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In order to gain an evolutionary perspective on host-parasite-microbe interactions, evolutionary studies encompassing microbes across host and parasite species are necessary to identify patterns of cospeciation and speciation following host shifts. With appropriate experimental systems, geographic variations affecting the role of microbes in host-parasite interactions can be assessed by using a complete cross-experimental design, in which hosts from different localities are infected with parasites from their corresponding localities in the presence of either microbes isolated from the same localities or microbes from different test localities. Finally, when possible, experimental evolution of parasites and hosts in the presence or absence of the identified microbes can been used to test the effect of specific microbes on the evolution of the system and to identify mechanisms involved in parasite-microbe interaction. Phase one will compile information on previously characterized parasite-associated microbes and parasite-microbe interactions (already partially reviewed in [[15]-[16], [53]]), mine genomic and transcriptomic databases to detect microbial sequences, and characterize the complete microbiome of a set of parasites representing diverse taxa and environments. [Extracted from the article]

Recently, we observed a 15% decrease in the incidence of type 1 diabetes (T1D) in Australian 0-4-year-old children following the introduction of RV vaccination [[2], [3]], suggesting that RV vaccination could contribute to the primary prevention of this autoimmune disease. Australian surveillance data [[11]] show that the prevalence of RV G3 strains increased slightly along with an increase in strain diversity in the post-RV vaccine era, but G3 remains a minor component of disease-causing RV strains. RV was prevalent in nurseries, and the change to rooming-in would have altered the timing of exposure to RV, delaying it until later in the first year of life when, based on NOD mouse studies [[17]-[19]], RV might promote rather than retard development of diabetes. [Extracted from the article]

Reversal reactions (RRs) in leprosy are characterized by a reduction in the number of bacilli in lesions associated with an increase in cell-mediated immunity against the intracellular bacterium Mycobacterium leprae, the causative pathogen of leprosy. To identify the mechanisms that contribute to cell-mediated immunity in leprosy, we measured changes in the whole blood-derived transcriptome of patients with leprosy before, during and after RR. We identified an 'RR signature' of 1017 genes that were upregulated at the time of the clinical diagnosis of RR. Using weighted gene correlated network analysis (WGCNA), we detected a module of 794 genes, bisque4, that was significantly correlated with RR, of which 434 genes were part of the RR signature. An enrichment for both IFN-γ and IFN-β downstream gene pathways was present in the RR signature as well as the RR upregulated genes in the bisque4 module, including those encoding proteins of the guanylate binding protein (GBP) family that contributes to antimicrobial responses against mycobacteria. Specifically, GBP1, GBP2, GBP3 and GBP5 mRNAs were upregulated in the RR peripheral blood transcriptome, with GBP1, GBP2 and GBP5 mRNAs also upregulated in the RR disease lesion transcriptome. These data indicate that RRs involve a systemic upregulation of IFN-γ downstream genes including GBP family members as part of the host antimicrobial response against mycobacteria. [ABSTRACT FROM AUTHOR]

Background: The landscape of mosquito-borne disease risk has changed dramatically in recent decades, due to the emergence and reemergence of urban transmission cycles driven by invasive Aedes aegypti and Ae. albopictus. Insecticide resistance is already widespread in the yellow fever mosquito, Ae. Aegypti; is emerging in the Asian tiger mosquito Ae. Albopictus; and is now threatening the global fight against human arboviral diseases such as dengue, yellow fever, chikungunya, and Zika. Because the panel of insecticides available for public health is limited, it is of primary importance to preserve the efficacy of existing and upcoming active ingredients. Timely implementation of insecticide resistance management (IRM) is crucial to maintain the arsenal of effective public health insecticides and sustain arbovirus vector control. Methodology and principal findings: This Review is one of a series being generated by the Worldwide Insecticide resistance Network (WIN) and aims at defining the principles and concepts underlying IRM, identifying the main factors affecting the evolution of resistance, and evaluating the value of existing tools for resistance monitoring. Based on the lessons taken from resistance strategies used for other vector species and agricultural pests, we propose a framework for the implementation of IRM strategies for Aedes mosquito vectors. Conclusions and significance: Although IRM should be a fixture of all vector control programs, it is currently often absent from the strategic plans to control mosquito-borne diseases, especially arboviruses. Experiences from other public health disease vectors and agricultural pests underscore the need for urgent action in implementing IRM for invasive Aedes mosquitoes. Based on a plan developed for malaria vectors, here we propose some key activities to establish a global plan for IRM in Aedes spp. [ABSTRACT FROM AUTHOR]

Background: Triatoma brasiliensis, a triatomine-bug vector of Chagas disease, evolved in the semiarid Caatinga, where it occupies rocky outcrops, shrubby cacti, and human dwellings. Dwellings and rocks are considered high-quality microhabitats for this saxicolous species, whereas cacti probably represent secondary, lower-quality microhabitats. This 'microhabitat-quality hierarchy' hypothesis predicts that T. brasiliensis populations occupying dwellings or rocks should endure harsh environmental conditions better than their cactus-living relatives. Methods/Findings: We tested this prediction by comparing T. brasiliensis infestation (proportion of microhabitats with bugs), density (bugs per microhabitat), and crowding (bugs per infested microhabitat) in dwellings, rocks, and cacti sampled before and during the extreme drought that ravaged the Caatinga in 2012–2016. We used random-intercepts generalized linear mixed models to account for microhabitat spatial clustering and for variations in bug-catch effort; we assessed model performance and computed model-averaged effect estimates using Akaike's information criterion. Pre-drought infestation was similar across microhabitat types; during the drought, infestation remained stable in dwellings and rocks but dropped in cacti. Pre-drought bug density declined from dwellings to rocks to cacti; an additional decline associated with the drought was largely comparable across microhabitats, albeit perhaps somewhat larger in cacti. Finally, pre-drought bug crowding was higher in dwellings than in rocks or cacti and changed little during the drought–possibly with a downward trend in dwellings and an upward trend in cacti. Conclusions: Triatoma brasiliensis populations fared better in dwellings and rocks than in cacti during extreme drought. Estimates of microhabitat and drought effects on infestation, density, and crowding suggest that only a few cacti (versus many rocks and dwellings) represent good-quality habitat under such extremely harsh conditions. Our findings provide empirical support to the microhabitat-quality hierarchy hypothesis, and imply that T. brasiliensis can endure extreme climate by exploiting high-quality microhabitats, whether wild or man-made, in the semiarid Caatinga. [ABSTRACT FROM AUTHOR]

Aedes (Stegomyia) aegypti (L.) and Ae. (Stegomyia) albopictus (Skuse) mosquitoes can transmit dengue, chikungunya, yellow fever, and Zika viruses. Limited surveillance has led to uncertainty regarding the geographic ranges of these vectors globally, and particularly in regions at the present-day margins of habitat suitability such as the contiguous United States. Empirical habitat suitability models based on environmental conditions can augment surveillance gaps to describe the estimated potential species ranges, but model accuracy is unclear. We identified previously published regional and global habitat suitability models for Ae. aegypti (n = 6) and Ae. albopictus (n = 8) for which adequate information was available to reproduce the models for the contiguous U.S. Using a training subset of recently updated county-level surveillance records of Ae. aegypti and Ae. albopictus and records of counties conducting surveillance, we constructed accuracy-weighted, probabilistic ensemble models from these base models. To assess accuracy and uncertainty we compared individual and ensemble model predictions of species presence or absence to both training and testing data. The ensemble models were among the most accurate and also provided calibrated probabilities of presence for each species. The quantitative probabilistic framework enabled identification of areas with high uncertainty and model bias across the U.S. where improved models or additional data could be most beneficial. The results may be of immediate utility for counties considering surveillance and control programs for Ae. aegypti and Ae. albopictus. Moreover, the assessment framework can drive future efforts to provide validated quantitative estimates to support these programs at local, national, and international scales. [ABSTRACT FROM AUTHOR]

Lorenz von Seidlein and colleagues discuss improving house designs in rural Africa to benefit health. [ABSTRACT FROM AUTHOR]

Dendritic spine development is crucial for the establishment of excitatory synaptic connectivity and functional neural circuits. Alterations in spine morphology and density have been associated with multiple neurological disorders. Autism candidate gene disconnected-interacting protein homolog 2 A (DIP2A) is known to be involved in acetylated coenzyme A (Ac-CoA) synthesis and is primarily expressed in the brain regions with abundant pyramidal neurons. However, the role of DIP2A in the brain remains largely unknown. In this study, we found that deletion of Dip2a in mice induced defects in spine morphogenesis along with thin postsynaptic density (PSD), and reduced synaptic transmission of pyramidal neurons. We further identified that DIP2A interacted with cortactin, an activity-dependent spine remodeling protein. The binding activity of DIP2A-PXXP motifs (P, proline; X, any residue) with the cortactin-Src homology 3 (SH3) domain was critical for maintaining the level of acetylated cortactin. Furthermore, Dip2a knockout (KO) mice exhibited autism-like behaviors, including excessive repetitive behaviors and defects in social novelty. Importantly, acetylation mimetic cortactin restored the impaired synaptic transmission and ameliorated repetitive behaviors in these mice. Altogether, our findings establish an initial link between DIP2A gene variations in autism spectrum disorder (ASD) and highlight the contribution of synaptic protein acetylation to synaptic processing. [ABSTRACT FROM AUTHOR]

Migratory cells use distinct motility modes to navigate different microenvironments, but it is unclear whether these modes rely on the same core set of polarity components. To investigate this, we disrupted actin-related protein 2/3 (Arp2/3) and the WASP-family verprolin homologous protein (WAVE) complex, which assemble branched actin networks that are essential for neutrophil polarity and motility in standard adherent conditions. Surprisingly, confinement rescues polarity and movement of neutrophils lacking these components, revealing a processive bleb-based protrusion program that is mechanistically distinct from the branched actin-based protrusion program but shares some of the same core components and underlying molecular logic. We further find that the restriction of protrusion growth to one site does not always respond to membrane tension directly, as previously thought, but may rely on closely linked properties such as local membrane curvature. Our work reveals a hidden circuit for neutrophil polarity and indicates that cells have distinct molecular mechanisms for polarization that dominate in different microenvironments. [ABSTRACT FROM AUTHOR]

How a child's brain develops specialization for print is poorly understood. One longstanding account is selective neuronal tuning to regularity of visual-orthographic features, which predicts a monotonically increased neural activation for inputs with higher regularity during development. However, we observed a robust interaction between a stimulus' orthographic regularity (bottom-up input) and children's lexical classification ability (top-down prediction): N1 response, which is the first negative component of the event-related potential (ERP) occurring at posterior electrodes, was stronger to lower-regularity stimuli, but only in children who were less efficient in lexically classifying these stimuli (high prediction error). In contrast, N1 responses were reduced to lower-regularity stimuli in children who showed high efficiency of lexical classification (low prediction error). The modulation of children's lexical classification efficiency on their neural responses to orthographic stimuli supports the predictive coding account of neural processes of reading. [ABSTRACT FROM AUTHOR]

Fundamental scientific advances can take decades to translate into improvements in human health. Shortening this interval would increase the rate at which scientific discoveries lead to successful treatment of human disease. One way to accomplish this would be to identify which advances in knowledge are most likely to translate into clinical research. Toward that end, we built a machine learning system that detects whether a paper is likely to be cited by a future clinical trial or guideline. Despite the noisiness of citation dynamics, as little as 2 years of postpublication data yield accurate predictions about a paper's eventual citation by a clinical article (accuracy = 84%, F1 score = 0.56; compared to 19% accuracy by chance). We found that distinct knowledge flow trajectories are linked to papers that either succeed or fail to influence clinical research. Translational progress in biomedicine can therefore be assessed and predicted in real time based on information conveyed by the scientific community's early reaction to a paper. [ABSTRACT FROM AUTHOR]

The striatum plays a fundamental role in motor learning and reward-related behaviors that are synergistically shaped by populations of D1 dopamine receptor (D1R)- and D2 dopamine receptor (D2R)-expressing medium spiny neurons (MSNs). How various neurotransmitter inputs converging on common intracellular pathways are parsed out to regulate distinct behavioral outcomes in a neuron-specific manner is poorly understood. Here, we reveal that distinct contributions of D1R-MSNs and D2R-MSNs towards reward and motor behaviors are delineated by the multifaceted signaling protein neurofibromin 1 (NF1). Using genetic mouse models, we show that NF1 in D1R-MSN modulates opioid reward, whereas loss of NF1 in D2R-MSNs delays motor learning by impeding the formation and consolidation of repetitive motor sequences. We found that motor learning deficits upon NF1 loss were associated with the disruption in dopamine signaling to cAMP in D2R-MSN. Restoration of cAMP levels pharmacologically or chemogenetically rescued the motor learning deficits seen upon NF1 loss in D2R-MSN. Our findings illustrate that multiplex signaling capabilities of MSNs are deployed at the level of intracellular pathways to achieve cell-specific control over behavioral outcomes. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the dependability and accuracy of midkine (MK) in the diagnosis of hepatocellular carcinoma (HCC). Methods: PubMed, EMBASE, Web of Science, China Biology Medicine disc and grey literature sources were searched from the date of database inception to January 2019. Two authors (B-H.Z. and B.L.) independently extracted the data and evaluated the study quality using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. The sensitivity, specificity, positive likelihood ratio (LR+) and negative likelihood ratio (LR−) were estimated using a bivariate model. Moreover, hierarchical summary receiver operating characteristic curves were generated. The diagnostic odds ratio (DOR) and area under the curve (AUC) were pooled using a univariate model. Results: Nine articles (11 studies) were included (1941 participants). The bivariate analysis revealed that the sensitivity and specificity of MK for HCC diagnosis were 0.85 (95% CI 0.78–0.91) and 0.83 (95% CI 0.76–0.88), respectively. We also found a LR+ of 5.05 (95% CI 3.33–7.40), a LR− of 0.18 (95% CI 0.11–0.28), a DOR of 31.74 (95% CI 13.98–72.09) and an AUC of 0.91 (95% CI 0.84–0.99). Subgroup analyses showed that MK provided the best efficiency for HCC diagnosis when the cutoff value was greater than 0.5 ng/mL. Conclusions: MK has an excellent diagnostic value for hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Studies conducted in time series could be far more informative than those that only capture a specific moment in time. However, when it comes to transcriptomic data, time points are sparse creating the need for a constant search for methods capable of extracting information out of experiments of this kind. We propose a feature selection algorithm embedded in a hidden Markov model applied to gene expression time course data on either single or even multiple biological conditions. For the latter, in a simple case-control study features or genes are selected under the assumption of no change over time for the control samples, while the case group must have at least one change. The proposed model reduces the feature space according to a two-state hidden Markov model. The two states define change/no-change in gene expression. Features are ranked in consonance with three scores: number of changes across time, magnitude of such changes and quality of replicates as a measure of how much they deviate from the mean. An important highlight is that this strategy overcomes the few samples limitation, common in transcriptome experiments through a process of data transformation and rearrangement. To prove this method, our strategy was applied to three publicly available data sets. Results show that feature domain is reduced by up to 90% leaving only few but relevant features yet with findings consistent to those previously reported. Moreover, our strategy proved to be robust, stable and working on studies where sample size is an issue otherwise. Hence, even with two biological replicates and/or three time points our method proves to work well. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) have commonly been used to identify candidate genes that control economically important traits in livestock. Our objective was to detect potential candidate genes associated mainly with muscle development traits related to dimension of hindquarter in cattle. A next generation sequencing (NGS) dataset to imputed to 12 million single nucleotide polymorphisms (SNPs) (from 1252 Simmental beef cattle) were used to search for genes affecting hindquarter traits using a linear, mixed model approach. We also used haplotype and linkage disequilibrium blocks to further support our identifications. We identified 202 significant SNPs in the bovine BTA4 chromosome region associated with width of hind leg, based on a stringent statistical threshold (p = 0.05/ effective number of SNPs identified). After exploring the region around these SNPs, we found candidate genes that were potentially related to the associated markers. More importantly, we identified a region of approximately 280 Kb on the BTA4 chromosome that harbored several muscle specific candidate genes, genes to be in a potential region for muscle development. However, we also found candidate gene SLC13A1 on BTA4, which seems to be associated with bone disorders (such as chondrodysplasia) in Simmental beef cattle. [ABSTRACT FROM AUTHOR]

Malaria is responsible for almost half a million deaths annually. The role of Vγ9Vδ2 γδ T cells in malaria is still unclear. Studies have reported an association between this cell subset and malaria symptoms and severity. Profiles of Vγ9Vδ2 γδ T cells in bigger cohorts with different levels of clinical severity have not been described. Proportion, numbers, and activation status of Vγ9Vδ2 γδ T cells were measured by flow cytometry in 59 healthy controls (HCs), 58 children with uncomplicated malaria (UM) and 67 with cerebral malaria (CM,) during acute malaria and in convalescence 28 days later. Vγ9Vδ2 γδ T cell were lower in children presenting with UM and CM than in HCs. Cell counts did not vary with malaria severity (CM median counts 40 x 103 cells/μL, IQR [23–103]; UM median counts 30 x 103 cells/μL [10–90], P = 0.224). Vγ9Vδ2 γδ T cell counts increased during convalescence for UM (70 [40–60] x 103 cells/μL and CM (90 [60–140] x 103 cells/μL), to levels similar to those in HCs (70 [50–140] x 103 cells/μL), p = 0.70 and p = 0.40 respectively. Expression of the activation markers CD69 and HLA-DR on Vγ9Vδ2 γδ T cells was higher in malaria cases than in controls (HCs vs UM or CM, p < 0.0001) but was similar between UM and CM. HLA-DR expression remained elevated at 28 days, suggesting sustained activation of Vγ9Vδ2 γδ T cells during recovery. Vγ9Vδ2 γδ T cell proportions and cells counts were suppressed in acute disease and normalized in convalescence, a phenomenon previously hypothesized to be due to transient migration of the cells to secondary lymphoid tissue. The presence of highly activated Vγ9Vδ2 γδ T cells suggests that this T cell subset plays a specific role in response to malaria infection. [ABSTRACT FROM AUTHOR]

A definitive endodermal cell lineage is a prerequisite for the efficient generation of mature endoderm derivatives that give rise to organs, such as the pancreas and liver. We previously reported that the induction of mesenchymal definitive endoderm cells depends on autocrine TGF-β signaling and that pharmacological blockage of TGF-β signaling by Repsox disrupts endoderm specification. The definitive endoderm arises from a primitive streak, which depends largely on TGF-β signaling. If the TGF-β pathway is blocked by Repsox, cell fate after the primitive streak induction is so-far unknown. We report here, that an induced primitive streak cell-population contained many T/SOX2 co-expressing cells, and subsequent inhibition of TGF-β signaling by Repsox promoted neuroectodermal cell fate, which was characterized using single-cell qPCR analysis and immunostaining. The process of epithelial-to-mesenchymal transition, which is inherent to the process of definitive endoderm differentiation, was also disrupted upon Repsox treatment. Our findings may provide a new approach to produce neural progenitors. [ABSTRACT FROM AUTHOR]

Purpose: MitraClip is the sole percutaneous device approved for functional mitral regurgitation (MR; FMR) but MR recurs in over one third of patients. As device-induced mechanical effects are a potential cause for MR recurrence, we tested the hypothesis that MitraClip increases leaflet stress and procedure-related strain in sub-valvular left ventricular (LV) myocardium in FMR associated with coronary disease (FMR-CAD). Methods: Simulations were performed using finite element models of the LV + mitral valve based on MRI of 5 sheep with FMR-CAD. Models were modified to have a 20% increase in LV volume (↑LV_VOLUME) and MitraClip was simulated with contracting beam elements (virtual sutures) placed between nodes in the center edge of the anterior (AL) and posterior (PL) mitral leaflets. Effects of MitraClip on leaflet stress in the peri-MitraClip region of AL and PL, septo-lateral annular diameter (SLAD), and procedure-related radial strain (Err) in the sub-valvular myocardium were calculated. Results: MitraClip increased peri-MitraClip leaflet stress at end-diastole (ED) by 22.3±7.1 kPa (p<0.0001) in AL and 14.8±1.2 kPa (p<0.0001) in PL. MitraClip decreased SLAD by 6.1±2.2 mm (p<0.0001) and increased Err in the sub-valvular lateral LV myocardium at ED by 0.09±0.04 (p<0.0001)). Furthermore, MitraClip in ↑LV_VOLUME was associated with persistent effects at ED but also at end-systole where peri-MitraClip leaflet stress was increased in AL by 31.9±14.4 kPa (p = 0.0268) and in PL by 22.5±23.7 kPa (p = 0.0101). Conclusions: MitraClip for FMR-CAD increases mitral leaflet stress and radial strain in LV sub-valvular myocardium. Mechanical effects of MitraClip are augmented by LV enlargement. [ABSTRACT FROM AUTHOR]

Background: The presence of infections is one of the main factors that leads to delays in healing or non-closure of cutaneous wounds. Although the goal of antibiotic use is to treat or prevent infection, there is currently no agreement on the effectiveness of these products. Aim: The aim of this study was to evaluate the efficacy of antibiotic use during the healing process of skin wounds in animal models not intentionally infected, as well as to analyze the advances and limitations of the studies carried out in this field. Main methods: This systematic review was performed according to the PRISMA guidelines, using a structured search on the MedLine (PubMed) and Scopus platforms to retrieve studies published until August 29, 2018, 13:35p.m. The studies included were limited to those that used excision or incision wound models and that were not intentionally infected. The data for the animal models, antibiotic used, and the main results of the studies were extracted, and compared where possible. Bias analysis and methodological quality assessments were examined through the SYRCLE's Risk of Bias tool. Key findings: Twenty-seven studies were selected. Overall, the effects of the antibiotic on the wound decreased inflammatory cell infiltration and promoted an increased number of fibroblasts, extracellular matrix constituents, re-epithelialization and tissue strength. A great deal of important information about the methodology was not presented, such as: the statistical analysis used, the animal model (sex and age), antibiotic dosage, blinding and randomization of the animals chosen. Significance: Based on the results found, we believe that antibiotic therapy can be considered a viable alternative for the treatment of cutaneous wounds. However, current evidence obtained from the methodological quality analysis points towards a high risk of bias. This is due to the incomplete characterization of the experimental design and treatment protocol, which compromises the reproducibility of the studies. [ABSTRACT FROM AUTHOR]

Background: Previous studies have assessed the incremental economic burden of treatment-resistant depression (TRD) versus non-treatment-resistant major depressive disorder (i.e., non-TRD MDD) in commercially-insured and Medicaid-insured patients, but none have focused on Medicare-insured patients. Objective: To assess healthcare resource utilization (HRU) and costs of patients with TRD versus non-TRD MDD or without major depressive disorder (MDD; i.e., non-MDD) in a Medicare-insured population. Methods: Adult patients were retrospectively identified from the Chronic Condition Warehouse de-identified 100% Medicare database (01/2010-12/2016). MDD was defined as ≥1 MDD diagnosis and ≥1 claim for an antidepressant. Patients initiated on a third antidepressant following two antidepressant treatment regimens of adequate dose and duration were considered to have TRD. The index date was defined as the date of the first antidepressant claim for the TRD and non-TRD MDD cohorts, and as a randomly imputed date for the non-MDD cohort. Patients with TRD were matched 1:1 to non-TRD MDD patients and randomly selected non-MDD patients based on propensity scores. Analyses were also performed for a subset of patients aged ≥65. Results: Of 29,543 patients with MDD, 3,225 (10.9%) met the study definition of TRD; 157,611 were included in the non-MDD cohort. Matched patients with TRD and non-TRD MDD were, on average, 58.9 and 59.0 years old, respectively. The TRD cohort had higher per-patient-per-year (PPPY) HRU than the non-TRD MDD (e.g., inpatient visits: incidence rate ratio [IRR] = 1.36) and non-MDD cohorts (e.g., inpatient visits: IRR = 1.84, all P<0.001). The TRD cohort had significantly higher total PPPY healthcare costs than the non-TRD MDD cohort ($25,517 vs. $20,425, adjusted cost difference = $3,385) and non-MDD cohort ($25,517 vs. $14,542, adjusted cost difference = $4,015, all P<0.001). Similar results were found for the subset of patients ≥65. Conclusion: Among Medicare-insured patients, those with TRD had higher HRU and costs compared to those with non-TRD MDD and non-MDD. [ABSTRACT FROM AUTHOR]

Serine proteases and its inhibitors are involved in physiological process and its deregulation lead to various diseases like Chronic Obstructive Pulmonary Disease (COPD), pulmonary emphysema, skin diseases, atherosclerosis, coagulation diseases, cancer, inflammatory diseases, neuronal disorders and other diseases. Serine protease inhibitors have been described in many species, as well as in plants, including cowpea beans (Vigna unguiculata (L.) Walp). Here, we purified and characterized a protease inhibitor, named VuEI (Vigna unguiculata elastase inhibitor), from Vigna unguiculata, with inhibitory activity against HNE (human neutrophil elastase) and chymotrypsin but has no inhibitory activity against trypsin and thrombin. VuEI was obtained by alkaline protein extraction followed by three different chromatographic steps in sequence. First, an ion exchange chromatography using Hitrap Q column was employed, followed by two reversed-phase chromatography using Source15RPC and ACE18 columns. The molecular mass of VuEI was estimated in 10.99 kDa by MALDI-TOF mass spectrometry. The dissociation constant (Ki) to HNE was 9 pM. These data indicate that VuEI is a potent inhibitor of human neutrophil elastase, besides to inhibit chymotrypsin. [ABSTRACT FROM AUTHOR]

Blood stream infections rank among the top seven causes of death of the general population. The aim of our study was to better understand the epidemiology of BSI in order to improve diagnostics and patient outcome. We used retrospective aggregated laboratory data of blood samples received from all public hospitals in Tyrol, Austria between 2006 and 2015. Microorganisms were categorized into obligatory, facultative, unusual pathogens and contaminants. The distribution, the cumulative incidence and antimicrobial susceptibility patterns were compared between the tertiary (TH) and regional peripheral hospitals (PH). Among 256,364 blood samples, 76.1% were from the TH The incidence of obligatory pathogens was 1.7 fold, and up to 3 times higher for facultative, unusual pathogens and contaminants in the TH and increased mainly due to an increase of E.coli, which was the most common isolated pathogen (n = 2,869), followed by Staphylococcus aureus (n = 1,439), Enterococcus sp. (n = 953) and Klebsiella sp. (n = 816). The distribution of obligatory pathogens differed between the hospital settings: In the TH Enterococcus sp. accounted for 40.8% and E.coli for 70.4%, respectively, whereas in the PH for 25.4% (p<0.0001) and 57.8%, respectively (p<0.0001) Antibiotic resistance of Gram negative bacteria and Staphylococcus aureus did not change during the observation period. Carbapenem resistance of Klebsiella sp. and vancomycin and linezolid resistance of Enterococcus faecium showed a non-significant increase since 2010 in the TH setting. We concluded that the incidence of BSI in TH was higher compared to PH. We observed higher contamination rates in the TH. We could not interpret the data of coagulase negative staphylococci due to lack of clinical data. We strongly recommend enhancement of training on blood culture sampling to decrease the rate of contamination. Due to differences in pathogen distribution and antimicrobial resistance between different hospital settings we recommend separate treatment guidelines for BSI by hospital setting. [ABSTRACT FROM AUTHOR]

We examined the influence of linear perspective cues and texture gradients in the perceptual rescaling of stimuli over a highly-salient Ponzo illusion of a corridor. We performed two experiments using the Method of Constant Stimuli where participants judged the size of one of two rings. In experiment 1, one ring was presented in the upper visual-field at the end of the corridor and the other in the lower visual-field at the front of the corridor. The perceived size of the top and bottom rings changed as a function of the availability of linear perspective and textures. In experiment 2, only one ring was presented either at the top or the bottom of the image. The perceived size of the top but not the bottom ring changed as a function of the availability of linear perspective and textures. In both experiments, the effects of the cues were additive. Perceptual rescaling was also stronger for the top compared to the bottom ring. Additional eye-tracking revealed that participants tended to gaze more in the upper than the lower visual-field. These findings indicate that top-down mechanisms provide an important contribution to the Ponzo illusion. Nonetheless, additional maximum likelihood estimation analyses revealed that linear perspective fulfilled a greater contribution in experiment 2, which is suggestive of a bottom-up mechanism. We conclude that both top-down and bottom-up mechanisms play important roles. However, the former seems to fulfil a more prominent role when both stimuli are presented in the image. [ABSTRACT FROM AUTHOR]

Fricative consonants are known to be pronounced by controlling turbulent flow inside a vocal tract. In this study, a simplified vocal tract model was proposed to investigate the characteristics of flow and sound during production of the fricative [s] in a word context. By controlling the inlet flow rate and tongue speed, the acoustic characteristics of [s] were reproduced by the model. The measurements with a microphone and a hot-wire anemometer showed that the flow velocity at the teeth gap and far-field sound pressure started oscillating before the tongue reached the /s/ position, and continued during tongue descent. This behaviour was not affected by the changes of the tongue speed. These results indicate that there is a time shift between source generation and tongue movement. This time shift can be a physical constraint in the articulation of words which include /s/. With the proposed model, we could investigate the effects of tongue speed on the flow and sound generation in a parametric way. The proposed methodology is applicable for other phonemes to further explore the aeroacoustics of phonation. [ABSTRACT FROM AUTHOR]

Background: Cost effectiveness analyses (CEAs) are widely used to evaluate the opportunity cost of health care investments. However, few functions that take equity concerns into account are available for such CEA methods, and these concerns are therefore at risk of being disregarded. Among the functions that have been developed, most focus on the distribution of health gains, as opposed to the distribution of lifetime health. This is despite the fact that there are good reasons to give higher priority to individuals and groups with a low quality adjusted life expectancy from birth (QALE). Also, an even distribution of health gains may imply an uneven distribution of lifetime health. Methods: We develop a systematic and explicit approach that allows for the inclusion of lifetime health concerns in CEAs, by creating a new priority weight function, PW = α+(t-γ)·C·e-β·(t-γ), where t is the health measure. PW has several desirable properties. First, it is continuous and smooth, ensuring that people with similar health characteristics are treated alike. For example, those who achieve 50 QALE should be treated similarly to those who achieve 49.9 QALE. Second, it is flexible regarding shape and outcome measure (i.e., caters to other measures than QALE), so that a broad range of values may be modelled. Third, the coefficients have distinct roles. This allows for the easy manipulation of the PW's shape. In order to demonstrate how PW may be applied, we use data from a previous study and estimated the coefficients of PW based on two approaches. Conclusions: Equity concerns are important when conducting CEAs, which means that suitable PWs should be developed. We do not intend to determine which PW is the most appropriate, but to illustrate how a flexible general PW can be estimated based on empirical data. [ABSTRACT FROM AUTHOR]

Biological, ecological, social, and technological systems are complex structures with multiple interacting parts, often represented by networks. Correlation matrices describing interdependency of the variables in such structures provide key information for comparison and classification of such systems. Classification based on correlation matrices could supplement or improve classification based on variable values, since the former reveals similarities in system structures, while the latter relies on the similarities in system states. Importantly, this approach of clustering correlation matrices is different from clustering elements of the correlation matrices, because our goal is to compare and cluster multiple networks–not the nodes within the networks. A novel approach for clustering correlation matrices, named "snakes-&-dragons," is introduced and illustrated by examples from neuroscience, human microbiome, and macroeconomics. [ABSTRACT FROM AUTHOR]

Roe deer (Capreolus capreolus) is the most abundant cervid in Europe and, as such, has a considerable impact over several human activities. Accurate roe deer population size estimates are useful to ensure their proper management. We tested 3 methods for estimating roe deer abundance (drive counts, pellet-group counts, and camera trapping) during two consecutive years (2012 and 2013) in the Apennines (Italy) in order to assess their precision and applicability. During the study period, population density estimates were: drive counts 21.89±12.74 roe deer/km2 and pellet-group counts 18.74±2.31 roe deer/km2 in 2012; drive counts 19.32±11.12 roe deer/km2 and camera trapping 29.05±7.48 roe deer/km2 in 2013. Precision of the density estimates differed widely among the 3 methods, with coefficients of variation ranging from 12% (pellet-group counts) to 58% (drive counts). Drive counts represented the most demanding method on account of the higher number of operators involved. Pellet-group counts yielded the most precise results and required a smaller number of operators, though the sampling effort was considerable. When compared to the other two methods, camera trapping resulted in an intermediate level of precision and required the lowest sampling effort. We also discussed field protocols of each method, considering that volunteers, rather than technicians, will more likely be appointed for these tasks in the near future. For this reason, we strongly suggest that for each method managers of population density monitoring projects take into account ease of use as well as the quality of the results obtained and the resources required. [ABSTRACT FROM AUTHOR]

Background: Fetal monitoring based on electrocardiographic (ECG) morphology is obtained from a single unipolar fetal scalp electrode. Ideally, it should be obtained from multiple leads, as ECG waveform depends on alignment between electrode and electrical heart axis. This alignment is unknown in fetuses. Besides, fetuses are surrounded by conductive media, which may influence ECG waveform. We explored the influence of electrode position and head orientation on ECG waveforms of unipolar and bipolar scalp ECGs recorded in air and in conductive medium. Methods: We recorded ECGs in one adult subject at five different scalp positions in five different head orientations both in dry and immersed conditions. The ratio between T-amplitude and QRS-amplitude (T/QRS ratio) of unipolar and bipolar scalp ECGs was determined and compared between all conditions. Results: In the dry condition, we observed in the unipolar leads little to no difference between different electrode positions (maximal T/QRS difference 0.00–0.01) and minor differences between head orientations (0.02–0.03), whereas bipolar leads showed no recognizable ECG signal at all. During the immersed condition, we found variation in the unipolar leads, both between electrode positions (maximal T/QRS difference 0.02–0.05) and between head orientations (0.03–0.06). Bipolar leads showed different ECG signals in contrasting head orientations. Conclusions: Both unipolar and bipolar scalp lead-derived ECG waveforms are influenced by electrode position and head orientation when the subject is submerged in a conductive medium. Fetal monitoring based on single scalp lead ECG waveform might be suboptimal, as it lacks correction for fetal head orientation and electrode position. [ABSTRACT FROM AUTHOR]

This systematic review and meta-analysis aimed to examine the effects of physical exercise cum cognitive-behavioural therapy (CBT) on alleviating pain intensity, functional disabilities, and mood/mental symptoms in those suffering with chronic musculoskeletal pain. MEDLINE, EMBASE, PubMEd, PsycINFO and CINAHL were searched to identify relevant randomised controlled trials from inception to 31 December 2018. The inclusion criteria were: (a) adults ≥18 years old with chronic musculoskeletal pain ≥3 months, (b) randomised controlled design, (c) a treatment arm consisting of physical intervention and CBT combined, (d) the comparison arm being waitlist, usual care or other non-pharmacological interventions such as physical exercise or CBT alone, and (e) outcomes including pain intensity, pain-related functional disabilities (primary outcomes), or mood/mental symptoms (secondary outcome). The exclusion criteria were: (a) the presence of comorbid mental illnesses other than depression and anxiety and (b) non-English publication. The search resulted in 1696 records and 18 articles were selected for review. Results varied greatly across studies, with most studies reporting null or small effects but a few studies reporting very large effects up to 2-year follow-up. Pooled effect sizes (Hedges' g) were ~1.00 for pain intensity and functional disability, but no effect was found for mood/mental symptoms. The effects were mainly driven by several studies reporting unusually large differences between the exercise cum CBT intervention and exercise alone. When these outliers were removed, the effect on pain intensity disappeared at post-intervention while a weak effect (g = 0.21) favouring the combined intervention remained at follow-up assessment. More consistent effects were observed for functional disability, though the effects were small (g = 0.26 and 0.37 at post-intervention and follow-up respectively). More importantly, the value of adding CBT to exercise interventions is questionable, as consistent benefits were not seen. The clinical implications and directions for future research are discussed. [ABSTRACT FROM AUTHOR]

Endothelial nitric oxide synthase (eNOS)-related vessel relaxation is a highly coordinated process that regulates blood flow and pressure and is dependent on caveolae. Here, we investigated the role of caveolar plasma membrane stabilization by the dynamin-related ATPase EHD2 on eNOS-nitric oxide (NO)-dependent vessel relaxation. Loss of EHD2 in small arteries led to increased numbers of caveolae that were detached from the plasma membrane. Concomitantly, impaired relaxation of mesenteric arteries and reduced running wheel activity were observed in EHD2 knockout mice. EHD2 deletion or knockdown led to decreased production of nitric oxide (NO) although eNOS expression levels were not changed. Super-resolution imaging revealed that eNOS was redistributed from the plasma membrane to internalized detached caveolae in EHD2-lacking tissue or cells. Following an ATP stimulus, reduced cytosolic Ca2+ peaks were recorded in human umbilical vein endothelial cells (HUVECs) lacking EHD2. Our data suggest that EHD2-controlled caveolar dynamics orchestrates the activity and regulation of eNOS/NO and Ca2+ channel localization at the plasma membrane. [ABSTRACT FROM AUTHOR]

The aim of our study was to compare early and long-term outcome of patients undergoing either on-pump or off-pump coronary artery bypass grafting with special focus on impairment of renal function. Five hundred ninety-three consecutive patients undergoing coronary artery bypass grafting were retrospectively analyzed. They were assigned either to on-pump (n = 281) or to off-pump (n = 312) group. Early and long-term outcomes were analyzed with special focus on renal function. Basic demographics and preoperative characteristics did not differ between groups (p>0.05) as well as postoperative renal parameters (p>0.05). Postoperative odds ratios (OR) of off-pump group in comparison to on-pump group were higher without reaching significance in terms of incidence of gastrointestinal complications and pneumonia (OR = 2.23 and 1.61, respectively) as well as hazard ratios (HR) on long-term follow-up for mortality and incidence of myocardial infarction (HR = 1.50 and 2.29, respectively). Kaplan-Meier estimation analysis also revealed similar results for both groups in terms of mid- and long-term survival (Breslow p = 0.062 and Log-Rank p = 0.064, respectively) and for incidence of myocardial infarction (Breslow p = 0.102 and Log-Rank p = 0.103, respectively). Our study suggests that use or not use of coronary artery bypass did not influence postoperative renal function. Odds of early outcomes were similar in both groups as well as incidence of myocardial infarction and mortality in long-term follow-up. [ABSTRACT FROM AUTHOR]

Objectives: An extended-wavelength diffuse reflectance spectroscopy (EWDRS) technique was evaluated for its ability to differentiate between and classify different skin and tissue types in an in vivo pig model. Materials and methods: EWDRS recordings (450–1550 nm) were made on skin with different degrees of pigmentation as well as on the pig snout and tongue. The recordings were used to train a support vector machine to identify and classify the different skin and tissue types. Results: The resulting EWDRS curves for each skin and tissue type had a unique profile. The support vector machine was able to classify each skin and tissue type with an overall accuracy of 98.2%. The sensitivity and specificity were between 96.4 and 100.0% for all skin and tissue types. Conclusion: EWDRS can be used in vivo to differentiate between different skin and tissue types with good accuracy. Further development of the technique may potentially lead to a novel diagnostic tool for e.g. non-invasive tumor margin delineation. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance (AMR) is a global crisis with impacts on the future health and welfare of humans and animals. Determining key factors that influence veterinarians' antimicrobial prescribing behaviours can bridge the gap between prescribing guidelines and clinical usage. Veterinarians practicing in Australia were surveyed on their frequency in prescribing different antibiotics; factors influencing their antibiotic prescribing behaviours; and their perceptions of current drivers of AMR. Antibiotics were prescribed in a third of consultations with key differences in the frequency of use of specific antibiotics by small companion animal (SCA), equine and livestock veterinarians, which broadly aligned with antibiotic registration restrictions in Australia. SCA veterinarians reported prescribing broad-spectrum antibiotics of higher importance to human health more frequently than livestock veterinarians. Factors that were reported as 'strong' or 'moderate' barriers to appropriate antibiotic prescribing were the 1) cost of culture and susceptibility testing and 2) lack of access to rapid and affordable diagnostic tests. Fear of losing clients, colleague pressure, and lack of their own understanding about antibiotics were considered to be 'no' or 'somewhat' of a barrier to appropriate prescribing by respondents. SCA veterinarians placed greater importance on the contribution of antibiotic use in livestock to AMR, than antibiotic use in companion animals. Despite reporting use of fewer, mostly narrow spectrum antibiotics of lower importance to human and animal health, livestock veterinarians were generally more aware of their potential contribution to AMR. This study provides insights into the similarities and differences in SCA, equine and livestock veterinarians practicing in Australia and informs sector-specific strategies to improve antimicrobial stewardship. [ABSTRACT FROM AUTHOR]

Transforming growth factor‑β1 (TGF-β1) is a versatile cytokine. It has context-dependent pro- and anti-cell proliferation functions. Activation of latent TGF-β1 requires release of the growth factor from pro-complexes and is regulated through TGF-β binding proteins. Two types of TGF-β binding partners, latent TGF-β-binding proteins (LTBPs) and leucine-rich-repeat-containing protein 32 (LRRC32), have been identified and their expression are cell specific. TGF-β1 also plays important roles in acute myeloid leukemia (AML) cells. However, the expression of LTBPs and LRRC32 are lacking in myeloid lineage cells and the binding protein of TGF-β1 in these cells are unknown. Here we show that a novel leucine-rich-repeat-containing protein family member, LRRC33, with high mRNA level in AML cells, to be the binding and regulating protein of TGF-β1 in AML cells. Using two representative cell lines MV4-11 and AML193, we demonstrate that the protein expression of LRRC33 and TGF-β1 are correlated. LRRC33 co-localizes and forms complex with latent TGF-β1 protein on the cell surface and intracellularly in these cells. Similar as in other cell types, the activation of TGF-β1 in MV4-11 and AML193 cells are also integrin dependent. We anticipate our study to be a starting point of more comprehensive research on LRRC33 as novel TGF-β regulating protein and potential non-genomic based drug target for AML and other myeloid malignancy. [ABSTRACT FROM AUTHOR]

Introduction: While extracorporeal membrane oxygenation (ECMO) is effective in preventing further hypoxemia and maintains blood flow in endotoxin-induced shock, ECMO alone does not reverse the hypotension. In this study, we tested whether concurrent vasopressor use with ECMO would provide increased circulatory support and blood flow, and characterized regional blood flow distribution to vital organs. Methods: Endotoxic shock was induced in piglets to achieve a 30% decrease in mean arterial pressure (MAP). Measurements of untreated pigs were compared to pigs treated with ECMO alone or ECMO and vasopressors. Results: ECMO provided cardiac support during vasodilatory endotoxic shock and improved oxygen delivery, but vasopressor therapy was required to return MAP to normotensive levels. Increased blood pressure with vasopressors did not alter oxygen consumption or extraction compared to ECMO alone. Regional microcirculatory blood flow (RBF) to the brain, kidney, and liver were maintained or increased during ECMO with and without vasopressors. Conclusion: ECMO support and concurrent vasopressor use improve regional blood flow and oxygen delivery even in the absence of full blood pressure restoration. Vasopressor-induced selective distribution of blood flow to vital organs is retained when vasopressors are administered with ECMO. [ABSTRACT FROM AUTHOR]

Recent research shows that preschool children born to opioid-dependent mothers are at increased risk for cognitive, psychomotor, attention, and social-emotional adjustment problems. But very little is known about their school-age functioning, particularly their educational achievement. This analysis examined the educational outcomes of a regional cohort of 100 prenatally methadone-exposed children who were prospectively studied from birth to age 9.5 years alongside a comparison group of 110 randomly identified non-exposed children born between 2003 and 2008. At age 9.5, as part of a comprehensive neurodevelopmental evaluation, children's teachers rated their achievement across the school curriculum, and children completed the Woodcock Johnson-III Tests of Achievement (WJ-III). Detailed information about the birth mother's social background, pregnancy substance use, and mental health was also collected during pregnancy/at term. Infant clinical data were collected after birth. Methadone-exposed children performed less well than non-exposed children across seven school curriculum areas rated by teachers (ps ≤.001), performed less well than non-exposed children on all reading and mathematics subtests of the WJ-III, and had higher rates of any educational delay on the WJ-III (57% vs. 15%), OR = 7.47 (3.71–15.02). Results were similar when children with severe intellectual impairment were excluded. After adjusting for confounding factors, methadone-exposed children had increased odds of educational delay, but this was only marginally significant (OR = 3.62, [1.01–13.01], p = .049). Maternal educational attainment level (OR = 0.69, [0.50–0.89], p = .006), and maternal benzodiazepine use during pregnancy (OR = 2.70 [1.03–7.12], p = .044) were also associated with later educational risk. Findings suggest that children born to opioid-dependent women enrolled in methadone maintenance are at high risk of educational delay by age 9.5 years. Children's academic difficulties appeared to reflect the effects of both adverse prenatal exposures and postnatal social risk. [ABSTRACT FROM AUTHOR]

Three human clinical isolates of bacteria (designated strains Em1, Em2 and Em3) had high average nucleotide identity (ANI) to Elizabethkingia meningoseptica. Their genome sizes (3.89, 4.04 and 4.04 Mb) were comparable to those of other Elizabethkingia species and strains, and exhibited open pan-genome characteristics, with two strains being nearly identical and the third divergent. These strains were susceptible only to trimethoprim/sulfamethoxazole and ciprofloxacin amongst 16 antibiotics in minimum inhibitory tests. The resistome exhibited a high diversity of resistance genes, including 5 different lactamase- and 18 efflux protein- encoding genes. Forty-four genes encoding virulence factors were conserved among the strains. Sialic acid transporters and curli synthesis genes were well conserved in E. meningoseptica but absent in E. anophelis and E. miricola. E. meningoseptica carried several genes contributing to biofilm formation. 58 glycoside hydrolases (GH) and 25 putative polysaccharide utilization loci (PULs) were found. The strains carried numerous genes encoding two-component system proteins (56), transcription factor proteins (187~191), and DNA-binding proteins (6~7). Several prophages and CRISPR/Cas elements were uniquely present in the genomes. [ABSTRACT FROM AUTHOR]

Stock price prediction is a popular yet challenging task and deep learning provides the means to conduct the mining for the different patterns that trigger its dynamic movement. In this paper, the task is to predict the close price for 25 companies enlisted at the Bucharest Stock Exchange, from a novel data set introduced herein. Towards this scope, two traditional deep learning architectures are designed in comparison: a long short-memory network and a temporal convolutional neural model. Based on their predictions, a trading strategy, whose decision to buy or sell depends on two different thresholds, is proposed. A hill climbing approach selects the optimal values for these parameters. The prediction of the two deep learning representatives used in the subsequent trading strategy leads to distinct facets of gain. [ABSTRACT FROM AUTHOR]

Abortion is uniquely connected to women's experiences yet women's attitudes towards legal abortion vary across the pro-choice/anti-abortion spectrum. Existing research has focused on sociodemographic characteristics to explain women's levels of abortion support. Here, we argue that abortion attitudes vary with women's perceptions of gender linked fate, or the extent to which some women see their fates as tied to other women. Drawing upon existing research showing that married white women report lower levels of gender linked fate than their non-married counterparts, we assess these relationships for abortion attitudes applying the 2012 American National Election Survey (n = 2,173). Using mediation analysis, we show that lower levels of gender linked fate among married white women (vs. non-married white women) explain their stronger opposition to abortion. As many state governments are increasingly legislating restricted access to legal abortion, understanding factors explaining opposition to legal abortion is urgently important. [ABSTRACT FROM AUTHOR]

Purple seed stain (PSS) of soybean (Glycine max (L.) Merr.) is a prevalent seed disease. It results in poor seed quality and reduced seed lot market grade, and thus undermines value of soybean worldwide. The objectives of this research were to evaluate the reaction of selected soybean genotypes collected from 15 countries representing maturity groups (MGs) III, IV, and V to PSS, and to identify new sources of resistance to PSS based on three years of evaluation of natural field infection by Cercospora spp. in the Mississippi Delta of the U. S. In this study, 42 soybean genotypes were evaluated in 2010, 2011, and 2012. Seventeen lines including six MG III (PI 88490, PI 504488, PI 417361, PI 548298, PI 437482, and PI 578486), seven MG IV (PI 404173, PI 346308, PI 355070, PI 416779, PI 80479, PI 346307, and PI 264555), and four MG V (PI 417567, PI 417420, PI 381659, and PI 407749) genotypes had significantly lower percent seed infection by Cercospora spp. than the susceptible checks and other genotypes evaluated (P ≤ 0.05). These genotypes of soybean can be used in developing soybean cultivars or germplasm lines with resistance to PSS and for genetic mapping of PSS resistance genes. In addition, among these 17 lines with different levels of resistance to PSS, nine soybean genotypes (PI 417361, PI 504488, PI 88490, PI 346308, PI 416779, PI 417567, PI 381659, PI 417567, and PI 407749) were previously reported as resistant to Phomopsis seed decay. Therefore, they could be useful in breeding programs to develop soybean cultivars with improved resistance to both seed diseases. [ABSTRACT FROM AUTHOR]

Background: Pancreatic islets are heavily vascularized in vivo yet lose this vasculature after only a few days in culture. Determining how to maintain islet vascularity in culture could lead to better outcomes in transplanting this tissue for the treatment of type 1 diabetes as well as provide insight into the complex communication between beta-cells and endothelial cells (ECs). We previously showed that islet ECs die in part due to limited diffusion of serum albumin into the tissue. We now aim to determine the impact of hypoxia on islet vascularization. Methods: We induced hypoxia in cultured mouse islets using the hypoxia mimetic cobalt chloride (100 μM CoCl2). We measured the impact on islet metabolism (two-photon NAD(P)H and Rh123 imaging) and function (insulin secretion and survival). We also measured the impact on hypoxia related transcripts (HIF-1α, VEGF-A, PDK-1, LDHA, COX4) and confirmed increased VEGF-A expression and secretion. Finally, we measured the vascularization of islets in static and flowing culture using PECAM-1 immunofluorescence. Results: CoCl2 did not induce significant changes in beta cell metabolism (NAD(P)H and Rh123), insulin secretion, and survival. Consistent with hypoxia induction, CoCl2 stimulated HIF-1α, PDK-1, and LDHA transcripts and also stimulated VEGF expression and secretion. We observed a modest switch to the less oxidative isoform of COX4 (isoform 1 to 2) and this switch was noted in the glucose-stimulated cytoplasmic NAD(P)H responses. EC morphology and survival were greater in CoCl2 treated islets compared to exogenous VEGF-A in both static (dish) and microfluidic flow culture. Conclusions: Hypoxia induction using CoCl2 had a positive effect on islet EC morphology and survival with limited impact on beta-cell metabolism, function, and survival. The EC response appears to be due to endogenous production and secretion of angiogenic factors (e.g. VEGF-A), and mechanistically independent from survival induced by serum albumin. [ABSTRACT FROM AUTHOR]

Objectives: Hepatitis C virus (HCV) causes both acute and chronic infection, which can potentially develop into cirrhosis and liver cancer. Healthcare systems are struggling to finance costly direct-acting antiviral agents through public funding for uninsured patients, despite the unprecedented high cure rates of these agents. Vulnerable populations are at higher risk of HCV infection. The personal importation scheme is based on the legal right to import any unauthorized generics for personal use. This study was designed to assess the knowledge and perceptions of stakeholders on unauthorized generics. Methods: We conducted an anonymous online survey based on the fictitious situation of a patient diagnosed with HCV who lacked mandatory health insurance and personal financial resources. Results: We obtained a sample of 781 respondents: 445 physicians, 77 pharmacists, 51 patients and 207 non-healthcare professionals. We found that only 36% and 58% of respondents believe that the quality and efficacy, respectively, of unauthorized generics are equivalent to their corresponding brand. An overwhelming majority (98%) favoured quality control upon arrival, and 31% felt they could recognize fraudulent websites. A total of 79% expressed support for financial assistance for vulnerable patients, and support among physicians was 83%. Conclusions: Overall, the limited knowledge of the efficacy and quality of unauthorized generics, despite evidence in peer-reviewed literature, contrasts with the overwhelmingly positive attitudes toward financial assistance for personal import. This finding emphasizes the need for clearer information on imported generics and the potential safety provided by buyers' club schemes to complete the WHO agenda of eradicating viral hepatitis by 2030 within otherwise excluded vulnerable populations. [ABSTRACT FROM AUTHOR]

In the pig, intrauterine competition (IUC) greatly affects postnatal traits, such as birth weight, but also locomotor capacities. In a previous study, our group discovered a lower motor performance in piglets with a low birth weight and low vitality (L piglets), compared to piglets with a normal birth weight and normal vitality (N piglets). In order to explain the force deficit causing this reduced motor performance, in a subsequent study, we investigated whether this deficit in L piglets was caused by a lower force generating capacity (FGC) of the extensors of the hind limb and/or a lower number of type II (fast-twitch) fibers in m. vastus lateralis. L piglets had a lower absolute FGC, but surprisingly, a higher relative FGC (to birth weight) in the hind limb, compared to N piglets. In addition, we found no differences in fiber composition of m. vastus lateralis. In the present study, we assessed whether this higher relative FGC is a common feature for front and hind limb locomotor muscles of L piglets. To that end, the physiological cross-sectional area of the main extensor muscles of the front limb was calculated from their volume and fiber length, in order to calculate both the absolute and the relative FGC. By immunohistochemical staining of m. triceps brachii caput longum, the percentage of type II (fast-contracting) fibers could be determined. Similar to the results of the hind limb, we found a smaller absolute FGC, but a larger relative FGC in the front limb of L piglets, compared to N piglets. In addition, m. triceps brachii caput longum did not have a different muscle fiber composition in L and N piglets. As such, we can conclude that IUC affects the locomotor muscles in the front and hind limb in a similar way and that the observed force deficit in L piglets cannot be explained by a different force generating capacity or a lower percentage of type II muscle fibers. [ABSTRACT FROM AUTHOR]

Early clinical successes are driving enthusiasm for fecal microbiota transplantation (FMT), the transfer of healthy gut bacteria through whole stool, as emerging research is linking the microbiome to many different diseases. However, preliminary trials have yielded mixed results and suggest that heterogeneity in donor stool may play a role in patient response. Thus, clinical trials may fail because an ineffective donor was chosen rather than because FMT is not appropriate for the indication. Here, we describe a conceptual framework to guide rational donor selection to increase the likelihood that FMT clinical trials will succeed. We argue that the mechanism by which the microbiome is hypothesized to be associated with a given indication should inform how healthy donors are selected for FMT trials, categorizing these mechanisms into four disease models and presenting associated donor selection strategies. We next walk through examples based on previously published FMT trials and ongoing investigations to illustrate how donor selection might occur in practice. Finally, we show that typical FMT trials are not powered to discover individual taxa mediating patient responses, suggesting that clinicians should develop targeted hypotheses for retrospective analyses and design their clinical trials accordingly. Moving forward, developing and applying novel clinical trial design methodologies like rational donor selection will be necessary to ensure that FMT successfully translates into clinical impact. [ABSTRACT FROM AUTHOR]

Objective: Analyze if in utero exposure to economic downturns is associated with worsened birth outcomes. Methods: We used birth records from all live singleton births in the 27 Brazilian state capitals between October 2012 and December 2016 (n = 2,952,430) and linked them to local unemployment rates according to the mother's residence. We estimated the association between different birth outcomes and the local unemployment rate in the three trimesters before birth. We included maternal characteristics and month, year and municipality fixed effects as covariates. We also estimated the association for different groups of mothers, based on marital status, educational level, age and race. Results: A 1 p.p. increase in the local unemployment rate in the trimester before birth is associated with 2.68% higher odds of being born with very low birthweight (< 1500 grams) (OR: 1.0268, 95% CI: 1.0006–1.0536). That result is pushed by the effect among newborns from mothers younger than 24 (OR: 1.0684, 95%CI: 1.0353–1.1024), from mothers with 11 years of schooling or less (OR: 1.0477, 95% CI: 1.0245–1.0714), and from brown or black mothers (OR: 1.0387, 95%CI: 1.0156–1.0624). The associations among children born from younger, less educated and black or brown mothers are robust to the application of a procedure to control for multiple testing, albeit the results considering the whole sample are not. Conclusions: Our study shows that there is an association between in utero exposure to higher unemployment rates during the last gestational trimester and the odds of being born with VLBW among children born from mothers younger than 24 years old, with less of 11 years of education and black or brown. These results suggest that children born from women of low socioeconomic status are more vulnerable to in utero exposure to economic downturns. [ABSTRACT FROM AUTHOR]

Superoxide dismutases (SODs), as a family of metalloenzymes related to the removal of reactive oxygen species (ROS), have not previously been investigated at genome-wide level in tea plant. In this study, 10 CsSOD genes were identified in tea plant genome, including 7 Cu/Zn-SODs (CSDs), 2 Fe-SODs (FSDs) and one Mn-SOD (MSD), and phylogenetically classified in three subgroups, respectively. Physico-chemical characteristic, conserved motifs and potential protein interaction analyses about CsSOD proteins were carried out. Exon-intron structures and codon usage bias about CsSOD genes were also examined. Exon-intron structures analysis revealed that different CsSOD genes contained various number of introns. On the basis of the prediction of regulatory miRNAs of CsSODs, a modification 5' RNA ligase-mediated (RLM)-RACE was performed and validated that csn-miR398a-3p-1 directly cleaves CsCSD4. By prediction of cis-acting elements, the expression patterns of 10 CsSOD genes and their regulatory miRNAs were detected under cold, drought, exogenous methyl jasmonate (MeJA) and gibberellin (GA3) treatments. The results showed that most of CsSODs except for CsFSD2 were induced under cold stress and CsCSDs may play primary roles under drought stress; exogenous GA3 and MeJA could also stimulated/inhibited distinct CsSODs at different stages. In addition, we found that csn-miR398a-3p-1 negatively regulated the expression of CsCSD4 may be a crucial regulatory mechanism under cold stress. This study provides a certain basis for the studies about stress resistance in tea plants, even provide insight into comprehending the classification, evolution, diverse functions and influencing factors of expression patterns for CsSOD genes. [ABSTRACT FROM AUTHOR]

Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and hyperplasia, as well as cartilage and bone destruction. Several proteins are associated with the pathogenesis of the disease. Galectin-9 belongs to the family of lectins that are involved in various biological processes and have anti-inflammatory activity. Objective: To investigate associations between the SNPs of the GAL-9 gene (LGALS9) and serum levels in rheumatoid arthritis patients. We extracted DNA from 356 subjects, 156 RA patients and 200 healthy controls from northeastern Brazil. Three polymorphisms (rs4795835, rs3763959, and rs4239242) in the LGALS9 gene were selected and genotyped using TaqMan SNP genotyping assay. Serum concentrations of galectin-9 were analyzed by ELISA. Results: The rs4239242 TT genotype showed a positive association with RA (p = 0.0032, odds ratio = 0.28), and heterozygous TC were prevalent in the control group compared to RA patients (p = 0.0001, odds ratio = 7.99). Galectin-9 serum levels were significantly increased in RA patients compared to the control group (p<0.0001). Patients in remission had high levels of galectin compared to the moderate activity group (p<0.0001). Regarding the Clinical Disease Activity Index (CDAI), patients in remission or low activity presented high levels of galectin when compared to patients in severity (p<0.0001). Patients performing moderate activity had a significant value compared to patients who were in high disease severity (p = 0.0064). Interestingly, the AG genotype (rs3763959) has been associated with a higher presence of bone erosion in RA patients (p = 0.0436). The SNP rs4239242 TT genotype showed a positive association with RA in comparison to the control group. The AG genotype (rs3763959) has been associated with a higher presence of bone erosion in RA patients. [ABSTRACT FROM AUTHOR]

Fertility in Ghana has declined steadily since 1980, however, a slight increase was observed between 2008 and 2014. While several factors may account for this pattern, research on the contribution of type of union is limited. This study examined differentials in the fertility of women in different types of union. Secondary data from 6,285 (weighted) ever-married women aged 15–49 years were analysed using compare means, t-test, analysis of variance, Poisson and binary logistic regression analyses. The findings indicate that, independent of other factors, fertility among remarried women is higher compared to first-time married women but this does not hold true when other factors are controlled for. Additionally, there was no significant difference in the fertility of remarried women who were in union and women who were in union in a first-time marriage. However, compared to remarried women who were currently in a union, fertility was significantly lower among remarried women who were not currently in union (β = -0.121, p<0.01) and women who have been married only once but were not currently in union (β = -0.212, p<0.001). Further analysis revealed that remarried women were significantly more likely to desire more children and less likely to use any method of contraception compared to first-time married women. There is the need for further research to better understand the fertility needs of remarried women. [ABSTRACT FROM AUTHOR]

Many in vivo studies suggest that inhalational anesthetics can accelerate or prevent the progression of neuropathology and cognitive impairments in Alzheimer Disease (AD), but the synaptic mechanisms mediating these ambiguous effects are unclear. Here, we show that repeated exposures of neonatal and old triple transgenic AD (3xTg) and non-transgenic (NonTg) mice to isoflurane (Iso) distinctly increased neurodegeneration as measured by S100β levels, intracellular Aβ, Tau oligomerization, and apoptotic markers. Spatial cognition measured by reference and working memory testing in the Morris Water Maze (MWM) were altered in young NonTg and 3xTg. Field recordings in the cornu ammonis 1 (CA1) hippocampus showed that neonatal control 3xTg mice exhibited hypo-excitable synaptic transmission, reduced paired-pulse facilitation (PPF), and normal long-term potentiation (LTP) compared to NonTg controls. By contrast, the old control 3xTg mice exhibited hyper-excitable synaptic transmission, enhanced PPF, and unstable LTP compared to NonTg controls. Repeated Iso exposures reduced synaptic transmission and PPF in neonatal NonTg and old 3xTg mice. LTP was normalized in old 3xTg mice, but reduced in neonates. By contrast, LTP was reduced in old but not neonatal NonTg mice. Our results indicate that Iso-mediated neuropathologic and cognitive defects in AD mice are associated with synaptic pathologies in an age-dependent manner. Based on these findings, the extent of this association with age and, possibly, treatment paradigms warrant further study. [ABSTRACT FROM AUTHOR]