitogen-activated protein (MAP) kinase phosphatases (MKPs) are a family of dual specific phosphatases which regulate the functional activity of the major MAP kinase subfamilies through tyrosine and threonine dephosphorylation [1]. At least eleven isoforms exist each with different structures, subcellular distributi... |
10.1371/journal.ppat.1004326 | EVM005: An Ectromelia-Encoded Protein with Dual Roles in NF-κB Inhibition and Virulence | Poxviruses contain large dsDNA genomes encoding numerous open reading frames that manipulate cellular signalling pathways and interfere with the host immune response. The NF-κB signalling cascade is an important mediator of innate immunity and inflammation, and is tightly regulated by ubiquitination at several key poin... | Poxviruses are large dsDNA viruses that are renowned for regulating cellular pathways and manipulating the host immune response, including the NF-κB pathway. NF-κB inhibition by poxviruses is a growing area of interest and this family of viruses has developed multiple mechanisms to manipulate the pathway. Here, we focu... | The NF-κB family of transcription factors activate potent pro-inflammatory and anti-viral immune responses that are activated by a variety of signalling pathways [1], [2]. The family consists of five members, p50, p52, p65 (RelA), RelB, and c-Rel, which function as homo- or heterodimers to activate specific genes. The ... |
10.1371/journal.ppat.1007179 | A cancer-associated Epstein-Barr virus BZLF1 promoter variant enhances lytic infection | Latent Epstein-Barr virus (EBV) infection contributes to both B-cell and epithelial-cell malignancies. However, whether lytic EBV infection also contributes to tumors is unclear, although the association between malaria infection and Burkitt lymphomas (BLs) may involve excessive lytic EBV replication. A particular vari... | Whether excessive lytic EBV infection increases the risk of EBV-induced cancers is not clear. A particular variant (Zp-V3) of the viral promoter driving expression of the EBV immediate-early BZLF1 (Z) protein that mediates lytic viral reactivation has been reported to be over-represented (relative to the prototype Zp-P... | Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with a variety of different types of human malignancies, including B-cell lymphomas and nasopharyngeal carcinoma. EBV infects approximately 90% of the world’s population, and like all herpesviruses, EBV persists in the host for life. EBV establi... |
10.1371/journal.pmed.1002337 | Low-intensity cognitive-behaviour therapy interventions for obsessive-compulsive disorder compared to waiting list for therapist-led cognitive-behaviour therapy: 3-arm randomised controlled trial of clinical effectiveness | Obsessive-compulsive disorder (OCD) is prevalent and without adequate treatment usually follows a chronic course. “High-intensity” cognitive-behaviour therapy (CBT) from a specialist therapist is current “best practice.” However, access is difficult because of limited numbers of therapists and because of the disabling ... | Many people suffer from obsessive-compulsive disorder (OCD), and if they do not get treatment, it can be a long-term problem.
Although cognitive-behaviour therapy (CBT) with a therapist is effective, many people struggle to get access because of limited numbers of therapists.
Low-intensity versions of CBT (written or w... | Obsessive-compulsive disorder (OCD) has an estimated lifetime prevalence of 2%–3% and is rated among the top 10 causes of disability worldwide, with an estimated US$8.4 billion attributable to OCD in the United States [1]. Providing accessible and effective care for OCD is a priority worldwide.
However, there is evide... |
10.1371/journal.ppat.1006659 | Disrupting assembly of the inner membrane complex blocks Plasmodium falciparum sexual stage development | Transmission of malaria parasites relies on the formation of a specialized blood form called the gametocyte. Gametocytes of the human pathogen, Plasmodium falciparum, adopt a crescent shape. Their dramatic morphogenesis is driven by the assembly of a network of microtubules and an underpinning inner membrane complex (I... | Transmission of the malaria parasite from humans to mosquitoes relies on the formation of the specialised blood stage gametocyte. Plasmodium falciparum gametocytes mature over about 10 days, during which time they undergo a remarkable morphological transformation, eventually adopting a characteristic crescent shape. Th... | Plasmodium falciparum, the deadliest of the human malaria parasites, continues to impose an enormous economic and public health burden globally, resulting in about 480,000 deaths each year [1]. Nonetheless, considerable progress has been made in preventing and treating malaria infections and in targeting the mosquito v... |
10.1371/journal.pgen.1002780 | An Engineering Approach to Extending Lifespan in C. elegans | We have taken an engineering approach to extending the lifespan of Caenorhabditis elegans. Aging stands out as a complex trait, because events that occur in old animals are not under strong natural selection. As a result, lifespan can be lengthened rationally using bioengineering to modulate gene expression or to add e... | We used bioengineering to extend the lifespan of C. elegans by expressing genes acting in critical aging pathways. We overexpressed five genes that act in endogenous worm aging pathways, as well as two genes from zebrafish encoding molecular functions not normally present in worms. For example, we used zebrafish genes ... | Recent advances in genome technology and systems biology have made it possible to use engineering approaches to create new biological systems. Examples include the construction of a synthetic genetic oscillator in bacteria [1], engineering quorum sensing (the ability to respond to population density) in yeast by integr... |
10.1371/journal.pntd.0006558 | Multi locus sequence typing of Burkholderia pseudomallei isolates from India unveils molecular diversity and confers regional association in Southeast Asia | Burkholderia pseudomallei, the causative agent for melioidosis, has become a public health problem in India and across the world. Melioidosis can be difficult to diagnose because of the inconsistent clinical presentations of the disease. This study aims to determine the genetic diversity among the clinical isolates of ... | Burkholderia pseudomallei, a gram negative bacteria, is the causative agent for melioidosis. Annually, around 165,000 people suffer from melioidosis worldwide. B. pseudomallei is present in wet soil and stagnant water. It enters the human body via percutaneous inoculation, inhalation, aspiration, and occasionally inges... | Burkholderia pseudomallei, the causative agent of the infectious disease melioidosis, is estimated to cause 165,000 cases of human melioidosis per year worldwide [1]. B. pseudomallei, an environmental saprophyte is commonly found in wet soil and stagnant water throughout endemic regions. The mode of infection is by inh... |
10.1371/journal.pbio.0050039 | Absence of Ret Signaling in Mice Causes Progressive and Late Degeneration of the Nigrostriatal System | Support of ageing neurons by endogenous neurotrophic factors such as glial cell line–derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) may determine whether the neurons resist or succumb to neurodegeneration. GDNF has been tested in clinical trials for the treatment of Parkinson disease (P... | What does a neuron need to survive? Our body produces its own survival factors for neurons, so-called neurotrophic factors, which have additional roles in neuron differentiation, growth, and function. Declining production of a neurotrophic factor or impaired signal transduction in ageing neurons may contribute to patho... | The ventral mesencephalon contains the majority of dopaminergic (DA) neurons in the vertebrate brain with important functions for maintaining the mental and physical health of the organism. They form two prominent pathways: DA neurons of the substantia nigra pars compacta (SNpc) extend their axons mainly into the dorsa... |
10.1371/journal.ppat.1006469 | T-dependent B cell responses to Plasmodium induce antibodies that form a high-avidity multivalent complex with the circumsporozoite protein | The repeat region of the Plasmodium falciparum circumsporozoite protein (CSP) is a major vaccine antigen because it can be targeted by parasite neutralizing antibodies; however, little is known about this interaction. We used isothermal titration calorimetry, X-ray crystallography and mutagenesis-validated modeling to ... | Vaccines aim to protect by inducing the immune system to make molecules called antibodies that can recognize molecules on the surface of invading pathogens. In the case of malaria, our most advanced vaccine candidates aim to promote the production of antibodies that recognize the circumsporozoite protein (CSP) molecule... | Malaria caused by Plasmodium falciparum causes the deaths of around 430,000 people each year [1]. The most advanced vaccine candidate for malaria is the RTS,S/AS01 vaccine which consists of a truncated version of the sporozoite-surface circumsporozoite protein (CSP), packaged in a Hepatitis C core virus-like particle d... |
10.1371/journal.pgen.1000092 | Novel Roles for MLH3 Deficiency and TLE6-Like Amplification in DNA Mismatch Repair-Deficient Gastrointestinal Tumorigenesis and Progression | DNA mismatch repair suppresses gastrointestinal tumorgenesis. Four mammalian E. coli MutL homologues heterodimerize to form three distinct complexes: MLH1/PMS2, MLH1/MLH3, and MLH1/PMS1. To understand the mechanistic contributions of MLH3 and PMS2 in gastrointestinal tumor suppression, we generated Mlh3−/−;Apc1638N and... | Approximately one million people every year are diagnosed with colorectal cancer worldwide, and about five hundred thousand of these people subsequently perish from the disease. Colorectal cancer is thought to develop through a series of early and later stages (called cancer initiation and progression, respectively). D... | Colorectal cancer (CRC) is one of the common malignancies in industrialized countries. Lynch syndrome, a highly penetrant disorder that confers predisposition to cancer of the colorectum, endometrium and other extra-colonic sites [1], is caused by germline mutations in DNA Mismatch Repair genes (MMR). Including sporadi... |
10.1371/journal.pcbi.1002633 | On Genetic Specificity in Symbiont-Mediated Host-Parasite Coevolution | Existing theory of host-parasite interactions has identified the genetic specificity of interaction as a key variable affecting the outcome of coevolution. The Matching Alleles (MA) and Gene For Gene (GFG) models have been extensively studied as the canonical examples of specific and non-specific interaction. The gener... | Coevolution between hosts and parasites is believed to be central to a number of biological phenomena, most notably the observed patterns of biodiversity and the origins of sexual reproduction. However, classical mathematical models of host-parasite coevolution account neither for the hosts' use of bacterial symbionts ... | Parasitism is one of the main lifestyles in nature and a major source of evolutionary pressure. Despite its central place in evolutionary ecology, however, the details of the genetic architecture underlying resistance and infectivity are not known for most host-parasite associations. Mathematical models of host-parasit... |
10.1371/journal.ppat.1003982 | Highly Active Antiretroviral Therapies Are Effective against HIV-1 Cell-to-Cell Transmission | HIV-1 cell-to-cell transmission allows for 2–3 orders of magnitude more efficient viral spread than cell-free dissemination. The high local multiplicity of infection (MOI) observed at cell-cell contact sites may lower the efficacy of antiretroviral therapies (ART). Here we test the efficacy of commonly used antiretrovi... | HIV-1 cell-to-cell transmission has gained interest due to its potential role in AIDS pathogenesis. It has recently been suggested that antiretroviral therapies fail during cell-to-cell transmission because of the high number of particles transferred at sites of cell-cell contacts. However, these findings stand in cont... | Highly active antiretroviral therapy (HAART) has significantly reduced the mortality rate and has increased the life span of HIV-infected patients by maintaining viral loads below detection levels, thus preventing the onset of AIDS [1], [2], [3], [4]. However, the presence of a stable latent reservoir, poor treatment a... |
10.1371/journal.ppat.1007120 | B cell clonal lineage alterations upon recombinant HIV-1 envelope immunization of rhesus macaques | Broadly neutralizing HIV-1 antibodies (bNAbs) isolated from infected subjects display protective potential in animal models. Their elicitation by immunization is thus highly desirable. The HIV-1 envelope glycoprotein (Env) is the sole viral target of bnAbs, but is also targeted by binding, non-neutralizing antibodies. ... | Broadly neutralizing HIV-1 antibodies (bNAbs) display protective potentials against experimental animal infection and thus are believed to be a key component of an effective HIV vaccine. bNAbs are derived from B cells that express B cell receptors formed by specific VH/VL alleles. We report that the variable domains of... | Following HIV-1 infection, serum neutralizing antibody responses against the evolving autologous viral swarm are generated by the vast majority of infected subjects, usually within the first few months of infection [1–6]. In 10–30% of infected subjects, antibodies capable of neutralizing not only the autologous virus b... |
10.1371/journal.pgen.1000056 | Small RNA-Directed Epigenetic Natural Variation in Arabidopsis thaliana | Progress in epigenetics has revealed mechanisms that can heritably regulate gene function independent of genetic alterations. Nevertheless, little is known about the role of epigenetics in evolution. This is due in part to scant data on epigenetic variation among natural populations. In plants, small interfering RNA (s... | Phenotypic variation has been mainly attributed to their differences in genetic materials, i.e., the DNA sequence. The advances in Epigenetics in past decades has revealed it as a fundamental mechanism that could inheritably influence gene function without change in DNA sequence, but by modulating chemical modification... | Epigenetics, defined as the study of heritable alteration in gene expression without changes in DNA sequence, has greatly expanded our understanding of inheritance [1]. A recent study of DNA methylation by tiling array analysis of Arabidopsis Chromosome 4 in Col and Ler showed that although transposable elements (TEs) ... |
10.1371/journal.pgen.1005124 | MAPK Signaling Pathway Alters Expression of Midgut ALP and ABCC Genes and Causes Resistance to Bacillus thuringiensis Cry1Ac Toxin in Diamondback Moth | Insecticidal crystal toxins derived from the soil bacterium Bacillus thuringiensis (Bt) are widely used as biopesticide sprays or expressed in transgenic crops to control insect pests. However, large-scale use of Bt has led to field-evolved resistance in several lepidopteran pests. Resistance to Bt Cry1Ac toxin in the ... | Biopesticide and transgenic crops based on Bacillus thuringiensis (Bt) Cry toxins are widely used worldwide, yet the development of field resistance seriously threatens their sustainability. Unraveling these resistance mechanisms are of great importance for delaying insect field resistance evolution. The diamondback mo... | The Gram-positive entomopathogen Bacillus thuringiensis (Bt) is the most widely used biopesticide due to its highly specific activity and environmental safety [1]. The insecticidal activity of Bt is largely attributed to diverse δ-endotoxins (Cry toxins) produced during sporulation [2]. Transgenic crops harboring Bt to... |
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