doi stringlengths 28 28 | title stringlengths 19 311 | abstract stringlengths 217 5.08k | plain language summary stringlengths 115 4.83k | article stringlengths 3.87k 161k |
|---|---|---|---|---|
10.1371/journal.pcbi.1005859 | Invariant recognition drives neural representations of action sequences | Recognizing the actions of others from visual stimuli is a crucial aspect of human perception that allows individuals to respond to social cues. Humans are able to discriminate between similar actions despite transformations, like changes in viewpoint or actor, that substantially alter the visual appearance of a scene.... | Recognizing the actions of others from video sequences across changes in viewpoint, gait or illumination is a hallmark of human visual intelligence. A large number of studies have highlighted which areas in the human brain are involved in the processing of biological motion, while others have described how single neuro... | Humans’ ability to recognize the actions of others is a crucial aspect of visual perception. Remarkably, the accuracy with which we can finely discern what others are doing is largely unaffected by transformations that substantially change the visual appearance of a given scene, but do not change the semantics of what ... |
10.1371/journal.ppat.1007188 | Retrograde axonal transport of rabies virus is unaffected by interferon treatment but blocked by emetine locally in axons | Neuroinvasive viruses, such as alpha herpesviruses (αHV) and rabies virus (RABV), initially infect peripheral tissues, followed by invasion of the innervating axon termini. Virus particles must undergo long distance retrograde axonal transport to reach the neuron cell bodies in the peripheral or central nervous system ... | Rabies virus (RABV) and alpha herpesviruses (αHV) (e.g. herpes simplex virus) evolved to enter the nervous system efficiently each time they infect a host. In most mammals, RABV reaches the brain, causing a fatal encephalitis. Whereas, αHV remain in the peripheral nervous system in a quiescent but reactivatable state. ... | Unlike most nervous system pathogens, which are either accidental or opportunistic, some neuroinvasive viruses have evolved strategies to enter and exit the nervous system. One successful strategy is that of rabies virus (RABV), a neuroinvasive human and animal pathogen of the Rhabdoviridae family. A zoonotic rabies in... |
10.1371/journal.pntd.0005264 | Severe Fever with Thrombocytopenia Syndrome in South Korea, 2013-2015 | Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that was recently identified in China, South Korea and Japan. The objective of the study was to evaluate the epidemiologic and clinical characteristics of SFTS in South Korea.
SFTS is a reportable disease in South Korea. We included al... | Severe fever with thrombocytopenia (SFTS) is an emerging infectious disease that was first discovered in China in 2009. Subsequently, SFTS has also been found in South Korea and Japan. Here, we report the epidemiologic and clinical characteristics of 172 confirmed SFTS cases in South Korea that occurred since the first... | Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that is caused by a novel SFTS virus (SFTSV) which was first reported in China in 2011 [1]. China’s neighboring two countries, South Korea and Japan, have also reported the infection [2, 3]. The virus is transmitted to humans through t... |
10.1371/journal.pcbi.1004043 | Synaptic Plasticity Enables Adaptive Self-Tuning Critical Networks | During rest, the mammalian cortex displays spontaneous neural activity. Spiking of single neurons during rest has been described as irregular and asynchronous. In contrast, recent in vivo and in vitro population measures of spontaneous activity, using the LFP, EEG, MEG or fMRI suggest that the default state of the cort... | Neural networks, whether artificial or biological, consist of individual units connected together that mutually send and receive parcels of energy called spikes. While simply described, there is a vast space of possible implementations, instantiations, and varieties of neural networks. Some of these networks are critic... | The mammalian cortex presents a challenging complex system for the study of information processing, behavioral adaptation, and self-organization. At rest, a state in which there is no obvious sensory input or motor output, neural activity in the cortex is predominantly spontaneous, or ongoing. At the single neuron leve... |
10.1371/journal.pgen.1006167 | Dnmt3a Regulates Proliferation of Muscle Satellite Cells via p57Kip2 | Cell differentiation status is defined by the gene expression profile, which is coordinately controlled by epigenetic mechanisms. Cell type-specific DNA methylation patterns are established by chromatin modifiers including de novo DNA methyltransferases, such as Dnmt3a and Dnmt3b. Since the discovery of the myogenic ma... | How muscle homeostasis is maintained is not completely elucidated yet. Epigenetic disorders such as Beckwith-Wiedemann syndrome, which causes hypergrowth of skeletal muscles and rhabdomyosarcoma, indicate that epigenetic regulations such as DNA methylation, contribute to this homeostasis control. DNA methylation is med... | Myogenic differentiation program has been extensively studied as a model of tissue differentiation since the discovery of MyoD [1]. Although much is known about the gene cascade of myogenesis [2,3], the epigenetic mechanisms that regulate the physiological and pathological condition of skeletal muscles remain unknown [... |
10.1371/journal.pbio.2006767 | The Cdk8/19-cyclin C transcription regulator functions in genome replication through metazoan Sld7 | Accurate genome duplication underlies genetic homeostasis. Metazoan Mdm2 binding protein (MTBP) forms a main regulatory platform for origin firing together with Treslin/TICRR and TopBP1 (Topoisomerase II binding protein 1 (TopBP1)–interacting replication stimulating protein/TopBP1-interacting checkpoint and replication... | Efficient and well-regulated DNA replication origin firing is central to ensure complete and accurate genome duplication before cell division. We here use bioinformatics and cultured human cells to understand the role of the essential origin firing factor Mdm2 binding protein (MTBP). We prove that MTBP is orthologous t... | Eukaryotic cells must faithfully replicate their genomic DNA exactly once before each cell division in order to ensure genetic homeostasis through successive cell generations. Initiation of DNA replication is a major step of replication control by the cell cycle and the DNA damage checkpoint, ensuring faithful genome d... |
10.1371/journal.ppat.1003575 | Aspergillus Galactosaminogalactan Mediates Adherence to Host Constituents and Conceals Hyphal β-Glucan from the Immune System | Aspergillus fumigatus is the most common cause of invasive mold disease in humans. The mechanisms underlying the adherence of this mold to host cells and macromolecules have remained elusive. Using mutants with different adhesive properties and comparative transcriptomics, we discovered that the gene uge3, encoding a f... | Invasive aspergillosis is the most common mold infection in humans, predominately affecting immunocompromised patients. The mechanisms by which the mold Aspergillus fumigatus adheres to host tissues and causes disease are poorly understood. In this report, we compared mutants of Aspergillus with different adhesive prop... | The incidence of invasive mold infections due to the fungus Aspergillus fumigatus has increased dramatically in hematology patients receiving intensive cytotoxic chemotherapy or undergoing hematopoietic stem cell transplantation [1]. Despite the advent of new antifungal therapies, the mortality of invasive aspergillosi... |
10.1371/journal.ppat.1003564 | Phosphorylation of Calcineurin at a Novel Serine-Proline Rich Region Orchestrates Hyphal Growth and Virulence in Aspergillus fumigatus | The fungus Aspergillus fumigatus is a leading infectious killer in immunocompromised patients. Calcineurin, a calmodulin (CaM)-dependent protein phosphatase comprised of calcineurin A (CnaA) and calcineurin B (CnaB) subunits, localizes at the hyphal tips and septa to direct A. fumigatus invasion and virulence. Here we ... | Invasive fungal infections are a leading cause of death in immunocompromised patients. Translating molecular understanding into tangible clinical benefit has been difficult due to the fact that fungal pathogens and their hosts have similar physiology. The calcineurin pathway is an important signaling cascade in all euk... | Invasive fungal infections are a leading cause of death in immunocompromised patients [1]. With a 40–60% mortality rate, invasive aspergillosis, caused by the filamentous fungus Aspergillus fumigatus, is the most frequent fungal cause of mortality [2]. Through both genetic and pharmacologic inhibition, we have establis... |
10.1371/journal.ppat.1002073 | A Freeze Frame View of Vesicular Stomatitis Virus Transcription Defines a Minimal Length of RNA for 5′ Processing | The RNA synthesis machinery of vesicular stomatitis virus (VSV) comprises the genomic RNA encapsidated by the viral nucleocapsid protein (N) and associated with the RNA dependent RNA polymerase, the viral components of which are a large protein (L) and an accessory phosphoprotein (P). The 241 kDa L protein contains all... | Using a prototype of the nonsegmented negative strand RNA viruses, vesicular stomatitis virus, we probed the spatial relationship between the RNA dependent RNA polymerase and 5′ mRNA capping and methylation activities of the large polymerase protein. Because the 5′ mRNA processing reactions dramatically impact the nucl... | The RNA synthesis machinery of the non-segmented negative-strand (NNS) RNA viruses contains at its core a large polymerase protein (L) that possesses all the enzymatic activities for genome transcription and replication. During transcription, L catalyzes nucleotide polymerization [1]–[3] as well as each step of mRNA ca... |
10.1371/journal.ppat.1005636 | Comparative Structural and Functional Analysis of Bunyavirus and Arenavirus Cap-Snatching Endonucleases | Segmented negative strand RNA viruses of the arena-, bunya- and orthomyxovirus families uniquely carry out viral mRNA transcription by the cap-snatching mechanism. This involves cleavage of host mRNAs close to their capped 5′ end by an endonuclease (EN) domain located in the N-terminal region of the viral polymerase. W... | Segmented negative strand viruses (sNSV) such as Influenza, Lassa or Hantaan viruses are responsible for a large number of severe human infectious diseases. Currently, there are vaccines and antiviral treatments available for influenza but none for the infections caused by other sNSV. All carry out transcription by the... | Segmented negative strand viruses (sNSVs) represent one of the most threatening groups of emerging viruses for global health [1]. They are classified in three main families: Orthomyxoviridae, Bunyaviridae and Arenaviridae with respectively six to eight, three and two genome segments [2]. Seasonal and pandemic influenza... |
10.1371/journal.pntd.0003446 | Conservation and Immunogenicity of Novel Antigens in Diverse Isolates of Enterotoxigenic Escherichia coli | Enterotoxigenic Escherichia coli (ETEC) are common causes of diarrheal morbidity and mortality in developing countries for which there is currently no vaccine. Heterogeneity in classical ETEC antigens known as colonization factors (CFs) and poor efficacy of toxoid-based approaches to date have impeded development of a ... | Infectious diarrhea is one of the leading causes of death among young children in developing countries, and a major cause of morbidity in all age groups. The enterotoxigenic Escherichia coli contribute substantially to this burden of diarrheal illness, and have been a focus of vaccine development efforts for more than ... | The enterotoxigenic Escherichia coli (ETEC) are among the most common causes of infectious diarrhea worldwide. Importantly, ETEC are disproportionately represented in cases of severe diarrheal illness as well as in deaths due to diarrhea among young children in developing countries [1].
These pathogens cause diarrhea ... |
10.1371/journal.ppat.1002497 | Enhancement of Chemokine Function as an Immunomodulatory Strategy Employed by Human Herpesviruses | Herpes simplex virus (HSV) types 1 and 2 are highly prevalent human neurotropic pathogens that cause a variety of diseases, including lethal encephalitis. The relationship between HSV and the host immune system is one of the main determinants of the infection outcome. Chemokines play relevant roles in antiviral respons... | Chemokines are chemotactic cytokines that direct the flux of leukocytes to the site of injury and infection, playing a relevant role in the antiviral response. An uncontrolled, unorganized chemokine response is beneath the onset and maintenance of several immunopathologies. During millions of years of evolution, viruse... | Herpes simplex virus type 1 and 2 (HSV-1 and HSV-2, respectively) and varizella zoster virus (VZV) are the three human members of the Alphaherpesvirinae subfamily, which establish latency in the sensory ganglia of the peripheral nervous system. Both HSV-1 and -2 are highly prevalent viruses with values around 90% for H... |
10.1371/journal.pntd.0003046 | Efficacy and Safety of Praziquantel, Tribendimidine and Mebendazole in Patients with Co-infection of Clonorchis sinensis and Other Helminths | Both tribendimidine and mebendazole are broad-spectrum drugs for anti-intestinal nematodes. We aim to assess the efficacy and safety of tribendimidine and mebendazole in patients with co-infection of Clonorchis sinensis and other helminths.
We performed a randomized open-label trial in Qiyang, People's Republic of Chin... | Co-infection of Clonorchis sinensis and other helminths is common in places with poor settings. Preventive chemotherapy is commonly used to control the co-infection of helminths due to lack of effective vaccine. It is important to investigate the efficacy and safety of tribendimidine, a broad-spectrum anti-intestinal n... | Clonorchiasis is one of the neglected food-borne trematodiasis caused by infection of Clonorchis sinensis (C. sinensis), which is mainly prevalent in East and Southeast Asia, especially in the People's Republic of China (P.R. China), the Republic of Korea, northern part of Vietnam, and the far eastern part of Russia [1... |
10.1371/journal.pntd.0001894 | A New Strategy Based on Smrho Protein Loaded Chitosan Nanoparticles as a Candidate Oral Vaccine against Schistosomiasis | Schistosomiasis is one of the most important neglected tropical diseases and an effective control is unlikely in the absence of improved sanitation and vaccination. A new approach of oral vaccination with alginate coated chitosan nanoparticles appears interesting because their great stability and the ease of target acc... | Schistosomiasis is one of the most important neglected tropical diseases and an effective control is unlikely in the absence of improved sanitation and vaccine. The selection of a suitable delivery system and an adjuvant to aid in the stimulation of the appropriate immune response is a critical step in the path to the ... | Schistosomiasis remains one of the most prevalent diseases in the world and so a significant public health problem, especially in developing countries [1]. This parasitic disease affects more than 240 million people worldwide, with a further 700 million individuals living at risk of infection [2] and it causes up to 25... |
10.1371/journal.ppat.1006147 | Evidence for Integrin – Venus Kinase Receptor 1 Alliance in the Ovary of Schistosoma mansoni Females Controlling Cell Survival | In metazoan integrin signaling is an important process of mediating extracellular and intracellular communication processes. This can be achieved by cooperation of integrins with growth factor receptors (GFRs). Schistosoma mansoni is a helminth parasite inducing schistosomiasis, an infectious disease of worldwide signi... | Parasites of the genus Schistosoma cause schistosomiasis, a life-threatening infectious disease for humans and animals worldwide. Among the remarkable biological features of schistosomes is the differentiation of the female gonads which is controlled by pairing with the male and a prerequisite for egg production. Eggs,... | Communication of cells with their environment is an essential requirement to regulate fundamental biological processes such as cell growth and differentiation. Different types of membrane-linked receptors mediate these communication processes, sometimes in a solitary, single receptor-mediated way, sometimes in a cooper... |
10.1371/journal.ppat.1003902 | Reengineering Redox Sensitive GFP to Measure Mycothiol Redox Potential of Mycobacterium tuberculosis during Infection | Mycobacterium tuberculosis (Mtb) survives under oxidatively hostile environments encountered inside host phagocytes. To protect itself from oxidative stress, Mtb produces millimolar concentrations of mycothiol (MSH), which functions as a major cytoplasmic redox buffer. Here, we introduce a novel system for real-time im... | Approximately 30% of the global population is infected with Mycobacterium tuberculosis (Mtb). Persistence of Mtb in host phagocytes depends on its ability to resist oxidant-mediated antibacterial responses. Mycothiol (MSH) is the main antioxidant that provides an abundant source of reducing equivalent, which protects M... | It is estimated that nearly 2 billion people currently suffer from latent Mycobacterium tuberculosis (Mtb) infection and ∼1.4 million people succumb to tuberculosis (TB) annually [1] and [www.who.int/tb]. The ability of Mtb to adapt and resist killing by the immune system facilitates its survival, replication, and pers... |
10.1371/journal.pntd.0005185 | First Identification and Description of Rickettsioses and Q Fever as Causes of Acute Febrile Illness in Nicaragua | Rickettsial infections and Q fever present similarly to other acute febrile illnesses, but are infrequently diagnosed because of limited diagnostic tools. Despite sporadic reports, rickettsial infections and Q fever have not been prospectively studied in Central America.
We enrolled consecutive patients presenting with... | Rickettsial infections and Q fever cause illness characterized by fever and non-specific symptoms and signs. Not only are these infections difficult to recognize, they are also difficult to diagnose because of limitations in existing tests for them. Despite sporadic reports, rickettsial infections and Q fever have not ... | Rickettsioses, including spotted fever group (SFGR) and typhus group (TGR), and Q fever (caused by Coxiella burnetii) are increasingly recognized worldwide [1]. Both rickettsioses and Q fever often manifest as undifferentiated fever and cannot easily be distinguished clinically from other causes of acute febrile illnes... |
10.1371/journal.pcbi.1006430 | Network mechanisms underlying the role of oscillations in cognitive tasks | Oscillatory activity robustly correlates with task demands during many cognitive tasks. However, not only are the network mechanisms underlying the generation of these rhythms poorly understood, but it is also still unknown to what extent they may play a functional role, as opposed to being a mere epiphenomenon. Here w... | Oscillations are ubiquitous in the brain and often correlate with distinct cognitive tasks. Nonetheless their role in shaping network dynamics, and hence in driving behavior during such tasks is poorly understood. Here we provide a comprehensive study of the effect of periodic drive on neuronal networks exhibiting mult... | Oscillations are ubiquitous in neuronal systems and span temporal scales over several orders of magnitude [1]. Some prominent rhythms, such as occipital alpha waves during eye-closure [2] or slow-oscillations during non-REM sleep [3] are indicative of a particular behavioral state. Other rhythms have been specifically ... |
10.1371/journal.pgen.1004310 | dGTP Starvation in Escherichia coli Provides New Insights into the Thymineless-Death Phenomenon | Starvation of cells for the DNA building block dTTP is strikingly lethal (thymineless death, TLD), and this effect is observed in all organisms. The phenomenon, discovered some 60 years ago, is widely used to kill cells in anticancer therapies, but many questions regarding the precise underlying mechanisms have remaine... | Starvation of cells for DNA precursor dTTP is strikingly lethal in many organisms, like bacteria, yeast, and human cells. This type of death is unusual in that starvation for other nutritional requirements generally results in growth arrest, but not in death. The phenomenon is called thymineless death (TLD), because it... | Starvation of cells for the DNA precursor dTTP can cause rapid cell death in all domains of life [1]. This phenomenon, called thymineless death (TLD), was first discovered in 1954 in E. coli upon exposing thymine-requiring (thyA) strains to medium lacking thymine [2]. As TLD can be promoted in cells from bacteria to ma... |
10.1371/journal.pntd.0004936 | Sero-Molecular Epidemiology of Japanese Encephalitis in Zhejiang, an Eastern Province of China | Sporadic Japanese encephalitis (JE) cases still have been reported in Zhejiang Province in recent years, and concerns about vaccine cross-protection and population-level immunity have been raised off and on within the public health sphere. Genotype I (GI) has replaced GIII as the dominant genotype in Asian countries du... | Japanese encephalitis (JE) remains one of the most significant public health problems in Asia and the Western Pacific region. A JE viral infection can cause death and severe sequelae. Vaccination is the most effective method for preventing JE currently. After decades of routine vaccination, the number of JE cases decli... | Japanese encephalitis (JE) is a common mosquito-borne viral encephalitis disease and it is prevalent in Asia, the Western Pacific, and northern Australia. It is estimated that approximately 67,900 JE cases occur worldwide annually, with a fatality rate range from 20% to 30%. Though reported cases have decreased dramati... |
10.1371/journal.pgen.1006213 | Exploiting Single-Cell Quantitative Data to Map Genetic Variants Having Probabilistic Effects | Despite the recent progress in sequencing technologies, genome-wide association studies (GWAS) remain limited by a statistical-power issue: many polymorphisms contribute little to common trait variation and therefore escape detection. The small contribution sometimes corresponds to incomplete penetrance, which may resu... | Genetic association studies are usually conducted on phenotypes measured at the scale of whole tissues or individuals, and not at the scale of individual cells. However, some common traits, such as cancer, can result from a minority of cells that adopted a special behavior. From one individual to another, DNA variants ... | Modern genetics aims to identify DNA variants contributing to common trait variation between individuals. A high motivation to map such variants is shared worldwide because many heritable traits relate to social and economical preoccupations, such as human health or agronomical and industrial yields. In addition to the... |
10.1371/journal.ppat.1003737 | The Inflammatory Kinase MAP4K4 Promotes Reactivation of Kaposi's Sarcoma Herpesvirus and Enhances the Invasiveness of Infected Endothelial Cells | Kaposi's sarcoma (KS) is a mesenchymal tumour, which is caused by Kaposi's sarcoma herpesvirus (KSHV) and develops under inflammatory conditions. KSHV-infected endothelial spindle cells, the neoplastic cells in KS, show increased invasiveness, attributed to the elevated expression of metalloproteinases (MMPs) and cyclo... | Kaposi's sarcoma (KS) is a tumour caused by Kaposi's sarcoma herpesvirus (KSHV) and dysregulated inflammation. Both factors contribute to the high angiogenicity and invasiveness of KS. Various cellular kinases have been reported to regulate the KSHV latent-lytic switch and thereby virus pathogenicity. In this study, we... | Kaposi's sarcoma (KS) is a mesenchymal tumour caused by Kaposi's sarcoma herpesvirus (KSHV) [1], which originates from blood and lymphatic vessels and develops under the influence of inflammatory cytokines [2]–[4]. Local or systemic inflammation and immunosuppression are important additional risk factors [5], [6]. In a... |
10.1371/journal.pgen.1003462 | Npc1 Acting in Neurons and Glia Is Essential for the Formation and Maintenance of CNS Myelin | Cholesterol availability is rate-limiting for myelination, and prior studies have established the importance of cholesterol synthesis by oligodendrocytes for normal CNS myelination. However, the contribution of cholesterol uptake through the endocytic pathway has not been fully explored. To address this question, we us... | The myelin sheath in the central nervous system is a specialized extension of the oligodendrocyte plasma membrane that serves as an electrical insulator to ensure proper nerve conduction. To accomplish this, myelin is enriched in lipids, particularly unesterified cholesterol, which is an essential and limiting componen... | Ensheathment of axons by myelin is an evolutionary feature of the vertebrate nervous system that is accomplished by the extended and specialized plasma membranes of oligodendrocytes in the CNS and Schwann cells in the PNS. Myelin contains at least 70% lipids by dry weight [1], and this high ratio of lipid to protein en... |
10.1371/journal.pntd.0005505 | Rapid Surveillance for Vector Presence (RSVP): Development of a novel system for detecting Aedes aegypti and Aedes albopictus | The globally important Zika, dengue and chikungunya viruses are primarily transmitted by the invasive mosquitoes, Aedes aegypti and Aedes albopictus. In Australia, there is an increasing risk that these species may invade highly urbanized regions and trigger outbreaks. We describe the development of a Rapid Surveillanc... | Aedes (Stegomyia) vectors of dengue, Zika and chikungunya viruses utilize artificial and natural containers as larval habitats. Adults do not usually disperse far (< 500 m) from these larval habitats in urban and peri-urban environments. Highly heterogeneous distributions raise significant logistic challenges to conduc... | Aedes aegypti and Aedes albopictus are invasive mosquito species and global vectors of Zika (ZIKV) [1], dengue (DENVs) [2] and chikungunya (CHIKV) [3] viruses. Both species can coexist in the same ecological niche [4, 5] and share characteristics that are likely to make their detection difficult in the early stages of ... |
10.1371/journal.pntd.0006980 | Insights into antitrypanosomal drug mode-of-action from cytology-based profiling | Chemotherapy continues to have a major impact on reducing the burden of disease caused by trypanosomatids. Unfortunately though, the mode-of-action (MoA) of antitrypanosomal drugs typically remains unclear or only partially characterised. This is the case for four of five current drugs used to treat Human African Trypa... | African trypanosomes cause devastating and lethal diseases in humans and livestock. These parasites are transmitted among mammals by tsetse flies and circulate and grow in blood and tissue fluids. There are several drugs available to treat patients but, despite their use for many decades, we know relatively little abou... | Chemotherapy is central to the control of the neglected tropical diseases caused by African trypanosomes (Trypanosoma brucei spp), South American trypanosomes (Trypanosoma cruzi) and Leishmania spp; the related kinetoplastid parasites [1]. The current drugs suffer problems with complex administration, efficacy, toxicit... |
10.1371/journal.pgen.1007032 | Dopamine negatively modulates the NCA ion channels in C. elegans | The NALCN/NCA ion channel is a cation channel related to voltage-gated sodium and calcium channels. NALCN has been reported to be a sodium leak channel with a conserved role in establishing neuronal resting membrane potential, but its precise cellular role and regulation are unclear. The Caenorhabditis elegans ortholog... | Dopamine is a neurotransmitter that acts in the brain by binding seven transmembrane receptors that are coupled to heterotrimeric GTP-binding proteins (G proteins). Neuronal G proteins often function by modulating ion channels that control membrane excitability. Here we identify a molecular cascade downstream of dopami... | Heterotrimeric G proteins modulate neuronal activity in response to experience or environmental changes. Gq is one of the four types of heterotrimeric G protein alpha subunits [1] and is a positive regulator of neuronal activity and synaptic transmission [2–4]. In the canonical Gq pathway, Gq activates phospholipase Cβ... |
10.1371/journal.ppat.1006301 | A novel Meloidogyne graminicola effector, MgGPP, is secreted into host cells and undergoes glycosylation in concert with proteolysis to suppress plant defenses and promote parasitism | Plant pathogen effectors can recruit the host post-translational machinery to mediate their post-translational modification (PTM) and regulate their activity to facilitate parasitism, but few studies have focused on this phenomenon in the field of plant-parasitic nematodes. In this study, we show that the plant-parasit... | Post-translational modification (PTM) is a tool used by prokaryotic and eukaryotic cells to regulate protein activity, and many unique and important functions of proteins depend on appropriate PTMs. Evidence is emerging that plant pathogen effectors can utilize the host post-translational machinery to mediate their PTM... | Root-knot nematodes (RKNs) are one of the most economically important plant-parasitic nematodes (PPNs), infecting more than 5500 plant species [1,2]. The soil-borne RKNs devastate varieties of crop plants, resulting in about $70 billion losses in worldwide agriculture annually [3]. Generally, the second-stage juveniles... |
10.1371/journal.pgen.1005565 | The Dedicated Chaperone Acl4 Escorts Ribosomal Protein Rpl4 to Its Nuclear Pre-60S Assembly Site | Ribosomes are the highly complex macromolecular assemblies dedicated to the synthesis of all cellular proteins from mRNA templates. The main principles underlying the making of ribosomes are conserved across eukaryotic organisms and this process has been studied in most detail in the yeast Saccharomyces cerevisiae. Yea... | Ribosomes are the molecular machines that generate proteins from mRNA templates. The biogenesis of eukaryotic ribosomes is an outstandingly complex process, in which around 80 ribosomal proteins and four ribosomal RNAs are accurately pieced together. Actively growing yeast cells must produce more than 160’000 ribosomal... | The biogenesis of ribosomes is a fundamental cellular process whose main principles are conserved from the lower eukaryote Saccharomyces cerevisiae to mammalian organisms. S. cerevisiae 80S ribosomes are composed of two unequal subunits, a small 40S (SSU) and a large 60S (LSU) ribosomal subunit (r-subunit), which conta... |
10.1371/journal.pgen.1002307 | A Noncoding Point Mutation of Zeb1 Causes Multiple Developmental Malformations and Obesity in Twirler Mice | Heterozygous Twirler (Tw) mice develop obesity and circling behavior associated with malformations of the inner ear, whereas homozygous Tw mice have cleft palate and die shortly after birth. Zeb1 is a zinc finger protein that contributes to mesenchymal cell fate by repression of genes whose expression defines epithelia... | Twirler (Tw) mice have a combination of abnormalities that includes cleft palate, malformations of the inner ear, hearing loss, vestibular dysfunction, obesity, and lymphoid hypoplasia. In this study, we show that the underlying mutation affects the Zeb1 gene. Zeb1 was already known to encode a protein normally express... | Twirler (Tw) spontaneously arose in a crossbred stock of mice segregating multiple recessive mutant alleles [1]. Heterozygous Tw mice develop obesity after three months of age, and exhibit stereotypic behavior that includes waltzing, spinning, and horizontal head-shaking [1]. This behavior is thought to result from mal... |
10.1371/journal.pbio.0060015 | Inhibitory Phosphorylation of Separase Is Essential for Genome Stability and Viability of Murine Embryonic Germ Cells | Activity of separase, a cysteine protease that cleaves sister chromatid cohesin at the onset of anaphase, is tightly regulated to ensure faithful chromosome segregation and genome stability. Two mechanisms negatively regulate separase: inhibition by securin and phosphorylation on serine 1121. To gauge the physiological... | Higher eukaryotes rely on a separate cell lineage, the germline, to pass genetic information from generation to generation. To ensure faithful transmission of genetic information, cell cycle checkpoint mechanisms are engaged during mitotic and meiotic divisions of germ cells. The identity and function of these checkpoi... | Faithful transmission of duplicated genetic material is of fundamental importance to the viability of all organisms. In eukaryotes, sister chromatids are closely connected by cohesin complexes established during S phase. The core cohesin complex is composed of the protein subunits Smc1, Smc3, Scc1, and Scc3 [1] and is ... |
10.1371/journal.pgen.1004412 | A Population Genetic Signal of Polygenic Adaptation | Adaptation in response to selection on polygenic phenotypes may occur via subtle allele frequencies shifts at many loci. Current population genomic techniques are not well posed to identify such signals. In the past decade, detailed knowledge about the specific loci underlying polygenic traits has begun to emerge from ... | The process of adaptation is of fundamental importance in evolutionary biology. Within the last few decades, genotyping technologies and new statistical methods have given evolutionary biologists the ability to identify individual regions of the genome that are likely to have been important in this process. When adapta... | Population and quantitative genetics were in large part seeded by Fisher's insight [1] that the inheritance and evolution of quantitative characters could be explained by small contributions from many independent Mendelian loci [2]. While still theoretically aligned [3], these two fields have often been divergent in em... |
10.1371/journal.pgen.1005737 | Seed Dormancy in Arabidopsis Requires Self-Binding Ability of DOG1 Protein and the Presence of Multiple Isoforms Generated by Alternative Splicing | The Arabidopsis protein DELAY OF GERMINATION 1 (DOG1) is a key regulator of seed dormancy, which is a life history trait that determines the timing of seedling emergence. The amount of DOG1 protein in freshly harvested seeds determines their dormancy level. DOG1 has been identified as a major dormancy QTL and variation... | The Arabidopsis protein DELAY OF GERMINATION 1 (DOG1) is an important regulator of seed dormancy and controls the timing of seedling emergence. The amount of DOG1 protein in mature seeds correlates with their dormancy level. It has been demonstrated that DOG1 is an important contributor to natural variation for seed do... | Alternative splicing has an important role in the post-transcriptional regulation of higher eukaryotes, but it was long believed to be of minor significance in plants. During the last years consecutive reports demonstrated a steadily increasing percentage of alternatively spliced genes in plants. At the beginning of th... |
10.1371/journal.pcbi.1003713 | Network Analysis of Breast Cancer Progression and Reversal Using a Tree-Evolving Network Algorithm | The HMT3522 progression series of human breast cells have been used to discover how tissue architecture, microenvironment and signaling molecules affect breast cell growth and behaviors. However, much remains to be elucidated about malignant and phenotypic reversion behaviors of the HMT3522-T4-2 cells of this series. W... | The HMT3522 isogenic human breast cancer progression series has been used to study the effect of various drugs on the reversion of the breast cancer cells. Despite significant efforts to delineate key signaling events responsible for phenotypic reversion of the malignant HMT3522-T4-2 (T4-2) breast cells in this series,... | A major challenge in systems biology is to uncover dynamic changes in cellular pathways that either respond to the changing microenvironment of cells, or drive cellular transformation during various biological processes such as cell cycle, differentiation, and development. These changes may involve rewiring of transcri... |
10.1371/journal.pntd.0007080 | Detection of Zika virus in mouse mammary gland and breast milk | Clinical reports of Zika Virus (ZIKV) RNA detection in breast milk have been described, but evidence conflicts as to whether this RNA represents infectious virus. We infected post-parturient AG129 murine dams deficient in type I and II interferon receptors with ZIKV. ZIKV RNA was detected in pup stomach milk clots (SMC... | Can Zika virus be transmitted from nursing mothers to their children via breast milk? Only 4 years have passed since the Zika virus outbreak in Brazil, and much remains to be understood about the transmission and health consequences of Zika infection. To date, some case reports have detected Zika virus RNA in the breas... | Zika virus (ZIKV) is an enveloped virus with a positive-sense, single-stranded RNA genome [1]. For over half a century, this flavivirus was regarded as an arbovirus leading to self-limiting, febrile disease. However, confirmation of or association with new syndromes, including teratogenesis, adult Guillain Barre Syndro... |
10.1371/journal.pgen.1004059 | DNA Methylation Changes Separate Allergic Patients from Healthy Controls and May Reflect Altered CD4+ T-Cell Population Structure | Altered DNA methylation patterns in CD4+ T-cells indicate the importance of epigenetic mechanisms in inflammatory diseases. However, the identification of these alterations is complicated by the heterogeneity of most inflammatory diseases. Seasonal allergic rhinitis (SAR) is an optimal disease model for the study of DN... | T-cells, a type of white blood cell, are an important part of the immune-system in humans. T-cells allow us to adapt our immune-response to the various infectious agents we encounter during life. However, T-cells can also cause disease when they target the body's own cells, e.g. Psoriasis, or when they react to a harml... | The modest effects of genetic variants in inflammatory diseases indicate the importance of epigenetic mechanisms like DNA methylation to disease pathology. However, studies of inflammatory diseases have shown conflicting results. In monozygotic twins discordant for multiple sclerosis (MS), no significant differences in... |
10.1371/journal.ppat.1007883 | HIV and HCV augments inflammatory responses through increased TREM-1 expression and signaling in Kupffer and Myeloid cells | Chronic infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) affects an estimated 35 million and 75 million individuals worldwide, respectively. These viruses induce persistent inflammation which often drives the development or progression of organ-specific diseases and even cancer including He... | Although HIV antiviral therapy has limited the progression to AIDS in infected patients, there is still significant morbidity and mortality from HIV-driven diseases due to sustained inflammation. In this study, we sought to elucidate how HIV and HCV could impact inflammation in the liver and cause progressive liver dis... | Cell-intrinsic innate immune responses provide the first line of defense against invading viral pathogens. These early innate immune responses not only blunt the initial spread of infection but also activate the adaptive immune system and secondary host defense mechanisms. However, the immune reaction must be controlle... |
10.1371/journal.pmed.1002736 | The effect of a programme to improve men’s sedentary time and physical activity: The European Fans in Training (EuroFIT) randomised controlled trial | Reducing sitting time as well as increasing physical activity in inactive people is beneficial for their health. This paper investigates the effectiveness of the European Fans in Training (EuroFIT) programme to improve physical activity and sedentary time in male football fans, delivered through the professional footba... | Gender-sensitised lifestyle change programmes in a professional sport setting are an exciting development in men’s health promotion, with the potential to engage men who are underserved by most programmes.
A healthy lifestyle and weight management programme delivered in professional sporting settings (Football Fans in ... | Physical activity is important in preventing chronic diseases, including cardiovascular disease, type 2 diabetes, and several cancers [1,2]. Global recommendations from the World Health Organisation (WHO) advise at least 150 minutes per week in moderate-to-vigorous physical activity. Recent estimates show that nearly o... |
10.1371/journal.pgen.1002025 | Eight Common Genetic Variants Associated with Serum DHEAS Levels Suggest a Key Role in Ageing Mechanisms | Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands—yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-relat... | Dehydroepiandrosterone sulphate (DHEAS), mainly secreted by the adrenal gland, is the most abundant circulating steroid in humans. It shows a significant physiological decline after the age of 25 and diminishes about 95% by the age of 85 years, which has led to speculation that a relative DHEAS deficiency may contribut... | Dehydroepiandrosterone sulphate (DHEAS), mainly secreted by the adrenal gland, is the most abundant circulating steroid in humans. It acts as an inactive precursor which is converted initially into DHEA and thereafter into active androgens and estrogens in peripheral target tissues [1]. In humans the serum concentratio... |
10.1371/journal.pgen.1002579 | Promoter Nucleosome Organization Shapes the Evolution of Gene Expression | Understanding why genes evolve at different rates is fundamental to evolutionary thinking. In species of the budding yeast, the rate at which genes diverge in expression correlates with the organization of their promoter nucleosomes: genes lacking a nucleosome-free region (denoted OPN for “Occupied Proximal Nucleosomes... | Species diverge by mutations that change protein structure or protein regulation. While the evolution of protein sequence was studied extensively, much less is known about the divergence of gene expression. To better understand the process of gene expression evolution, we characterized the early genomic response of yea... | The plasticity of biological traits is manifested on multiple time scales. Regulatory mechanisms govern the physiological adaptation of an individual to changing conditions. On evolutionary time scales, phenotypes are modulated by genetic mutations. Although operating on very different time scales, regulatory variance ... |
10.1371/journal.pgen.1007058 | Gli3 is a negative regulator of Tas1r3-expressing taste cells | Mouse taste receptor cells survive from 3–24 days, necessitating their regeneration throughout adulthood. In anterior tongue, sonic hedgehog (SHH), released by a subpopulation of basal taste cells, regulates transcription factors Gli2 and Gli3 in stem cells to control taste cell regeneration. Using single-cell RNA-Seq ... | Adult taste cell regeneration is essential for maintaining peripheral taste cells throughout life. The Shh pathway is an important regulator of taste bud development and regeneration in both embryonic and adult stages. We show that the transcription factor Gli3, an important effector of the Shh pathway, is expressed in... | In mouse tongue taste buds are found in three types of papillae: anterior fungiform (FF), lateral foliate (FO), and posterior circumvallate (CV). The numerous FF papillae each contain a single taste bud, while the two FO and single CV papillae each contain hundreds of taste buds [1, 2]. Each taste bud contains ~50–100 ... |
10.1371/journal.ppat.1002263 | A Trigger Enzyme in Mycoplasma pneumoniae: Impact of the Glycerophosphodiesterase GlpQ on Virulence and Gene Expression | Mycoplasma pneumoniae is a causative agent of atypical pneumonia. The formation of hydrogen peroxide, a product of glycerol metabolism, is essential for host cell cytotoxicity. Phosphatidylcholine is the major carbon source available on lung epithelia, and its utilization requires the cleavage of deacylated phospholipi... | Mycoplasma pneumoniae serves as a model organism for bacteria with very small genomes that are nonetheless independently viable. These bacteria infect the human lung and cause an atypical pneumonia. The major virulence determinant of M. pneumoniae is hydrogen peroxide that is generated during the utilization of glycero... | Pathogenic bacteria have developed a large battery of enzymes and mechanisms for extracting nutrients from their hosts, and the requirement for nutrient acquisition can be regarded as one of the driving forces for virulence [1]–[3]. In consequence, the metabolic capabilities of a pathogen reflect its adaptation to a pa... |
10.1371/journal.pcbi.1002028 | Disentangling the Roles of Approach, Activation and Valence in Instrumental and Pavlovian Responding | Hard-wired, Pavlovian, responses elicited by predictions of rewards and punishments exert significant benevolent and malevolent influences over instrumentally-appropriate actions. These influences come in two main groups, defined along anatomical, pharmacological, behavioural and functional lines. Investigations of the... | Beautiful background music in a shop may well tempt us to buy something we neither need nor want. Valenced stimuli have broad and profound influences on ongoing choice behaviour. After replicating known findings whereby approach is enhanced by appetitive Pavlovian stimuli and inhibited by aversive ones, we extend this ... | The functional architecture of responding involves two fundamental components that are behaviourally [1] and computationally [2] separable: Pavlovian and instrumental. The instrumental component respects the stimulus-dependent contingency between responses and their outcomes (stimulus-response and action-outcome learni... |
10.1371/journal.pntd.0001651 | Use of Oxfendazole to Control Porcine Cysticercosis in a High-Endemic Area of Mozambique | A randomized controlled field trial to evaluate the effectiveness of a single oral dose of 30 mg/kg of oxfendazole (OFZ) treatment for control of porcine cysticercosis was conducted in 4 rural villages of Angónia district, north-western Mozambique. Two hundred and sixteen piglets aged 4 months were selected and assigne... | Porcine cysticercosis is an infection of pigs caused by the larval stage of Taenia solium, a tapeworm that causes taeniosis in humans. The disease is very common in developing countries where it is a serious public health risk and causes significant economic losses in pig production. Many control strategies in developi... | Taenia solium is the etiologic agent of cysticercosis, an important zoonotic infection involving humans and pigs. The life cycle of this parasite includes pigs as the normal intermediate hosts, harbouring the larval cysts in many parts of the body causing cysticercosis, and humans as definitive hosts, harbouring the ad... |
10.1371/journal.pgen.1005059 | Genome-Wide Association Studies in Dogs and Humans Identify ADAMTS20 as a Risk Variant for Cleft Lip and Palate | Cleft lip with or without cleft palate (CL/P) is the most commonly occurring craniofacial birth defect. We provide insight into the genetic etiology of this birth defect by performing genome-wide association studies in two species: dogs and humans. In the dog, a genome-wide association study of 7 CL/P cases and 112 con... | Cleft lip with or without cleft palate (CL/P) is a commonly occurring birth defect that can lead to a lifetime of complications in affected children. To better understand the genetic cause of these disorders, we investigated CL/P in both dogs and humans. Genome-wide association studies in both species independently ide... | Nonsyndromic orofacial clefts, notably cleft lip (CL) with or without cleft palate (CL/P) and isolated cleft palate (CP), are the most common craniofacial birth defects in humans and represent a substantial personal and societal burden. Clefts affect approximately 1 in 700 individuals[1], with a lifetime cost of treatm... |
10.1371/journal.pntd.0007429 | Aedes aegypti microRNA, miR-2944b-5p interacts with 3'UTR of chikungunya virus and cellular target vps-13 to regulate viral replication | RNA interference is among the most important mechanisms that serve to restrict virus replication within mosquitoes, where microRNAs (miRNAs) are important in regulating viral replication and cellular functions. These miRNAs function by binding to complementary sequences mostly in the untranslated regions of the target.... | Aedes aegypti mosquito transmits pathogenic viruses like chikungunya virus (CHIKV). Inside the vector, the virus replicates in a way so that it is able to survive within the mosquito without causing damage to it. However, once in the mammalian host, it becomes pathogenic and induces death to the infected cells. Amongst... | Mosquitoes aid the transmission of several pathogenic viruses collectively called arboviruses that mainly belong to the Flaviviridae and Togaviridae families. These are single-stranded RNA viruses that replicate actively within the mosquitoes and reach titers that are then transmitted by the vector to a vertebrate host... |
10.1371/journal.pntd.0002896 | Community Knowledge and Attitudes and Health Workers' Practices regarding Non-malaria Febrile Illnesses in Eastern Tanzania | Although malaria has been the leading cause of fever for many years, with improved control regimes malaria transmission, morbidity and mortality have decreased. Recent studies have increasingly demonstrated the importance of non-malaria fevers, which have significantly improved our understanding of etiologies of febril... | Understanding the awareness of the community on non-malaria febrile illnesses is crucial, especially during the recent decline of malaria episodes of malaria. This study conducted focus group discussions with communities to assess their awareness of non-malaria febrile illnesses. In addition, in-depth interviews with h... | Febrile illnesses due to different etiological agents are the common causes of morbidity and mortality in developing countries [1]. Malaria has been the leading cause of fever in sub- Saharan Africa for many years [2]. For instance, in Tanzania, malaria was contributing to about 42% of hospital diagnoses and 32% of hos... |
10.1371/journal.pgen.1003574 | DNA Methylation Restricts Lineage-specific Functions of Transcription Factor Gata4 during Embryonic Stem Cell Differentiation | DNA methylation changes dynamically during development and is essential for embryogenesis in mammals. However, how DNA methylation affects developmental gene expression and cell differentiation remains elusive. During embryogenesis, many key transcription factors are used repeatedly, triggering different outcomes depen... | Animal bodies are constructed from many different specialized cell types that are generated during embryogenesis from a single fertilized egg, and acquire their specific characteristics through a series of differentiation steps. After being committed to a specific cell type, it is generally difficult for differentiated... | Development is based on a series of cell-fate decisions and commitments. Transcription factors and epigenetic mechanisms coordinately regulate these processes [1], [2]. Transcription factors play dominant roles in instructing lineage determination and cell reprogramming [3], [4]. Transcription factor and co-factor netw... |
10.1371/journal.pgen.1007916 | An African-specific haplotype in MRGPRX4 is associated with menthol cigarette smoking | In the U.S., more than 80% of African-American smokers use mentholated cigarettes, compared to less than 30% of Caucasian smokers. The reasons for these differences are not well understood. To determine if genetic variation contributes to mentholated cigarette smoking, we performed an exome-wide association analysis in... | An exome-wide association study revealed a significant association between menthol cigarette use and coding variants in MRGPRX4, which encodes a G-protein coupled receptor expressed in sensory neurons. The variant haplotype is found only in populations of African ancestry, and encodes a receptor that displays reduced a... | Cigarette smoking remains a leading cause of preventable disease and mortality in the United States, contributing to >480,000 deaths annually [1]. Although the overall rates of smoking have declined dramatically over the last 50 years [1], the use of mentholated cigarettes has not, and has actually increased in some gr... |
10.1371/journal.pcbi.1003661 | On the Origins of Suboptimality in Human Probabilistic Inference | Humans have been shown to combine noisy sensory information with previous experience (priors), in qualitative and sometimes quantitative agreement with the statistically-optimal predictions of Bayesian integration. However, when the prior distribution becomes more complex than a simple Gaussian, such as skewed or bimod... | The process of decision making involves combining sensory information with statistics collected from prior experience. This combination is more likely to yield ‘statistically optimal’ behavior when our prior experiences conform to a simple and regular pattern. In contrast, if prior experience has complex patterns, we m... | Humans have been shown to integrate prior knowledge and sensory information in a probabilistic manner to obtain optimal (or nearly so) estimates of behaviorally relevant stimulus quantities, such as speed [1], [2], orientation [3], direction of motion [4], interval duration [5]–[8] and position [9]–[11]. Prior expectat... |
10.1371/journal.pgen.1008338 | Reduction of mRNA export unmasks different tissue sensitivities to low mRNA levels during Caenorhabditis elegans development | Animal development requires the execution of specific transcriptional programs in different sets of cells to build tissues and functional organs. Transcripts are exported from the nucleus to the cytoplasm where they are translated into proteins that, ultimately, carry out the cellular functions. Here we show that in Ca... | The Central Dogma of Biology schematically highlights the transmission of genetic information stored in DNA, through RNA, to the formation of proteins. This general flow implicates RNA export from the nucleus to the cytoplasm and proper protein localization within the eukaryotic cell. Ultimately, proteins are the cell’... | Cell differentiation and morphogenesis rely on the expression of specific genes that are translated into proteins in specific sets of cells to ensure the correct formation of the organs and body plan. The physical separation between genomic DNA and the cytoplasm in eukaryotic cells makes it necessary to export RNA thro... |
10.1371/journal.pcbi.1004381 | Multiscale Estimation of Binding Kinetics Using Brownian Dynamics, Molecular Dynamics and Milestoning | The kinetic rate constants of binding were estimated for four biochemically relevant molecular systems by a method that uses milestoning theory to combine Brownian dynamics simulations with more detailed molecular dynamics simulations. The rate constants found using this method agreed well with experimentally and theor... | We estimated the kon rate constant of four biochemically relevant ligand-receptor systems using milestoning theory. All results closely resemble experimentally and theoretically determined results, indicating that this technique may be applied toward accurate estimation of binding rate constants for additional ligand-r... | Estimating kinetics is an important and challenging task in computational biophysics. The kinetic rate constants of ligand-receptor interactions, in particular the kon and koff values, play an important role in enzymology[1] and drug discovery[2]. Kinetic rate constants of ligand-receptor association and dissociation a... |
10.1371/journal.pcbi.1004031 | The Formation of Multi-synaptic Connections by the Interaction of Synaptic and Structural Plasticity and Their Functional Consequences | Cortical connectivity emerges from the permanent interaction between neuronal activity and synaptic as well as structural plasticity. An important experimentally observed feature of this connectivity is the distribution of the number of synapses from one neuron to another, which has been measured in several cortical la... | The connectivity between neurons is modified by different mechanisms. On a time scale of minutes to hours one finds synaptic plasticity, whereas mechanisms for structural changes at axons or dendrites may take days. One main factor determining structural changes is the weight of a connection, which, in turn, is adapted... | The connectivity between neurons - i.e., the number of synapses and their transmission efficiencies (weights) - determines information processing and storage in neural networks and, thus, also the cortex. Thus, in order to understand the functionality of cortical neural networks, we have to understand how they generate... |
10.1371/journal.pbio.1001540 | When the Most Potent Combination of Antibiotics Selects for the Greatest Bacterial Load: The Smile-Frown Transition | Conventional wisdom holds that the best way to treat infection with antibiotics is to ‘hit early and hit hard’. A favoured strategy is to deploy two antibiotics that produce a stronger effect in combination than if either drug were used alone. But are such synergistic combinations necessarily optimal? We combine mathem... | We take an evolutionary approach to a problem from the medical sciences in seeking to understand how our knowledge of rapid bacterial evolution should shape the way we treat pathogens with antibiotic drugs. We pay particular attention to combinations of different drugs that are purposefully used to produce potent thera... | Our arsenal of antimicrobials boasts a wide diversity of drugs and we continue to invest in the search for new ones [1]. Yet bacteria adapt so readily to their ambient environment that all antibiotics in clinical use have bacteria that resist them [2],[3]. A Staphylococcus aureus infection traced in vivo yielded over t... |
10.1371/journal.pntd.0001242 | Lymphatic Filariasis: A Method to Identify Subclinical Lower Limb Change in PNG Adolescents | Lymphedema related to lymphatic filariasis (LF) is a disabling condition that commonly manifests in adolescence. Fifty-three adolescents, 25 LF infected and 28 LF non-infected, in age and sex-matched groups, using the Binax ICT rapid card test for filarial antigen were recruited to the study. None of the participants h... | The effects of lymphatic filariasis (LF) on the lymphatic system often become apparent during adolescence when the lower limb swells due to lymphedema and males develop hydrocele. Currently there is no simple or mobile field method to identify those at greatest risk of developing lymphedema or those with early subclini... | The mosquito-borne parasitic disease lymphatic filariasis (LF) is endemic in around 81 tropical countries, has a global burden of around 120 million cases, and is classified by the World Health organization as the second most common cause of long term disability after mental illness [1]. Three species of filarial paras... |
10.1371/journal.pbio.1002421 | Epidermal Growth Factor Receptor-Dependent Mutual Amplification between Netrin-1 and the Hepatitis C Virus | Hepatitis C virus (HCV) is an oncogenic virus associated with the onset of hepatocellular carcinoma (HCC). The present study investigated the possible link between HCV infection and Netrin-1, a ligand for dependence receptors that sustains tumorigenesis, in particular in inflammation-associated tumors. We show that Net... | Viruses and bacteria are implicated in 15%–20% of total cancer occurrences. Hepatitis C virus (HCV) infection is one of the main causative agents of liver cancer. “Dependence receptors” are a class of receptors that auto-activate and trigger apoptosis in the absence of their ligands, and “dependence receptor” ligands s... | Cancers triggered by microbial oncogenes account for approximately 16% of cancer occurrences [1]. Hepatitis C virus (HCV) is a major etiologic agent of hepatocellular carcinoma (HCC), the fifth most common cancer worldwide [2]. The epidermal growth factor receptor (EGFR) is a host factor for entry of HCV [3, 4] as well... |
10.1371/journal.ppat.1003598 | Activation of Ran GTPase by a Legionella Effector Promotes Microtubule Polymerization, Pathogen Vacuole Motility and Infection | The causative agent of Legionnaires' disease, Legionella pneumophila, uses the Icm/Dot type IV secretion system (T4SS) to form in phagocytes a distinct “Legionella-containing vacuole” (LCV), which intercepts endosomal and secretory vesicle trafficking. Proteomics revealed the presence of the small GTPase Ran and its ef... | Legionella pneumophila is an environmental bacterium that grows within free-living amoebae and, upon inhalation, in human lung macrophages, thus causing the severe pneumonia Legionnaires' disease. Within amoebae or macrophages the bacteria form a distinct membrane-bound replication niche, the “Legionella-containing vac... | The amoebae-resistant environmental bacterium Legionella pneumophila is the causative agent of a severe pneumonia termed Legionnaires' disease [1], [2]. In free-living amoebae as well as in macrophages of the innate immune system, L. pneumophila employs an apparently conserved mechanism to form a replication-permissive... |
10.1371/journal.pgen.1001074 | Disease-Associated Mutations That Alter the RNA Structural Ensemble | Genome-wide association studies (GWAS) often identify disease-associated mutations in intergenic and non-coding regions of the genome. Given the high percentage of the human genome that is transcribed, we postulate that for some observed associations the disease phenotype is caused by a structural rearrangement in a re... | Genome-wide association studies identify mutations in the human genome that correlate with a particular disease. It is common to find mutations associated with disease in the non-coding region of the genome. These non-coding mutations are more difficult to interpret at a molecular level, because they do not affect the ... | Genome-Wide Association Studies (GWAS) pinpoint mutations associated to a disease state with single nucleotide precision [1]–[4]. In some cases, the molecular cause of the disease is evident from the mutation data alone. For example, if the mutation results in a premature stop codon, the production of a truncated prote... |
10.1371/journal.pntd.0003756 | Prioritising Infectious Disease Mapping | Increasing volumes of data and computational capacity afford unprecedented opportunities to scale up infectious disease (ID) mapping for public health uses. Whilst a large number of IDs show global spatial variation, comprehensive knowledge of these geographic patterns is poor. Here we use an objective method to priori... | Maps have long been used to not only visualise, but also to inform infectious disease control efforts, identify and predict areas of greatest risk of specific diseases, and better understand the epidemiology of disease over various spatial scales. In spite of the utilities of such outputs, globally comprehensive maps h... | Maps provide an essential evidence-base to support progress towards global health commitments [1]. For example, they provide important baseline estimates of disease limits [2–7], transmission [8–10] and clinical burden [11–14]; underpin surveillance systems and outbreak tracking [15,16]; help target resource allocation... |
10.1371/journal.ppat.1006965 | Contributions from the silent majority dominate dengue virus transmission | Despite estimates that, each year, as many as 300 million dengue virus (DENV) infections result in either no perceptible symptoms (asymptomatic) or symptoms that are sufficiently mild to go undetected by surveillance systems (inapparent), it has been assumed that these infections contribute little to onward transmissio... | Most dengue virus infections result in either no perceptible symptoms or symptoms that are so mild that they go undetected by surveillance systems. It is unclear how much these infections contribute to the overall transmission and burden of dengue. At an individual level, we show that people with asymptomatic infection... | Though often assumed benign, it is increasingly recognized that for many pathogens, clinically inapparent infections can represent a sizeable portion of the infectious reservoir [1–3] and contribute substantially to pathogen transmission [4]. Understanding the contribution to transmission from people with inapparent in... |
10.1371/journal.ppat.1005220 | Calcium Regulation of Hemorrhagic Fever Virus Budding: Mechanistic Implications for Host-Oriented Therapeutic Intervention | Hemorrhagic fever viruses, including the filoviruses (Ebola and Marburg) and arenaviruses (Lassa and Junín viruses), are serious human pathogens for which there are currently no FDA approved therapeutics or vaccines. Importantly, transmission of these viruses, and specifically late steps of budding, critically depend u... | Filoviruses (Ebola and Marburg viruses) and arenaviruses (Lassa and Junín viruses) are high-priority pathogens that hijack host proteins and pathways to complete their replication cycles and spread from cell to cell. Here we provide genetic and pharmacological evidence to demonstrate that the host calcium channel prote... | There is an urgent and unmet need for safe and effective therapeutics against high priority pathogens, including filoviruses (Ebola and Marburg) and arenaviruses (Lassa fever and Junín), which can cause fatal infections in humans. We and others have established that enveloped RNA viruses, including hemorrhagic fever vi... |
10.1371/journal.pntd.0001482 | Clinical and Virological Study of Dengue Cases and the Members of Their Households: The Multinational DENFRAME Project | Dengue has emerged as the most important vector-borne viral disease in tropical areas. Evaluations of the burden and severity of dengue disease have been hindered by the frequent lack of laboratory confirmation and strong selection bias toward more severe cases.
A multinational, prospective clinical study was carried o... | Dengue is the most important mosquito-borne viral disease in humans. This disease is now endemic in more than 100 countries and threatens more than 2.5 billion people living in tropical countries. It currently affects about 50 to 100 million people each year. It causes a wide range of symptoms, from an inapparent to mi... | Dengue is the most important mosquito-borne viral disease of humans. The disease is now endemic in more than 100 countries and threatens more than 2.5 billion people. It currently affects about 50 to 100 million people each year [1]. Dengue viruses (DENV) are enveloped, single-stranded positive-sense RNA viruses (famil... |
10.1371/journal.pntd.0006671 | Direct nucleic acid analysis of mosquitoes for high fidelity species identification and detection of Wolbachia using a cellphone | Manipulation of natural mosquito populations using the endosymbiotic bacteria Wolbachia is being investigated as a novel strategy to reduce the burden of mosquito-borne viruses. To evaluate the efficacy of these interventions, it will be critical to determine Wolbachia infection frequencies in Aedes aegypti mosquito po... | Mosquitoes spread many human pathogens and novel approaches are required to reduce the burden of mosquito-borne disease. One promising approach is transferring Wolbachia into Aedes aegypti mosquitoes where it blocks transmission of arboviruses like dengue, Zika and Yellow fever viruses and spreads through mosquito popu... | Mosquitoes are vectors that can transmit an array of pathogens that often cause devastating human diseases [1]. Traditionally considered a problem for tropical regions, mosquitoes are increasingly becoming a global public health challenge [2, 3] due to a changing global environment, urbanization, increases in the globa... |
10.1371/journal.pgen.1000363 | hnRNP I Inhibits Notch Signaling and Regulates Intestinal Epithelial Homeostasis in the Zebrafish | Regulated intestinal stem cell proliferation and differentiation are required for normal intestinal homeostasis and repair after injury. The Notch signaling pathway plays fundamental roles in the intestinal epithelium. Despite the fact that Notch signaling maintains intestinal stem cells in a proliferative state and pr... | Many gastrointestinal diseases are characterized by unbalanced proliferation and differentiation of intestinal epithelial cells. Accumulating evidence implicates the Notch pathway as a fundamental regulator of intestinal epithelial proliferation and differentiation. Deregulation of Notch causes intestinal defects, such... | The intestinal epithelium undergoes rapid cell turnover. Renewal of the intestinal epithelium relies on intestinal stem cells in the crypts of Lieberkuhn that are distributed circumferentially around the base of finger-like intestinal villi. New intestinal epithelial cells are continuously produced by stem cells in the... |
10.1371/journal.ppat.1000322 | Functional Analysis of the Leading Malaria Vaccine Candidate AMA-1 Reveals an Essential Role for the Cytoplasmic Domain in the Invasion Process | A key process in the lifecycle of the malaria parasite Plasmodium falciparum is the fast invasion of human erythrocytes. Entry into the host cell requires the apical membrane antigen 1 (AMA-1), a type I transmembrane protein located in the micronemes of the merozoite. Although AMA-1 is evolving into the leading blood-s... | Malaria is one of the most lethal parasitic diseases worldwide, causing more than 1 million fatalities per annum. Drug resistance is widespread, and a vaccine is not available. One of the leading blood stage vaccine candidates is the apical membrane antigen 1 (AMA-1), which is well-conserved among apicomplexan parasite... | Invasion of red blood cells (RBCs) is one of the critical points in the erythrocytic life cycle of the malaria parasite Plasmodium falciparum. The invasive form of the parasite, the merozoite, harbours a set of specialized secretory organelles, in particular two varieties called rhoptries and micronemes, which house ke... |
10.1371/journal.pcbi.1004442 | A Bayesian Attractor Model for Perceptual Decision Making | Even for simple perceptual decisions, the mechanisms that the brain employs are still under debate. Although current consensus states that the brain accumulates evidence extracted from noisy sensory information, open questions remain about how this simple model relates to other perceptual phenomena such as flexibility ... | How do we decide whether a traffic light signals stop or go? Perceptual decision making research investigates how the brain can make these simple but fundamentally important decisions. Current consensus states that the brain solves this task simply by accumulating sensory information over time to make a decision once e... | Research in perceptual decision making investigates how people categorise observed stimuli. By presenting stimuli embedded in large amounts of noise, experimenters prolong the time it takes a subject to make a decision about the stimulus. This makes the decision making process observable for hundreds of milliseconds an... |
10.1371/journal.pcbi.1003098 | Consistent Estimation of Gibbs Energy Using Component Contributions | Standard Gibbs energies of reactions are increasingly being used in metabolic modeling for applying thermodynamic constraints on reaction rates, metabolite concentrations and kinetic parameters. The increasing scope and diversity of metabolic models has led scientists to look for genome-scale solutions that can estimat... | The metabolism of living organisms is a complex system with a large number of parameters and interactions. Nevertheless, it is governed by a strict set of rules that make it somewhat predictable and amenable to modeling. The laws of thermodynamics play a pivotal role by determining reaction feasibility and by governing... | A living system, like any other physical system, obeys the laws of thermodynamics. In the context of metabolism, the laws of thermodynamics have been successfully applied in several modeling schemes to improve accuracy in predictions and eliminate infeasible functional states. For instance, several methodologies that r... |
10.1371/journal.pgen.1003188 | Suv4-20h Histone Methyltransferases Promote Neuroectodermal Differentiation by Silencing the Pluripotency-Associated Oct-25 Gene | Post-translational modifications (PTMs) of histones exert fundamental roles in regulating gene expression. During development, groups of PTMs are constrained by unknown mechanisms into combinatorial patterns, which facilitate transitions from uncommitted embryonic cells into differentiated somatic cell lineages. Repres... | The quest of modern developmental biology is a detailed molecular description of the process that leads from the fertilized egg to the complex and highly differentiated adult organism. This process is controlled largely on the level of gene expression. While early embryonic cells are pluripotent and capable of transcri... | Embryonic development is controlled by fine-tuned differential gene expression. A succession of regulatory protein networks unfolds the zygotic gene expression program along a hierarchy of decisions, leading from the embryonic ground state to the epiblast and then to germ layers, which become patterned into cell type a... |
10.1371/journal.ppat.1006615 | Cell cycle stage-specific transcriptional activation of cyclins mediated by HAT2-dependent H4K10 acetylation of promoters in Leishmania donovani | Chromatin modifications affect several processes. In investigating the Leishmania donovani histone acetyltransferase HAT2, using in vitro biochemical assays and HAT2-heterozygous genomic knockout we found the constitutively nuclear HAT2 acetylated histone H4K10 in vitro and in vivo. HAT2 was essential. HAT2-depleted ce... | Leishmania donovani causes Visceral Leishmaniasis (VL), a disease that plagues the world’s poor, particularly in Brazil, Sudan and the Indian sub-continent. If not treated in timely manner VL can be fatal, and due to emerging drug resistance the search for new drug targets continues. Thus, the parasite’s cellular proce... | Histone post-translational modifications (PTMs) impact nuclear processes either by generally altering chromatin structure to make it more permissive/repressive to incoming transcription/replication/repair machinery, or by serving as flags recognized by specific proteins that modulate the various DNA-related processes. ... |
10.1371/journal.pntd.0001370 | Proteomic Analysis of Excretory-Secretory Products of Heligmosomoides polygyrus Assessed with Next-Generation Sequencing Transcriptomic Information | The murine parasite Heligmosomoides polygyrus is a convenient experimental model to study immune responses and pathology associated with gastrointestinal nematode infections. The excretory-secretory products (ESP) produced by this parasite have potent immunomodulatory activity, but the protein(s) responsible has not be... | Gastrointestinal (GI) nematode infections are major causes of human and animal disease. Much of their morbidity is associated with establishment of chronic infections in the host, reflecting the deployment of mechanisms to evade and modulate the immune response. The molecules responsible for these activities are poorly... | Gastrointestinal (GI) nematode infections are major causes of disease in both humans and animals. Infections with Ascaris lumbricoides, hookworms (Necator americanus and Ancylostoma duodenalis), Trichuris trichiura, and Strongyloides stercoralis are highly prevalent in developing countries, affecting ∼1 billion people ... |
10.1371/journal.pbio.1002132 | Targeting the Cell Stress Response of Plasmodium falciparum to Overcome Artemisinin Resistance | Successful control of falciparum malaria depends greatly on treatment with artemisinin combination therapies. Thus, reports that resistance to artemisinins (ARTs) has emerged, and that the prevalence of this resistance is increasing, are alarming. ART resistance has recently been linked to mutations in the K13 propelle... | Resistance to artemisinin antimalarials, some of the most effective antimalarial drugs, has emerged in Southeast Asia, jeopardizing malaria control. We have undertaken a detailed study of artemisinin-sensitive and-resistant strains of Plasmodium falciparum, the parasite responsible for malaria, taken directly from the ... | Malaria remains a scourge of humanity, affecting hundreds of millions of people and causing ~600,000 deaths each year [1]. Infection with Plasmodium falciparum is responsible for the majority of severe malaria cases. During the asexual blood phase of its lifecycle, this protozoan parasite invades, grows, and multiplies... |
10.1371/journal.pbio.1001218 | Lhx2 and Lhx9 Determine Neuronal Differentiation and Compartition in the Caudal Forebrain by Regulating Wnt Signaling | Initial axial patterning of the neural tube into forebrain, midbrain, and hindbrain primordia occurs during gastrulation. After this patterning phase, further diversification within the brain is thought to proceed largely independently in the different primordia. However, mechanisms that maintain the demarcation of bra... | The thalamus is the interface between the body and the brain. It connects sensory organs with higher brain areas and modulates processes such as sleep, alertness, and consciousness. Our knowledge about the embryonic development of this central relay station is still fragmented. Here, we show that the transcription fact... | Segmentation is a fundamental step during vertebrate brain development. It involves patterning of the cranial neural tube into distinct and segregated transverse units aligned serially along the longitudinal axis [1]. The most important prerequisite for segmentation are borders between the successive neuromeres to allo... |
10.1371/journal.pntd.0006036 | Complex antigen presentation pathway for an HLA-A*0201-restricted epitope from Chikungunya 6K protein | The adaptive cytotoxic T lymphocyte (CTL)-mediated immune response is critical for clearance of many viral infections. These CTL recognize naturally processed short viral antigenic peptides bound to human leukocyte antigen (HLA) class I molecules on the surface of infected cells. This specific recognition allows the ki... | The arboviral pathogen Chikungunya virus (CHIKV) is a serious threat to global health, and is considered a priority re-emerging virus. This pathogen causes acute febrile infection in patients, leading to debilitating arthralgia and arthritis. In recent years, CHIKV has spread quickly in tropical and subtropical countri... | The mosquito-borne Chikungunya virus (CHIKV), a member of the Alphavirus genus of the Togaviridae family, causes an acute febrile infection in patients that leads to debilitating arthralgia and arthritis. Identified in the former Tanganyika territory in 1952 [1–3], this arboviral pathogen caused numerous epidemics in A... |
10.1371/journal.pntd.0002190 | Fluctuations at a Low Mean Temperature Accelerate Dengue Virus Transmission by Aedes aegypti | Environmental factors such as temperature can alter mosquito vector competence for arboviruses. Results from recent studies indicate that daily fluctuations around an intermediate mean temperature (26°C) reduce vector competence of Aedes aeygpti for dengue viruses (DENV). Theoretical predictions suggest that the mean t... | Mosquitoes in the wild are exposed to daily fluctuations in temperature, but in the laboratory, the effect of temperature on vector competence is generally assessed using constant temperatures. Recent studies demonstrate that realistic fluctuations in temperature around an intermediate mean (26°C) can alter life-histor... | The ability of Aedes aegypti to transmit viruses, in particular dengue viruses (DENV), has long been known to be influenced by temperature [1]–[6]. It is generally assumed that higher mean temperatures facilitate DENV transmission due to faster virus propagation and dissemination within the vector. Vector competence, t... |
10.1371/journal.pmed.1002151 | Obstetric Facility Quality and Newborn Mortality in Malawi: A Cross-Sectional Study | Ending preventable newborn deaths is a global health priority, but efforts to improve coverage of maternal and newborn care have not yielded expected gains in infant survival in many settings. One possible explanation is poor quality of clinical care. We assess facility quality and estimate the association of facility ... | Large increases in access to health facilities in many low- and middle-income countries (LMIC) have not produced equivalent gains in newborn survival.
Little data or evidence on the quality of delivery care in LMICs is currently available, and even less is known on the mortality impact of facility quality.
We designed ... | Eliminating preventable infant mortality is a global health priority, reaffirmed in Sustainable Development Goal 3.2, which aims to reduce neonatal mortality to 12 per 1,000 live births by 2030 [1]. This is an ambitious goal: currently, over 2.5 million infants die each year in the first month of life [2]; neonatal mor... |
10.1371/journal.pntd.0006508 | MicroRNA and cellular targets profiling reveal miR-217 and miR-576-3p as proviral factors during Oropouche infection | Oropouche Virus is the etiological agent of an arbovirus febrile disease that affects thousands of people and is widespread throughout Central and South American countries. Although isolated in 1950’s, still there is scarce information regarding the virus biology and its prevalence is likely underestimated. In order to... | Oropouche Virus causes typical arboviral febrile illness and is widely distributed in tropical region of Americas, mainly Amazon region, associated with cases of encephalitis. 500,000 people are estimated to be infected with Oropouche worldwide and some states in Brazil detected higher number of cases among other arbov... | Oropouche Virus (OROV) is the etiological agent of Oropouche fever, an arthropod-borne viral disease characterized by symptoms like fever, headache, myalgia, arthralgia, malaise, photophobia, nausea, vomiting, dizziness, skin rash, and in few cases encephalitis and meningitis [1–7]. It was first described in Trinidad i... |
10.1371/journal.pgen.1000533 | Evolution of Mutational Robustness in the Yeast Genome: A Link to Essential Genes and Meiotic Recombination Hotspots | Deleterious mutations inevitably emerge in any evolutionary process and are speculated to decisively influence the structure of the genome. Meiosis, which is thought to play a major role in handling mutations on the population level, recombines chromosomes via non-randomly distributed hot spots for meiotic recombinatio... | Sexual life cycles constitute a costly alternative to vegetative modes of reproduction. Two categories of hypotheses seek to explain why sexual life cycles exist: those investigating the selective advantages that have driven the evolution of individual parts of this life cycle and those rationalizing the advantages sex... | Mating and meiosis are the masterpieces of an evolutionary invention thought to meet the challenges of changing environmental conditions that need to be solved by mutational inventions. Among the many hypotheses that govern the various benefits of mating and meiosis [1], two main hypotheses stand out: enhanced purging ... |
10.1371/journal.pntd.0001023 | Mining a Cathepsin Inhibitor Library for New Antiparasitic Drug Leads | The targeting of parasite cysteine proteases with small molecules is emerging as a possible approach to treat tropical parasitic diseases such as sleeping sickness, Chagas' disease, and malaria. The homology of parasite cysteine proteases to the human cathepsins suggests that inhibitors originally developed for the lat... | Diseases like malaria and sleeping sickness are caused by tropical parasites and represent a major cause of mortality and morbidity in the developing world. A pragmatic approach to discover new drugs for these diseases is to search for drug leads among existing small molecule collections generated in the for-profit pha... | There is a critical need for new drugs to treat neglected tropical diseases [1], [2], [3], [4]. Current therapies are limited by inadequate efficacy, drug resistance, or toxicity. Chagas' disease, for example, remains the leading cause of heart disease in Latin America, with between 8 and 12 million people currently in... |
10.1371/journal.pgen.1002929 | Convergence of the Transcriptional Responses to Heat Shock and Singlet Oxygen Stresses | Cells often mount transcriptional responses and activate specific sets of genes in response to stress-inducing signals such as heat or reactive oxygen species. Transcription factors in the RpoH family of bacterial alternative σ factors usually control gene expression during a heat shock response. Interestingly, several... | An important property of living systems is their ability to survive under conditions of stress such as increased temperature or the presence of reactive oxygen species. Central to the function of these stress responses are transcription factors that activate specific sets of genes needed for this response. Despite the ... | Transcriptional responses to stress are critical to cell growth and survival. In bacteria, stress responses are often controlled by alternative σ factors that direct RNA polymerase to transcribe promoters different from those recognized by the primary σ factor [1], [2]. Therefore, identifying the target genes for a par... |
10.1371/journal.pcbi.1003127 | Pathway-based Screening Strategy for Multitarget Inhibitors of Diverse Proteins in Metabolic Pathways | Many virtual screening methods have been developed for identifying single-target inhibitors based on the strategy of “one–disease, one–target, one–drug”. The hit rates of these methods are often low because they cannot capture the features that play key roles in the biological functions of the target protein. Furthermo... | Many drug development strategies focus on designing inhibitors for single targets. These inhibitors often lose potency owing to mutations in the protein binding sites and are ineffective for complex diseases. Multitarget inhibitors can decrease probability of drug resistance and enhance the therapeutic efficiency; howe... | The concept of “one–disease, one–target, one–drug” has dominated drug development strategy for decades [1], [2]. Based on this strategy, many virtual screening methods have been developed and applied successfully for identifying specific inhibitors of a single target [3]–[5]. However, the hit rates of these screening m... |
10.1371/journal.pcbi.1003211 | Structural Similarities and Differences between Amyloidogenic and Non-Amyloidogenic Islet Amyloid Polypeptide (IAPP) Sequences and Implications for the Dual Physiological and Pathological Activities of These Peptides | IAPP, a 37 amino-acid peptide hormone belonging to the calcitonin family, is an intrinsically disordered protein that is coexpressed and cosecreted along with insulin by pancreatic islet β-cells in response to meals. IAPP plays a physiological role in glucose regulation; however, in certain species, IAPP can aggregate ... | IAPP, a 37 amino-acid peptide hormone belonging to the calcitonin family, is an intrinsically disordered peptide produced along with insulin by pancreatic islet β-cells in response to meals. In its functional form, IAPP acts as a synergic partner of insulin to reduce blood glucose. IAPP can, however, also play a pathol... | The Islet Amyloid Polypeptide/IAPP (also known as amylin) is coexpressed and cosecreted with insulin by pancreatic islet β-cells [1]–[3] and acts as a synergistic partner of insulin to limit after-meal glucose excursions [4]. IAPP belongs to the calcitonin (CT) family of peptides (See Table S1 in Text S1 ) [5]–[7]. The... |
10.1371/journal.ppat.1006359 | Genetically-barcoded SIV facilitates enumeration of rebound variants and estimation of reactivation rates in nonhuman primates following interruption of suppressive antiretroviral therapy | HIV and SIV infection dynamics are commonly investigated by measuring plasma viral loads. However, this total viral load value represents the sum of many individual infection events, which are difficult to independently track using conventional sequencing approaches. To overcome this challenge, we generated a genetical... | Elucidation of HIV dynamics is essential for a thorough understanding of viral transmission, therapeutic interventions, pathogenesis, and immune evasion. The complex dynamics of reservoir establishment and viral recrudescence upon therapy removal present the primary obstacles to developing a functional cure. We sought ... | A major obstacle to developing a cure for HIV is the establishment in early infection of long-lived viral reservoirs, defined as sources of virus that can persist over extended periods despite seemingly effective suppressive combination antiretroviral therapy (cART), that can cause recrudescent viremia if cART is inter... |
10.1371/journal.pbio.1001750 | The Velvet Family of Fungal Regulators Contains a DNA-Binding Domain Structurally Similar to NF-κB | Morphological development of fungi and their combined production of secondary metabolites are both acting in defence and protection. These processes are mainly coordinated by velvet regulators, which contain a yet functionally and structurally uncharacterized velvet domain. Here we demonstrate that the velvet domain of... | In many fungi, developmental processes and the synthesis of nonessential chemicals (secondary metabolites) are regulated by various external stimuli, such as light. Although fungi employ them for defensive purposes, secondary metabolites range from useful antibiotics to powerful toxins, so understanding the molecular p... | The fungal and the animal kingdom are related as they both belong to the ophistokonts with a common ancestor existing about 1 billion years ago [1],[2]. Animals have evolved with an elaborate inflammation and immune system for self-defence. Inflammation, the immune system, and animal development are controlled by vario... |
10.1371/journal.pntd.0000922 | The Extinction of Dengue through Natural Vulnerability of Its Vectors | Dengue is the world's most important mosquito-borne viral illness. Successful future management of this disease requires an understanding of the population dynamics of the vector, especially in the context of changing climates. Our capacity to predict future dynamics is reflected in our ability to explain the significa... | Dengue transmission has not always been confined to tropical areas. In some cases, this has been due to a reduced geographic range of the mosquitoes that are able to carry dengue viruses. In Australia, Aedes aegypti mosquitoes once occurred throughout temperate, drier parts of the country but are now restricted to the ... | Dengue fever is a public health problem of global importance, producing a spectrum of disease spanning febrile arthralgia to hemorrhagic death. Dengue viruses are transmitted between human hosts almost exclusively by Aedes (Stegomyia) aegypti and Aedes (Stg.) albopictus mosquitoes, both of which are well adapted to usi... |
10.1371/journal.pgen.1006737 | A fungal transcription factor essential for starch degradation affects integration of carbon and nitrogen metabolism | In Neurospora crassa, the transcription factor COL-26 functions as a regulator of glucose signaling and metabolism. Its loss leads to resistance to carbon catabolite repression. Here, we report that COL-26 is necessary for the expression of amylolytic genes in N. crassa and is required for the utilization of maltose an... | In nature, filamentous fungi sense nutrient availability in the surrounding environment and adjust their metabolism for optimal utilization, growth and reproduction. Carbon and nitrogen are two of major elements required for life. Within cells, signals from carbon and nitrogen catabolism are integrated, resulting in ba... | Filamentous fungi are one of the primary degraders of plant biomass because of their ability to produce enzymes that break down complex polysaccharides, including cellulose, hemicellulose, and pectin in the plant cell wall and starch, which is the major storage component in plants. Starch consists of two types of polys... |
10.1371/journal.pgen.1005436 | Dominance of Deleterious Alleles Controls the Response to a Population Bottleneck | Population bottlenecks followed by re-expansions have been common throughout history of many populations. The response of alleles under selection to such demographic perturbations has been a subject of great interest in population genetics. On the basis of theoretical analysis and computer simulations, we suggest that ... | Dominance has played a central role in classical genetics since its inception. However, the effect of dominance introduces substantial technical complications into theoretical models describing dynamics of alleles in populations. As a result, dominance is often ignored in population genetic models. Statistical tests fo... | In diploid organisms, the fitness effect of an allele, or a group of alleles, can be categorized as additive, dominant or recessive, or as part of a more general epistatic network. A large body of existing work is devoted to the development of statistical methods for the detection and quantification of selection using ... |
10.1371/journal.pbio.1000073 | Two Modes of Transcriptional Activation at Native Promoters by NF-κB p65 | The NF-κB family of transcription factors is crucial for the expression of multiple genes involved in cell survival, proliferation, differentiation, and inflammation. The molecular basis by which NF-κB activates endogenous promoters is largely unknown, but it seems likely that it should include the means to tailor tran... | Transcriptional activation by the NF-κB family of transcription factors is crucial for the expression of multiple genes involved in cell survival, proliferation, differentiation, and inflammation. The activation domain of the p65 subunit of NF-κB has been extensively studied in vitro and on artificial reporter plasmids... | The goal of understanding transcriptional activation encompasses the description of an unbroken chain of events leading from the binding of a transcription factor to its natural target promoters in an intact cell, until the initiation of mRNA synthesis by RNA polymerase II (pol-II). In the case of the NF-κB family of t... |
10.1371/journal.pbio.1001527 | Transcriptional Corepressors HIPK1 and HIPK2 Control Angiogenesis Via TGF-β–TAK1–Dependent Mechanism | Several critical events dictate the successful establishment of nascent vasculature in yolk sac and in the developing embryos. These include aggregation of angioblasts to form the primitive vascular plexus, followed by the proliferation, differentiation, migration, and coalescence of endothelial cells. Although transfo... | An essential step during early embryonic development is to establish elaborate vascular networks that provide nutrients to ensure the proper growth of the embryos. This process, known as angiogenesis, requires coordinated regulation of cell proliferation, migration, and differentiation in endothelial cells, which provi... | Vascular morphogenesis is controlled by an intricate interplay of extrinsic factors and their downstream signaling mechanisms [1],[2]. At the early stage of vascular development, several critical events dictate the successful establishment of nascent vasculature in yolk sac and in the developing embryos. These include ... |
10.1371/journal.pntd.0005751 | Urbanization is a main driver for the larval ecology of Aedes mosquitoes in arbovirus-endemic settings in south-eastern Côte d'Ivoire | Failure in detecting naturally occurring breeding sites of Aedes mosquitoes can bias the conclusions drawn from field studies, and hence, negatively affect intervention outcomes. We characterized the habitats of immature Aedes mosquitoes and explored species dynamics along a rural-to-urban gradient in a West Africa set... | Outbreaks of yellow fever and dengue caused by Aedes mosquitoes have been repeatedly reported in rural and urban areas in humid tropical Africa, including Côte d’Ivoire. Although controlling immature stages of Aedes mosquitoes in their aquatic habitats before they become adult vectors remains the best method to fight a... | Several Aedes species act as vectors of arboviral diseases, such as yellow fever, dengue, chikungunya, Rift Valley fever, and Zika virus infections that are of considerable public health relevance [1]. The transmission patterns of these arboviruses and their geographic expansion are expected to change due to environmen... |
10.1371/journal.pgen.1005183 | Auxin Influx Carriers Control Vascular Patterning and Xylem Differentiation in Arabidopsis thaliana | Auxin is an essential hormone for plant growth and development. Auxin influx carriers AUX1/LAX transport auxin into the cell, while auxin efflux carriers PIN pump it out of the cell. It is well established that efflux carriers play an important role in the shoot vascular patterning, yet the contribution of influx carri... | The vascular tissues in the shoot of Arabidopsis thaliana (Arabidopsis) plants are organized in vascular bundles, disposed in a conserved periodic radial pattern. It is known that this pattern emerges due to the accumulation of the phytohormone auxin, which is actively transported by the so-called efflux and the influx... | Auxin is an essential phytohormone for the control of plant growth and development. Its transport and distribution throughout the plant create numerous organized patterns in plant tissues, such as leaf venation [1], the wide variety of phyllotactic patterns [2–5], and the periodic shoot vascular patterning [6,7]. Auxin... |
10.1371/journal.pcbi.1002580 | The Generation of Phase Differences and Frequency Changes in a Network Model of Inferior Olive Subthreshold Oscillations | It is commonly accepted that the Inferior Olive (IO) provides a timing signal to the cerebellum. Stable subthreshold oscillations in the IO can facilitate accurate timing by phase-locking spikes to the peaks of the oscillation. Several theoretical models accounting for the synchronized subthreshold oscillations have be... | There is a profound interest in the dynamics of neuronal networks and the simulation of network models is a prevalent approach to study these dynamics. Generally, network models contain neurons that are connected mostly through chemical synapses to form either a completely regular topology (such as nearest neighbor con... | There is a profound interest in the dynamics of neuronal networks and the simulation of network models is a prevalent approach to study these dynamics. One aspect of network dynamics is the generation of oscillatory activity. It has been hypothesized that oscillations subserve brain-wide communications. For instance, “... |
10.1371/journal.ppat.1004480 | Candida albicans Ethanol Stimulates Pseudomonas aeruginosa WspR-Controlled Biofilm Formation as Part of a Cyclic Relationship Involving Phenazines | In chronic infections, pathogens are often in the presence of other microbial species. For example, Pseudomonas aeruginosa is a common and detrimental lung pathogen in individuals with cystic fibrosis (CF) and co-infections with Candida albicans are common. Here, we show that P. aeruginosa biofilm formation and phenazi... | In many human infections, several species of microbes are often present. This is typically the case with the disease cystic fibrosis, characterized by thick mucus in the lungs that is colonized by bacteria and fungi. Here, we show evidence that interactions between the bacterium Pseudomonas aeruginosa and the fungus Ca... | Pseudomonas aeruginosa is an opportunistic pathogen capable of causing severe nosocomial infections and infections in immunocompromised patients. P. aeruginosa is a common pathogen of individuals with cystic fibrosis (CF), a genetic disease that is caused by a mutation in the gene coding for the CFTR ion transporter an... |
10.1371/journal.pgen.1005000 | Transcriptome Wide Annotation of Eukaryotic RNase III Reactivity and Degradation Signals | Detection and validation of the RNA degradation signals controlling transcriptome stability are essential steps for understanding how cells regulate gene expression. Here we present complete genomic and biochemical annotations of the signals required for RNA degradation by the dsRNA specific ribonuclease III (Rnt1p) an... | RNA degradation is essential for gene regulation. The amount and timing of protein synthesis is determined, at least in part, by messenger RNA stability. Although RNA stability is determined by specific structural and sequence motif, the distribution of the degradation signals in eukaryotic genomes remains unclear. In ... | RNA stability is a critical determinant of gene expression required for the adjustment of RNA abundance in response to changes in growth conditions [1]. Alterations of mRNA stability are associated with many gene expression programs like T cell activation [2], response to osmotic shock [3] and change in carbon source [... |
10.1371/journal.pgen.1006172 | Orderly Replication and Segregation of the Four Replicons of Burkholderia cenocepacia J2315 | Bacterial genomes typically consist of a single chromosome and, optionally, one or more plasmids. But whole-genome sequencing reveals about ten per-cent of them to be multipartite, with additional replicons which by size and indispensability are considered secondary chromosomes. This raises the questions of how their r... | Unlike higher organisms, bacteria typically carry their genetic information on a single chromosome. But in a few bacterial families the genome includes one to three additional chromosome-like DNA molecules. Because these families are rich in pathogenic and environmentally versatile species, it is important to understan... | The long-held view that bacteria carry the essential part of their genomes on a single chromosome blurred about 25 years ago, when the species Rhodobacter sphaeroides was found to carry certain essential genes on a large replicon distinct from the main chromosome [1]. The size and essentiality of this replicon qualifie... |
10.1371/journal.ppat.1006335 | Kaposi Sarcoma Herpesvirus (KSHV) Latency-Associated Nuclear Antigen (LANA) recruits components of the MRN (Mre11-Rad50-NBS1) repair complex to modulate an innate immune signaling pathway and viral latency | Kaposi Sarcoma Herpesvirus (KSHV), a γ2-herpesvirus and class 1 carcinogen, is responsible for at least three human malignancies: Kaposi Sarcoma (KS), Primary Effusion Lymphoma (PEL) and Multicentric Castleman’s Disease (MCD). Its major nuclear latency protein, LANA, is indispensable for the maintenance and replication... | KSHV latency-associated nuclear antigen, LANA, is essential for the replication of latent viral episomes, their segregation to daughter cells and overcoming the p53-dependent cell cycle block induced by an activated DNA damage response. In addition, cytoplasmic forms of LANA have been shown to modulate cGAS-dependent i... | Kaposi Sarcoma Herpesvirus (KSHV or HHV-8, Human Herpesvirus 8), a γ2-herpesvirus or Rhadinovirus categorized as a class 1 carcinogen by the World Health Organization (WHO) [1–3], is responsible for Kaposi’s Sarcoma (KS), the most common cancer among HIV infected individuals (epidemic KS) and among men in Sub-Saharan A... |
10.1371/journal.pntd.0006221 | Promising approach to reducing Malaria transmission by ivermectin: Sporontocidal effect against Plasmodium vivax in the South American vectors Anopheles aquasalis and Anopheles darlingi | The mosquito resistance to the insecticides threatens malaria control efforts, potentially becoming a major public health issue. Alternative methods like ivermectin (IVM) administration to humans has been suggested as a possible vector control to reduce Plasmodium transmission. Anopheles aquasalis and Anopheles darling... | Malaria is one of the most important infectious diseases in the world with hundreds of millions of new cases every year. The disease is caused by parasites of the genus Plasmodium where Plasmodium vivax represent most of the cases in the Americas. Current strategies to combat malaria transmission are being implemented;... | The 2016 World Malaria Report (WHO) estimated 212 million cases of malaria worldwide, leading to 429,000 deaths, which illustrates that malaria remains an important public health problem. In the Americas, 389,390 cases and 87 deaths were reported in 2016 with Brazil reporting 24% and Peru 19% of the malaria cases [1]. ... |
10.1371/journal.ppat.1003813 | Biphasic Euchromatin-to-Heterochromatin Transition on the KSHV Genome Following De Novo Infection | The establishment of latency is an essential step for the life-long persistent infection and pathogenesis of Kaposi's sarcoma-associated herpesvirus (KSHV). While the KSHV genome is chromatin-free in the virions, the viral DNA in latently infected cells has a chromatin structure with activating and repressive histone m... | Although the KSHV genome is linear and chromatin-free in the virions, it circularizes and adopts a repressive chromatin structure in latently infected cells, inhibiting the majority of viral gene expression. In this study, we investigate the epigenetic regulatory mechanism of the pre-latency phase of KSHV infection. We... | Kaposi's sarcoma-associated herpesvirus (KSHV, Human herpesvirus 8 or HHV-8) is one of the seven currently known human tumor viruses and is associated with the pathogenesis of the multifocal, angiogenic and inflammatory cancer called Kaposi's sarcoma (KS) and certain B cell-originated neoplasias, including primary effu... |
10.1371/journal.ppat.1003412 | Efficient Sensing of Infected Cells in Absence of Virus Particles by Blasmacytoid Dendritic Cells Is Blocked by the Viral Ribonuclease Erns | Plasmacytoid dendritic cells (pDC) have been shown to efficiently sense HCV- or HIV-infected cells, using a virion-free pathway. Here, we demonstrate for classical swine fever virus, a member of the Flaviviridae, that this process is much more efficient in terms of interferon-alpha induction when compared to direct sti... | Plasmacytoid dendritic cells (pDC) represent the most potent producers of interferon type I and are therefore of major importance in antiviral defences. A TLR7-dependent induction of interferon-α in pDC by infected cells in the absence of virions has been demonstrated for hepatitis C virus. Here, we show that this path... | Although representing a rare cell type of the immune system, plasmacytoid dendritic cells (pDC) are the most important source of systemic interferon (IFN) type I in the early phase of many virus infections, and as such a critical early alarm system against viruses [1], [2]. This is based on the ability to produce aroun... |
10.1371/journal.pgen.1004506 | Playing RNase P Evolution: Swapping the RNA Catalyst for a Protein Reveals Functional Uniformity of Highly Divergent Enzyme Forms | The RNase P family is a diverse group of endonucleases responsible for the removal of 5′ extensions from tRNA precursors. The diversity of enzyme forms finds its extremes in the eukaryal nucleus where RNA-based catalysis by complex ribonucleoproteins in some organisms contrasts with single-polypeptide enzymes in others... | Many biocatalysts apparently evolved independently more than once, leading to structurally unrelated macromolecules catalyzing the same biochemical reaction. The RNase P enzyme family is an exceptional case of this phenomenon called convergent evolution. RNase P enzymes use not only unrelated, but chemically distinct m... | RNase P is the endonuclease that generates the 5′ end of tRNAs by removing transcriptional extensions [1]–[3]. It is an indispensable enzyme found in essentially all forms of life. Despite the apparently simple function and the highly conserved structure of the tRNA substrates, a bewildering diversity of enzyme forms a... |
10.1371/journal.pbio.0060327 | BEAF Regulates Cell-Cycle Genes through the Controlled Deposition of H3K9 Methylation Marks into Its Conserved Dual-Core Binding Sites | Chromatin insulators/boundary elements share the ability to insulate a transgene from its chromosomal context by blocking promiscuous enhancer–promoter interactions and heterochromatin spreading. Several insulating factors target different DNA consensus sequences, defining distinct subfamilies of insulators. Whether ea... | The genome of eukaryotes is packaged in chromatin, which consists of DNA, histones, and accessory proteins. This leads to a general repression of genes, particularly for those exposed to mostly condensed, heterochromatin regions. DNA sequences called chromatin insulators/boundary elements are able to insulate a gene fr... | Chromatin insulators/boundary elements (BEs) [1,2] are defined as sequences able to insulate a transgene from its chromosomal context and to block promiscuous enhancer–promoter interactions or heterochromatin spreading [1,3–5]. These elements are thought to subdivide the genome into functional chromosome domains, throu... |
10.1371/journal.pcbi.1006206 | Stochastic shielding and edge importance for Markov chains with timescale separation | Nerve cells produce electrical impulses (“spikes”) through the coordinated opening and closing of ion channels. Markov processes with voltage-dependent transition rates capture the stochasticity of spike generation at the cost of complex, time-consuming simulations. Schmandt and Galán introduced a novel method, based o... | Discrete state, continuous time Markov processes occur throughout cell biology, neuroscience, and ecology, representing the random dynamics of processes transitioning among multiple locations or states. Complexity reduction for such models aims to capture the essential dynamics and stochastic properties via a simpler r... | Variability in dynamical biological systems is ubiquitous. Discrete state, continuous time Markov process models are used throughout cell biology, neuroscience, and ecology to represent the random dynamics of processes transitioning among multiple locations or states [1–3]. Examples include transitions between states d... |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.