Miracle-dz/UniFAR-FTUs huggingface dataset:
Calcium Current Inactivation Rather than Pool Depletion Explains Reduced Exocytotic Rate with Prolonged Stimulation in Insulin-Secreting INS-1 832/13 Cells

Impairment in beta-cell exocytosis is associated with reduced insulin secretion and diabetes. Here we aimed to investigate the dynamics of Ca2+-dependent insulin exocytosis with respect to pool depletion and Ca2+-current inactivation. We studied exocytosis, measured as increase in membrane capacitance (ΔCm), as a function of calcium entry (Q) in insulin secreting INS-1 832/13 cells using patch clamp and mixed-effects statistical analysis. The observed linear relationship between ΔCm and Q suggests that Ca2+-channel inactivation rather than granule pool restrictions is responsible for the decline in exocytosis observed at longer depolarizations. INS-1 832/13 cells possess an immediately releasable pool (IRP) of ∼10 granules and most exocytosis of granules occurs from a large pool. The latter is attenuated by the calcium-buffer EGTA, while IRP is unaffected. These findings suggest that most insulin release occurs away from Ca2+-channels, and that pool depletion plays a minor role in the decline of exocytosis upon prolonged stimulation.
The Relationship between Physical Activity Intensity and Mental Health Status in Patients with Breast Cancer

The aim of this study was to investigate the correlation between physical activity (PA) level and mental health status in a population-based sample of Korean female patients with breast cancer. Our analysis included 76 patients with breast cancer and 44 healthy controls. The Korean versions of the International Physical Activity Questionnaire (IPAQ), Beck Depressive Inventory (BDI), State-Trait Anxiety Inventory-KY (STAI-KY), and Somatosensory Amplification Scale (SSAS), and Quality of Life (QOL) scale were assessed. The frequency of moderate PA level in breast cancer patients was significantly lower than that of healthy control subjects (t = −2.6; P = 0.011). In turn, the incidence of low PA level in breast cancer patients was significantly higher than that observed in healthy controls (t = 2.85; P = 0.005). A moderate PA level was inversely correlated with BDI score (r = −0.35; P = 0.008) and was positively correlated with QOL score (r = 0.38; P = 0.011). A low level of PA was inversely correlated with SSAS score (r = −0.39; P < 0.001). In healthy controls, a high level of PA was positively correlated with QOL score (r = 0.50; P = 0.043). Moderate PA level was inversely correlated with SSAS score (r = −0.59; P < 0.001). A low level of PA was also positively correlated with BDI score (r = 0.35; P = 0.008). A moderate or low intensity of PA was inversely correlated with depression and somatosensory amplification and was positively correlated with QOL in breast cancer patients. Finally, we suggest that progressively low-to-moderate levels of PA can be well adapted to positively impact several measures of mental health.
Response of Vegetation and Soil Carbon and Nitrogen Storage to Grazing Intensity in Semi-Arid Grasslands in the Agro-Pastoral Zone of Northern China

Overgrazing has been the primary cause of grassland degradation in the semi-arid grasslands of the agro-pastoral transition zone in northern China. However, there has been little evidence regarding grazing intensity impacts on vegetation change and soil C and N dynamics in this region. This paper reports the effects of four grazing intensities namely un-grazed (UG), lightly grazed (LG), moderately grazed (MG) and heavily grazed (HG) on vegetation characteristics and soil properties of grasslands in the Guyuan county in the agro-pastoral transition region, Hebei province, northern China. Our study showed that the vegetation height, canopy cover, plant species abundance and aboveground biomass decreased significantly with increased grazing intensity. Similarly, soil organic carbon (SOC) and total nitrogen (STN) in the 0–50 cm were highest under UG (13.3 kg C m−2 and 1.69 kg N m−2) and lowest under HG (9.8 kg C m−2 and 1.22 kg N m−2). Soil available nitrogen (SAN) was significantly lower under HG (644 kg N hm−2) than under other treatments (725–731 kg N hm−2) in the 0–50 cm. Our results indicate that the pasture management of “take half-leave half” has potential benefits for primary production and livestock grazing in this region. However, grazing exclusion was perhaps the most effective choice for restoring degraded grasslands in this region. Therefore, flexible rangeland management should be adopted in this region.
Clinical significance of changes in the Th17/Treg ratio in autoimmune liver disease

AIM To investigate the levels, ratios, and clinical significance of T helper 17 (Th17) cells and regulatory T (Treg) cells in the peripheral blood of patients with autoimmune liver disease (AILD). METHODS Forty-two AILD patients were included in the experimental group (group E), and 11 healthy subjects were recruited as the control group (group C). Flow cytometry was performed to determine the percentages of Th17 and Treg cells in peripheral blood lymphocytes. Furthermore, a range of biochemical indices was measured simultaneously in the blood of group E patients. RESULTS The percentage of Th17 cells and the Th17/Treg ratio were higher in group E than in group C (P < 0.01), whereas the percentage of Tregs was lower in the group E patients (P < 0.05). Patients in group E who were admitted with AILD in the active stage showed significantly higher Th17 percentages and Th17/Treg ratios than those measured in patients with AILD in remission (P < 0.05). In addition, among patients with AILD in the active stage, individuals that remained unhealed after hospitalization showed significantly higher baseline values of the Th17 percentage and the Th17/Treg ratio than those detected in patients who improved after treatment (P < 0.05). The results suggested that imbalance in the Th17/Treg ratio plays an important role in the pathogenesis and development of AILD. CONCLUSION A high Th17/Treg ratio appears to predict poor short-term prognosis in patients with AILD in the active stage.
Intracellular metabolic pathway distribution in diatoms and tools for genome-enabled experimental diatom research

Diatoms are important primary producers in the oceans and can also dominate other aquatic habitats. One reason for the success of this phylogenetically relatively young group of unicellular organisms could be the impressive redundancy and diversity of metabolic isoenzymes in diatoms. This redundancy is a result of the evolutionary origin of diatom plastids by a eukaryote–eukaryote endosymbiosis, a process that implies temporary redundancy of functionally complete eukaryotic genomes. During the establishment of the plastids, this redundancy was partially reduced via gene losses, and was partially retained via gene transfer to the nucleus of the respective host cell. These gene transfers required re-assignment of intracellular targeting signals, a process that simultaneously altered the intracellular distribution of metabolic enzymes compared with the ancestral cells. Genome annotation, the correct assignment of the gene products and the prediction of putative function, strongly depends on the correct prediction of the intracellular targeting of a gene product. Here again diatoms are very peculiar, because the targeting systems for organelle import are partially different to those in land plants. In this review, we describe methods of predicting intracellular enzyme locations, highlight findings of metabolic peculiarities in diatoms and present genome-enabled approaches to study their metabolism. This article is part of the themed issue ‘The peculiar carbon metabolism in diatoms’.
Vitamin D supplementation for improvement of chronic low‐grade inflammation in patients with type 2 diabetes: a systematic review and meta‐analysis of randomized controlled trials

Background Vitamin D has been proposed to have anti‐inflammatory properties; however, the effect of vitamin D supplementation on inflammation in type 2 diabetes has not been established. Objective The aim of this systematic review and meta‐analysis was to examine the effect of vitamin D supplementation on inflammatory markers in patients with type 2 diabetes and to identify relevant gaps in knowledge. Data sources MEDLINE, CINAHL, Embase, and EBM Reviews were searched systematically from inception to January 25, 2017. Study selection Randomized controlled trials (RCTs) investigating the effects of vitamin D supplementation (any form, route, and duration, and with any cosupplementation) compared with placebo or usual care on inflammatory markers in patients with type 2 diabetes were selected. Data extraction Study and sample characteristics and aggregate outcome data were extracted, risk of bias was determined, and quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Results Twenty‐eight RCTs were included, 20 of which had data available for pooling. In meta‐analyses of 20 RCTs (n = 1270 participants), vitamin D‐supplemented groups had lower levels of C‐reactive protein (standardized mean difference [SMD] −0.23; 95%CI, −0.37 to −0.09; P = 0.002) and tumor necrosis factor &agr; (SMD −0.49; 95%CI, −0.84 to −0.15; P = 0.005), a lower erythrocyte sedimentation rate (SMD −0.47; 95%CI, −0.89 to −0.05; P = 0.03), and higher levels of leptin (SMD 0.42; 95%CI, 0.04‐0.81; P = 0.03) compared with control groups. No differences were observed for adiponectin, interleukin 6, or E‐selectin (all P > 0.05). In meta‐regression and subgroup analyses, age, sex, body mass index, duration of diabetes, baseline vitamin D status, and dose and duration of supplementation did not alter the results. Conclusions This meta‐analysis provides level 1 evidence that vitamin D supplementation may reduce chronic low‐grade inflammation in patients with type 2 diabetes. Systematic Review Registration PROSPERO CRD42016047755. Available at: https://www.crd. york.ac. uk/prospero/display_record. php? RecordID=47755 (9/15/2016).
Clinical Features of Atopic Dermatitis in Adults Are Different according to Onset

Few studies of atopic dermatitis (AD) in adult patients have evaluated differences in clinical features of AD according to onset age. We aimed to characterize the clinical features of AD in adult patients according to age of onset. Subjects with AD outpatient visiting the Department of Dermatology at Kangnam Sacred Heart Hospital were recruited for this study. A dermatologist conducted clinical evaluation, a survey of demographics, and onset of AD-associated signs and symptoms for each participant. Total immunoglobulin E (IgE) was also tested. A total of 280 adult AD patients were enrolled, among which 232 patients (82.86%) showed pre-adult-onset (age < 18 years) and 48 patients (17.14%) had adult-onset (age ≥ 18 years) of AD. There were significant differences between the 2 groups in the area of initial involvement (P = 0.017) and in treatment history (P = 0.010). Interestingly, patients with body mass index (BMI) ≥ 25 showed significantly higher Eczema Area and Severity Index (EASI) scores than did patients with BMI < 25 in the pre-adult-onset adult AD group (P = 0.048). On the other hand, there were no significant differences in sex, family history, BMI, EASI, and total IgE between patients with pre-adult-onset AD and patients with adult-onset AD. Our findings suggest that, even though many common features exist, there are significant differences between the clinical characteristics of pre-adult-onset and adult-onset AD subgroups, in adult patients with AD.
The experience of couples being given an oxygen concentrator to use at home: A longitudinal interpretative phenomenological analysis

This longitudinal study explores the lived experience of four couples where one person from each couple is prescribed an oxygen concentrator to use at home. Transcripts were analysed using interpretative phenomenological analysis. The findings reported here focus on two super-ordinate themes: ‘the journey of acceptance’ and ‘negotiating changing relationships’. Participants described a gradual process of accepting the device into their lives, the impact on couple’s relationships and the role that expectations have in mediating that process. These themes suggest that patient education that considers the psychological and social issues may prove useful in facilitating the acceptance process.
The effect of different concentrations of topical ozone administration on bone formation in orthopedically expanded suture in rats.

BACKGROUND/OBJECTIVE The aim of this study was to investigate the effects of different concentrations of ozone (O3) therapy on bone regeneration in response to an expansion of the inter-premaxillary suture in rats. MATERIALS AND METHODS Forty-eight Wistar rats were randomly divided into four groups (n = 12). In groups I, II, and III, 1ml of O3 at 10, 25, and 40 µg/ml was injected at the premaxillary suture, respectively. In group IV (control group), 1ml of saline solution was injected at the same point during the expansion procedure for 5 days. Bone regeneration in the suture was evaluated histomorphometrically. The area of new bone and fibrotic area, the number of osteoblasts and osteoclasts, and the amount of vascularity were measured and compared. The density of the newly formed bone in the expansion area was measured by using cone beam computed tomography. Data were analyzed using the Kruskal-Wallis one-way analysis of variance and post hoc Student-Newman-Keuls tests. RESULTS New bone area, fibrotic area, osteoblast and osteoclast numbers, and the amount of vascularity were significantly higher in experimental groups compared with the control group (P < 0.001). The density of newly formed bone (P < 0.001), new bone formation (P = 0.009), number of capillaries (P < 0.001), number of osteoclasts (P = 0.016), and number of osteoblasts (P < 0.001) in the maxillary sutures were highest in the 25 μg/ml O3 group compared with the other experimental groups and control group. CONCLUSIONS/IMPLICATIONS The application of O3 therapy can stimulate bone regeneration in an orthopedically expanded inter-premaxillary suture during both the expansion and retention periods.
Effect of modified atmosphere on the storage life and quality of Eksotika papaya

Storage in modified atmosphere at 10 °C extended the storage life of Eksotika papaya. The packaging technique and composition of gases in the storage environment played important roles during storage. Bulk packaging (9–10 fruit/ pack) containing CO 2 and O 2 at 5% and 4% respectively helped to extend the storage life up to 3–4 weeks. The storage life was extended to about 5–6 weeks when the fruit were wrapped individually with gas composition in the environment containing 4% CO 2 and 8% O 2 . The use of ethylene absorbent during storage was also effective in reducing the ethylene gas content and thus the ripening process was retarded. With these conditions, the freshness of the fruit was maintained during storage without significant changes in the skin colour and fruit quality. Fruit ripened normally within 3–4 days when transferred to ambient temperature. The skin changed to yellow, and the pulp quality was still good and acceptable.
“I Don’t Know” My Cancer Risk

Background: Perceived risk is a central theoretical construct in health behavior research. Participants’ “don’t know” responses to perceived-risk items (DKPR) are usually excluded from analyses. Yet those who provide such responses may have unique cancer information needs. Objective: The hypotheses that DKPR responding may be due to cancer knowledge deficits or behavioral, skill, and attitudinal antecedents to knowledge deficits (information seeking, numeracy, and self-efficacy, respectively) were explored. Methods: Data from the 2005 Health Information National Trends Survey (HINTS; N = 1789), a US population-based survey, and an urban, minority, primary care clinic survey (N = 590) were analyzed. Multivariable logistic regressions were conducted to examine knowledge deficit explanations for responding DKPR to colon cancer risk perception questions (adjusting for demographics and family colorectal cancer history). Measures: Comparative (HINTS) and absolute verbal perceived risk of colon cancer (HINTS, clinic survey), knowledge of colon cancer risks and screening, cancer/health information-seeking behavior and self-efficacy (HINTS), and numeracy (clinic survey). Results: Greater knowledge of colon cancer prevention and screening, cancer and health information seeking, and numeracy were each associated with lower odds of providing a DKPR response. Limitations: The study was cross-sectional, which limits the ability to infer causal direction. The use of existing data sets limited our variable choices. Other plausible hypotheses may also explain DKPR responding. Conclusions: People who report that they don’t know their colon cancer risk may have low cancer knowledge and reduced knowledge acquisition behaviors and skills. Health behavior research could benefit from including data concerning DKPR responses to risk perception questions, because individuals who respond in this way may require interventions to address potential cancer risk knowledge deficits.
Rab GTPases in cilium formation and function

ABSTRACT Cilia are microtubule-based organelles extending from a basal body at the surface of eukaryotic cells. Cilia regulate cell and fluid motility, sensation and developmental signaling, and ciliary defects cause human diseases (ciliopathies) affecting the formation and function of many tissues and organs. Over the past decade, various Rab and Rab-like membrane trafficking proteins have been shown to regulate cilia-related processes such as basal body maturation, ciliary axoneme extension, intraflagellar transport and ciliary signaling. In this review, we provide a comprehensive overview of Rab protein ciliary associations, drawing on findings from multiple model systems, including mammalian cell culture, mice, zebrafish, C. elegans, trypanosomes, and green algae. We also discuss several emerging mechanistic themes related to ciliary Rab cascades and functional redundancy.
US-Based Drug Cost Parameter Estimation for Economic Evaluations

Introduction. In the United States, more than 10% of national health expenditures are for prescription drugs. Assessing drug costs in US economic evaluation studies is not consistent, as the true acquisition cost of a drug is not known by decision modelers. Current US practice focuses on identifying one reasonable drug cost and imposing some distributional assumption to assess uncertainty. Methods. We propose a set of Rules based on current pharmacy practice that account for the heterogeneity of drug product costs. The set of products derived from our Rules, and their associated costs, form an empirical distribution that can be used for more realistic sensitivity analyses and create transparency in drug cost parameter computation. The Rules specify an algorithmic process to select clinically equivalent drug products that reduce pill burden, use an appropriate package size, and assume uniform weighting of substitutable products. Three diverse examples show derived empirical distributions and are compared with previously reported cost estimates. Results. The shapes of the empirical distributions among the 3 drugs differ dramatically, including multiple modes and different variation. Previously published estimates differed from the means of the empirical distributions. Published ranges for sensitivity analyses did not cover the ranges of the empirical distributions. In one example using lisinopril, the empirical mean cost of substitutable products was $444 (range = $23–$953) as compared with a published estimate of $305 (range = $51–$523). Conclusions. Our Rules create a simple and transparent approach to creating cost estimates of drug products and assessing their variability. The approach is easily modified to include a subset of, or different weighting for, substitutable products. The derived empirical distribution is easily incorporated into 1-way or probabilistic sensitivity analyses.
Targeting the 5T4 oncofetal glycoprotein with an antibody drug conjugate (A1mcMMAF) improves survival in patient-derived xenograft models of acute lymphoblastic leukemia

Outcome in childhood acute lymphoblastic leukemia is prognosticated from levels of minimal residual disease after remission induction therapy. Higher levels of minimal residual disease are associated with inferior results even with intensification of therapy, thus suggesting that identification and targeting of minimal residual disease cells could be a therapeutic strategy. Here we identify high expression of 5T4 in subclonal populations of patient-derived xenografts from patients with high, post-induction levels of minimal residual disease. 5T4-positive cells showed preferential ability to overcome the NOD-scidIL2Rγnull mouse xenograft barrier, migrated in vitro on a CXCL12 gradient, preferentially localized to bone marrow in vivo and displayed the ability to reconstitute the original clonal composition on limited dilution engraftment. Treatment with A1mcMMAF (a 5T4-antibody drug conjugate) significantly improved survival without overt toxicity in mice engrafted with a 5T4-positive acute lymphoblastic leukemia cell line. Mice engrafted with 5T4-positive patient-derived xenograft cells were treated with combination chemotherapy or dexamethasone alone and then given A1mcMMAF in the minimal residual disease setting. Combination chemotherapy was toxic to NOD-scidIL2Rγnull mice. While dexamethasone or A1mcMMAF alone improved outcomes, the sequential administration of dexamethasone and A1mcMMAF significantly improved survival (P=0.0006) over either monotherapy. These data show that specifically targeting minimal residual disease cells improved outcomes and support further investigation of A1mcMMAF in patients with high-risk B-cell precursor acute lymphoblastic leukemia identified by 5T4 expression at diagnosis.
Chemo-enzymatic synthesis of lipid-linked GlcNAc2Man5 oligosaccharides using recombinant Alg1, Alg2 and Alg11 proteins

Abstract The biosynthesis of eukaryotic lipid-linked oligosaccharides (LLOs) that act as donor substrates in eukaryotic protein N-glycosylation starts on the cytoplasmic side of the endoplasmic reticulum and includes the sequential addition of five mannose units to dolichol-pyrophosphate-GlcNAc2. These reactions are catalyzed by the Alg1, Alg2 and Alg11 gene products and yield Dol-PP-GlcNAc2Man5, an LLO intermediate that is subsequently flipped to the lumen of the endoplasmic reticulum. While the purification of active Alg1 has previously been described, Alg11 and Alg2 have been mostly studied in vivo. We here describe the expression and purification of functional, full length Alg2 protein. Along with the purified soluble domains Alg1 and Alg11, we used Alg2 to chemo-enzymatically generate Dol-PP-GlcNAc2Man5 analogs starting from synthetic LLOs containing a chitobiose moiety coupled to oligoprenyl carriers of distinct lengths (C10, C15, C20 and C25). We found that while the addition of the first mannose unit by Alg1 was successful with all of the LLO molecules, the Alg2-catalyzed reaction was only efficient if the acceptor LLOs contained a sufficiently long lipid tail of four or five isoprenyl units (C20 and C25). Following conversion with Alg11, the resulting C20 or C25 -containing GlcNAc2Man5 LLO analogs were successfully used as donor substrates of purified single-subunit oligosaccharyltransferase STT3A from Trypanosoma brucei. Our results provide a chemo-enzymatic method for the generation of eukaryotic LLO analogs and are the basis of subsequent mechanistic studies of the enigmatic Alg2 reaction mechanism.