Miracle-dz/UniFAR-FTUs huggingface dataset:
Structures of closed and open states of a voltage-gated sodium channel

Significance Bacterial voltage-gated sodium channels serve as models of their vertebrate counterparts because they have similar functional components in a simpler structure. We present high-resolution structures of tightly closed and open states. In the closed state, the activation gate fully occludes the conduction pathway, and the intracellular C-terminal domain is revealed as a long four-helix bundle. In the open state, the activation gate has an orifice of ∼10 Å. Molecular dynamics simulations confirm that this conformation would allow permeation of hydrated Na+. These structures are significant advances because they provide a complete closed–open–inactivated conformational cycle in a single voltage-gated sodium channel and give insight into the structural basis for state-dependent binding of sodium channel-blocking drugs. Bacterial voltage-gated sodium channels (BacNavs) serve as models of their vertebrate counterparts. BacNavs contain conserved voltage-sensing and pore-forming domains, but they are homotetramers of four identical subunits, rather than pseudotetramers of four homologous domains. Here, we present structures of two NaVAb mutants that capture tightly closed and open states at a resolution of 2.8–3.2 Å. Introduction of two humanizing mutations in the S6 segment (NaVAb/FY: T206F and V213Y) generates a persistently closed form of the activation gate in which the intracellular ends of the four S6 segments are drawn tightly together to block ion permeation completely. This construct also revealed the complete structure of the four-helix bundle that forms the C-terminal domain. In contrast, truncation of the C-terminal 40 residues in NavAb/1–226 captures the activation gate in an open conformation, revealing the open state of a BacNav with intact voltage sensors. Comparing these structures illustrates the full range of motion of the activation gate, from closed with its orifice fully occluded to open with an orifice of ∼10 Å. Molecular dynamics and free-energy simulations confirm designation of NaVAb/1–226 as an open state that allows permeation of hydrated Na+, and these results also support a hydrophobic gating mechanism for control of ion permeation. These two structures allow completion of a closed–open–inactivated conformational cycle in a single voltage-gated sodium channel and give insight into the structural basis for state-dependent binding of sodium channel-blocking drugs.
Épidémiologie du cancer du pancréas dans le monde

Les adenocarcinomes canalaires de type exocrine representent la majorite des cancers du pancreas. Ce sont des tumeurs solides ainsi que les adenocarcinomes acineux et les pancreatoblastomes. Il existe aussi des tumeurs kystiques a potentiel de malignite variable. De rares cas de tumeurs mixtes exocrine / endocrine peuvent preter a confusion diagnostique. Les lesions neoplasiques benignes qui interviennent en tant que precurseurs du cancer sont les aires de neoplasie intraepitheliale canalaire, les lesions kystiques et les tumeurs solides pseudo papillaires. Les adenomes mucineux kystiques et les tumeurs intracanalaires papillaires mucineuses du pancreas ont un potentiel de malignite appreciable. Les adenomes sereux kystiques ne degenerent presque jamais. L'incidence de l'adenocarcinome du pancreas reste faible et varie entre 7 et 10 /100 000 dans les pays developpes. Elle est plus faible dans les pays en developpement. Le taux de mortalite est tres voisin du taux d'incidence car la survie a 5 ans est generalement inferieure a 5 %. L'epidemiologie causale est pauvre ; le seul facteur promoteur convaincant est le tabac. Il n'y a pas de place pour une prevention par depistage precoce systematique chez les personnes asymptomatiques, a l'exception des groupes a risque lies aux cas familiaux.
Arabidopsis ABCG34 contributes to defense against necrotrophic pathogens by mediating the secretion of camalexin

Significance Alternaria brassicicola infection causes dark spots on the leaves of most Brassica species, reducing the yield of economically important oilseed crops. In response to A. brassicicola infection, Arabidopsis thaliana and other Brassicaceae produce and secrete camalexin, a major phytoalexin imparting resistance to A. brassicicola. Because camalexin is toxic to the plant itself, specific transporters are needed for secretion. Here we show that the ABC transporter ABCG34 mediates the secretion of camalexin from the epidermal cells to the surface of leaves and thereby confers resistance to A. brassicicola infection. This work establishes a complete picture of a plant defense system, consisting of a toxic secondary metabolite, its transporter, and the disease phenotype caused by an economically important pathogen. Plant pathogens cause huge yield losses. Plant defense often depends on toxic secondary metabolites that inhibit pathogen growth. Because most secondary metabolites are also toxic to the plant, specific transporters are needed to deliver them to the pathogens. To identify the transporters that function in plant defense, we screened Arabidopsis thaliana mutants of full-size ABCG transporters for hypersensitivity to sclareol, an antifungal compound. We found that atabcg34 mutants were hypersensitive to sclareol and to the necrotrophic fungi Alternaria brassicicola and Botrytis cinerea. AtABCG34 expression was induced by A. brassicicola inoculation as well as by methyl-jasmonate, a defense-related phytohormone, and AtABCG34 was polarly localized at the external face of the plasma membrane of epidermal cells of leaves and roots. atabcg34 mutants secreted less camalexin, a major phytoalexin in A. thaliana, whereas plants overexpressing AtABCG34 secreted more camalexin to the leaf surface and were more resistant to the pathogen. When treated with exogenous camalexin, atabcg34 mutants exhibited hypersensitivity, whereas BY2 cells expressing AtABCG34 exhibited improved resistance. Analyses of natural Arabidopsis accessions revealed that AtABCG34 contributes to the disease resistance in naturally occurring genetic variants, albeit to a small extent. Together, our data suggest that AtABCG34 mediates camalexin secretion to the leaf surface and thereby prevents A. brassicicola infection.
Endoscopic Findings and Histopathological Pattern in Patients with Chronic Dyspepsia at Panti Rapih Hospital Jogjakarta

Background: To determine the relationship between clinical manifestation of chronic dyspepsia and endoscopic findings along with histopathological pattern by descriptive analysis. Methods: This study was a retrospective study. Subjects were patients with chronic dyspepsia who underwent endoscopic examination and gastric biopsy between June 2005 and July 2006. Result: There are 10.17% normal endoscopic results of 79 patients with chronic dyspepsia and almost 90% show abnormal result in endoscopic examination. The histopathological pattern is normal in 2.53% and 97.47% demonstrate abnormal result. The prevalence of Helicobacter pylori due to gastric ulcer is 1.26% and chronic atrophic gastritis is 3.80%. Conclusion: Most of chronic dyspepsia patients have abnormal endoscopic and histopathologic result. Keywords: chronic dyspepsia, endoscopic findings, histopathological pattern, Helicobacter pylori
Insight Into Resistance Phenotypes of Emergent Non 13-valent Pneumococcal Conjugate Vaccine Type Pneumococci Isolated From Invasive Disease After 13-valent Pneumococcal Conjugate Vaccine Implementation in France

Implementation of 13-valent conjugate pneumococcal vaccine in France has led to an overall antibiotic resistance decrease among invasive pneumococcal isolates. However, among emerging non-PCV13 serotypes, 12F, 24F, 15A and 35B are associated to antibiotic resistance and should be further monitored.
Frequency and characteristics of TBII‐seronegative patients in a population with untreated Graves’ hyperthyroidism: a prospective study

Objective It is claimed that second generation thyrotropin‐binding inhibitory immunoglobulin (TBII) assays have a very high sensitivity for the diagnosis of Graves’ hyperthyroidism (GH). However, studies evaluating the accuracy of TBII have been retrospective in nature and/or GH had not been diagnosed independently of TBII. The aim of the present study, therefore, was to prospectively evaluate the frequency and characteristics of TBII‐seronegative patients in a population of untreated GH diagnosed independent of serum TBII.
Left ventricular dysfunction in Klinefelter syndrome is associated to insulin resistance, abdominal adiposity and hypogonadism

Objective Epidemiological data suggest there is an increased risk of dying from heart disease among patients with Klinefelter syndrome (KS). Due to high prevalence of hypogonadism and metabolic syndrome, we speculated that patients with KS may have subclinical changes in the left ventricular function. Therefore, the aim was to assess left ventricular long axis function by tissue Doppler echocardiography in patients with KS and relate these findings to the metabolic status and testosterone levels.
Dimeric Drug Polymeric Micelles with Acid‐Active Tumor Targeting and FRET‐Traceable Drug Release

Trans‐activating transcriptional activator (TAT), a cell‐penetrating peptide, is extensively used for facilitating cellular uptake and nuclear targeting of drug delivery systems. However, the positively charged TAT peptide strongly interacts with serum components and undergoes substantial phagocytosis by the reticuloendothelial system, causing a short blood circulation in vivo. In this work, an acid‐active tumor targeting nanoplatform DA‐TAT‐PECL is developed to inhibit the nonspecific interactions of TAT in the bloodstream. 2,3‐dimethylmaleic anhydride (DA) is used to convert the TAT's amines to carboxylic acid; the resulting DA‐TAT is conjugated to poly(ethylene glycol)‐poly(ε‐caprolactone) (PEG‐PCL, PECL) to get DA‐TAT‐PECL. After self‐assembly into polymeric micelles, they are capable of circulating in the physiological condition for a long time and promoting cell penetration upon accumulation at the tumor site and deshielding the DA group. Moreover, camptothecin (CPT) is used as the anticancer drug and modified into a dimer (CPT)2‐ss‐Mal, in which two CPT molecules are connected by a reduction‐labile maleimide thioether bond. The Förster resonance energy transfer signal between CPT and maleimide thioether bond is monitored to visualize the drug release process, and effective targeted delivery of antitumor drugs is demonstrated. This pH/reduction dual‐responsive micelle system provides a new platform for high fidelity cancer therapy.
Critical role of caveolin-1 in ocular neovascularization and multitargeted antiangiogenic effects of cavtratin via JNK

Significance Caveolin-1 (Cav-1) is a major structural protein of caveolae found in cell membranes and is critical for numerous cellular functions. However, it remains unclear whether Cav-1 plays a role in ocular neovascularization, a major cause of blindness. In this study, we found that the gene deletion of Cav-1 exacerbates ocular neovascularization, and cavtratin, a cell permeable peptide mimicking Cav-1 function, inhibits ocular neovascularization by targeting multiple critical components of angiogenesis. Importantly, combined administration of cavtratin and anti–VEGF-A inhibits neovascularization more effectively, suggesting at least a partially VEGF-A–independent effect of cavtratin. Our findings reveal multitargeted effects of caveolin-1 and cavtratin in ocular neovascularization that may be of great therapeutic value for antiangiogenic therapy. Ocular neovascularization is a devastating pathology of numerous ocular diseases and is a major cause of blindness. Caveolin-1 (Cav-1) plays important roles in the vascular system. However, little is known regarding its function and mechanisms in ocular neovascularization. Here, using comprehensive model systems and a cell permeable peptide of Cav-1, cavtratin, we show that Cav-1 is a critical player in ocular neovascularization. The genetic deletion of Cav-1 exacerbated and cavtratin administration inhibited choroidal and retinal neovascularization. Importantly, combined administration of cavtratin and anti–VEGF-A inhibited neovascularization more effectively than monotherapy, suggesting the existence of other pathways inhibited by cavtratin in addition to VEGF-A. Indeed, we found that cavtratin suppressed multiple critical components of pathological angiogenesis, including inflammation, permeability, PDGF-B and endothelial nitric oxide synthase expression (eNOS). Mechanistically, we show that cavtratin inhibits CNV and the survival and migration of microglia and macrophages via JNK. Together, our data demonstrate the unique advantages of cavtratin in antiangiogenic therapy to treat neovascular diseases.
FOLIC ACID DEFICIENCY AND ABRUPT10 PLACENTAE

In a prospective study of 2949 singleton pregnancies of whom one‐third were treated with folic acid, the maternal serum folate concentration was assayed at booking and at 30 weeks gestation. No association was found between a low serum folate level and abruptio placentae either in the index pregnancy or in previous pregnancies, and folic acid therapy did not reduce the incidence of abruptio placentae.
Conceptual framework of the eco-physiological phases of insect diapause development justified by transcriptomic profiling

Significance Here we reassess the conceptual framework of insect diapause as a dynamic succession of endogenously and exogenously driven changes in physiology (“physiogenesis”) by assaying the gradual dynamics in the transcriptome as insects traverse the diapause developmental program. We show the objectivity and eco-physiological relevance of the different phases of diapause development by describing unique transcriptional profiles in each phase. Accordingly, the concept should serve future researchers as a general platform for the unification of timing scales and the interpretation of various “-omics” data obtained in diverse insect species encountering different ecological situations. We argue such standardized phasing of diapause development is critical for further molecular dissection of the mechanistic basis of insect diapause. Insects often overcome unfavorable seasons in a hormonally regulated state of diapause during which their activity ceases, development is arrested, metabolic rate is suppressed, and tolerance of environmental stress is bolstered. Diapausing insects pass through a stereotypic succession of eco-physiological phases termed “diapause development. ” The phasing is varied in the literature, and the whole concept is sometimes criticized as being too artificial. Here we present the results of transcriptional profiling using custom microarrays representing 1,042 genes in the drosophilid fly, Chymomyza costata. Fully grown, third-instar larvae programmed for diapause by a photoperiodic (short-day) signal were assayed as they traversed the diapause developmental program. When analyzing the gradual dynamics in the transcriptomic profile, we could readily distinguish distinct diapause developmental phases associated with induction/initiation, maintenance, cold acclimation, and termination by cold or by photoperiodic signal. Accordingly, each phase is characterized by a specific pattern of gene expression, supporting the physiological relevance of the concept of diapause phasing. Further, we have dissected in greater detail the changes in transcript levels of elements of several signaling pathways considered critical for diapause regulation. The phase of diapause termination is associated with enhanced transcript levels in several positive elements stimulating direct development (the 20-hydroxyecdysone pathway: Ecr, Shd, Broad; the Wnt pathway: basket, c-jun) that are countered by up-regulation in some negative elements (the insulin-signaling pathway: Ilp8, PI3k, Akt; the target of rapamycin pathway: Tsc2 and 4EBP; the Wnt pathway: shaggy). We speculate such up-regulations may represent the early steps linked to termination of diapause programming.
Critical structural fluctuations of proteins upon thermal unfolding challenge the Lindemann criterion

Significance In 1910 F. A. Lindemann introduced a practical criterion to predict the melting of crystals on the basis of the relative magnitude of thermal atomic fluctuations and the crystal lattice constant. The idea of a critical threshold for the local motions that would trigger melting also in disordered media like proteins has inspired important subsequent investigations. Here, a common scaling toward a constant value for the local fluctuations of a model protein in different environments is proved when approaching the unfolding temperature. This landmark result not only sheds unique light on the relationship between protein flexibility and stability, but also opens the possibility to predict protein unfolding in special environments (e.g., the cell interior) by following thermal local fluctuations. Internal subnanosecond timescale motions are key for the function of proteins, and are coupled to the surrounding solvent environment. These fast fluctuations guide protein conformational changes, yet their role for protein stability, and for unfolding, remains elusive. Here, in analogy with the Lindemann criterion for the melting of solids, we demonstrate a common scaling of structural fluctuations of lysozyme protein embedded in different environments as the thermal unfolding transition is approached. By combining elastic incoherent neutron scattering and advanced molecular simulations, we show that, although different solvents modify the protein melting temperature, a unique dynamical regime is attained in proximity of thermal unfolding in all solvents that we tested. This solvation shell-independent dynamical regime arises from an equivalent sampling of the energy landscape at the respective melting temperatures. Thus, we propose that a threshold for the conformational entropy provided by structural fluctuations of proteins exists, beyond which thermal unfolding is triggered.
Androgenetic alopecia and insulin resistance in young men

Background Epidemiological studies have associated androgenetic alopecia (AGA) with severe young‐age coronary artery disease and hypertension, and linked it to insulin resistance. We carried out a case–control study in age‐ and weight‐matched young males to study the link between AGA and insulin resistance using the homeostasis model assessment of insulin resistance (HOMA‐IR) index or metabolic syndrome clinical manifestations.
Brucellosis in humans and animals.

The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. The named authors alone are responsible for the views expressed in this publication. Brucellosis in humans and animals.
Species richness accelerates marine ecosystem restoration in the Coral Triangle

Significance The exceptional diversity of species in the coral reefs, seagrass meadows, and mangrove forests of the Coral Triangle and the many ecological functions and benefits to humans they provide have made them a high priority for conservation and fisheries management. Nevertheless, their degradation continues and calls for effective restoration. In an experimental restoration, we demonstrated that planting mixtures of diverse seagrass species improves their overall survival and growth and thus the trajectory toward successful restoration. Incorporating species diversity into restoration heralds a shift in practice from establishing a single founder species, and recognizes the widely documented positive effects that biodiversity has on ecosystem function and services. Biodiversity is often a restoration goal, but it also promises a means to improve success. Ecosystem restoration aims to restore biodiversity and valuable functions that have been degraded or lost. The Coral Triangle is a hotspot for marine biodiversity held in its coral reefs, seagrass meadows, and mangrove forests, all of which are in global decline. These coastal ecosystems support valuable fisheries and endangered species, protect shorelines, and are significant carbon stores, functions that have been degraded by coastal development, destructive fishing practices, and climate change. Ecosystem restoration is required to mitigate these damages and losses, but its practice is in its infancy in the region. Here we demonstrate that species diversity can set the trajectory of restoration. In a seagrass restoration experiment in the heart of the Coral Triangle (Sulawesi, Indonesia), plant survival and coverage increased with the number of species transplanted. Our results highlight the positive role biodiversity can play in ecosystem restoration and call for revision of the common restoration practice of establishing a single target species, particularly in regions having high biodiversity. Coastal ecosystems affect human well-being in many important ways, and restoration will become ever more important as conservation efforts cannot keep up with their loss.
ANÁLISE DA COMPOSIÇÃO CORPORAL DE ATLETAS DE NATAÇÃO DA CATEGORIA INFANTIL DO GÊNERO MASCULINO ANALYSIS OF MALE SWIMMERSBODY COMPOSITION OF THE INFANTILE CATEGORY

O proposito deste estudo foi avaliar ate onde o percentual de gordura, IMC, treinamento e sua frequencia interferem na performance de competidores de natacao adolescentes do sexo masculino. Foram avaliados 15 atletas com idades entre 12 e 14 anos (12,87 ± 0,6 anos), antes das provas, para nao ocorrer mudanca dos fluidos corporais, o que tende a aumentar as dobras cutâneas. Foram realizadas medidas antropometricas (peso e estatura), com estadiometro da marca Sanny ®, balanca digital da marca Plenna ® , alem de para as dobras cutâneas compasso da marca Lange ®, e percentual de gordura calculado a partir da somatoria das dobras cutâneas. A estimativa da composicao corporal atraves da tecnica antropometrica foi realizada conforme o protocolo desenvolvido por Guedes e colaboradores (1997), o qual utiliza 7 perimetros corporais. A analise estatistica foi realizada pelo programa Excel 2000 utilizando medias e desvio padrao. Os resultados encontrados nao corresponderam ao objetivo do estudo, pois nao foi demonstrado relacao nas variaveis propostas com melhor resultado em competicoes.
Kisspeptin serum levels in girls with central precocious puberty

Objective Central precocious puberty (CPP) causes early epiphyseal maturation, and early initiation of treatment improves final height. Unfortunately, there is no one parameter that can distinguish CPP from premature thelarche (PT), which is self‐limited and requires no therapy. In animal models, kisspeptin, the ligand for the G‐protein coupled receptor GPR54, was found to induce precocious activation of the gonadotrophic axis. Data on kisspeptin levels in girls with precocious puberty or in healthy prepubertal girls are lacking. We measured blood kisspeptin levels in girls with CPP and evaluated its potential as a clinical marker for CPP.