Mori Dream Spaces as fine moduli of quiver representations

We construct Mori Dream Spaces as fine moduli spaces of representations of bound quivers, thereby extending results of Craw--Smith \cite{CrawSmith} beyond the toric case. Any collection of effective line bundles $\mathscr{L}=(\mathscr{O}_X, L_1,..., L_r)$ on a Mori Dream Space $X$ defines a bound quiver of sections and a map from $X$ to a toric quiver variety $|\mathscr{L}|$ called the multigraded linear series. We provide necessary and sufficient conditions for this map to be a closed immersion and, under additional assumptions on $\mathscr{L}$, the image realises $X$ as the fine moduli space of $\vartheta$-stable representations of the bound quiver. As an application, we show how to reconstruct del Pezzo surfaces from a full, strongly exceptional collection of line bundles.Comment: 25 pages, 2 figures; v2 section 3 simplified, typos corrected; v3 final versio

Psychosocial determinants of depression in the community of the elderly with cardiovascular disease

The co-morbidity of cardiovascular disease (CVD) and depression is quite frequent in old people, and some potential biological and behavioural mechanisms linking them have been reported. Yet the impact of psychosocial factors on depression in the elderly with CVD remains unclear. This study aimed to analyze the psychosocial determinants of depression in the elderly with CVD. Using the Geriatric Mental Status-Automated Geriatric Examination for Computer Assisted Taxonomy, a community-based household survey was performed in 2,199 elderly people from the Anhui cohort third-wave survey from 2007 to 2009 and an extended study in Hubei from 2010 to 2011. Multiple logistic regression analyses were employed to assess the influence of psychosocial factors on depression. Among them, the prevalence of depression was 4.77%. Three factors were associated with depression in elderly in the community: self-assessed physical health status, anything else severely upsetting and unpleasantness with relatives, friends, or neighbors. In particular, associations of psychosocial factors with depression were more evident in individuals with CVD. This study confirms several psychosocial determinants of depression and the impact of CVD on the associations among the elderly, which provides some clues for interventional strategies of late-life depression

Personalized Estimate of Chemotherapy-Induced Nausea and Vomiting: Development and External Validation of a Nomogram in Cancer Patients Receiving Highly/Moderately Emetogenic Chemotherapy.

Chemotherapy-induced nausea and vomiting (CINV) is presented in over 30% of cancer patients receiving highly/moderately emetogenic chemotherapy (HEC/MEC). The currently recommended antiemetic therapy is merely based on the emetogenic level of chemotherapy, regardless of patient's individual risk factors. It is, therefore, critical to develop an approach for personalized management of CINV in the era of precision medicine.A number of variables were involved in the development of CINV. In the present study, we pooled the data from 2 multi-institutional investigations of CINV due to HEC/MEC treatment in Asian countries. Demographic and clinical variables of 881 patients were prospectively collected as defined previously, and 862 of them had full documentation of variables of interest. The data of 548 patients from Chinese institutions were used to identify variables associated with CINV using multivariate logistic regression model, and then construct a personalized prediction model of nomogram; while the remaining 314 patients out of China (Singapore, South Korea, and Taiwan) entered the external validation set. C-index was used to measure the discrimination ability of the model.The predictors in the final model included sex, age, alcohol consumption, history of vomiting pregnancy, history of motion sickness, body surface area, emetogenicity of chemotherapy, and antiemetic regimens. The C-index was 0.67 (95% CI, 0.62-0.72) for the training set and 0.65 (95% CI, 0.58-0.72) for the validation set. The C-index was higher than that of any single predictor, including the emetogenic level of chemotherapy according to current antiemetic guidelines. Calibration curves showed good agreement between prediction and actual occurrence of CINV.This easy-to-use prediction model was based on chemotherapeutic regimens as well as patient's individual risk factors. The prediction accuracy of CINV occurrence in this nomogram was well validated by an independent data set. It could facilitate the assessment of individual risk, and thus improve the personalized management of CINV

A reception study of machine translated subtitles for MOOCs

As access has grown to online courses in the form of MOOCs (Massive Open Online Courses), the language barrier has become an important issue for users worldwide. Machine translation (MT) appears to offer an alternative or complementary solution to existing forms of MOOC translation. Very little attention has been paid, however, to the use and utility of MT for MOOC content. The main goal of this research is to test the impact machine-translated subtitles have on Chinese viewers’ reception of MOOC content. We are interested in whether there is any difference between viewers’ reception of raw machine-translated subtitles as opposed to fully post-edited machine-translated (PEMT) subtitles and human-translated (HT) subtitles. Based on an eye-tracking experiment conducted at two Chinese universities and survey methods, we show that participants who were offered full PEMT subtitles scored better overall on our reception metrics than those who were offered raw MT subtitles. HT subtitles, on the other hand, did not necessarily lead to better reception as expected; in contrast, the participants who were offered HT subtitles performed the worst in some of our reception metrics

The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice

Nearly every extracellular ligand that has been found to play a role in regulating bone biology acts, at least in part, through MAPK pathways. Nevertheless, much remains to be learned about the contribution of MAPKs to osteoblast biology in vivo. Here we report that the p38 MAPK pathway is required for normal skeletogenesis in mice, as mice with deletion of any of the MAPK pathway member–encoding genes MAPK kinase 3 (Mkk3), Mkk6, p38a, or p38b displayed profoundly reduced bone mass secondary to defective osteoblast differentiation. Among the MAPK kinase kinase (MAP3K) family, we identified TGF-β–activated kinase 1 (TAK1; also known as MAP3K7) as the critical activator upstream of p38 in osteoblasts. Osteoblast-specific deletion of Tak1 resulted in clavicular hypoplasia and delayed fontanelle fusion, a phenotype similar to the cleidocranial dysplasia observed in humans haploinsufficient for the transcription factor runt-related transcription factor 2 (Runx2). Mechanistic analysis revealed that the TAK1–MKK3/6–p38 MAPK axis phosphorylated Runx2, promoting its association with the coactivator CREB-binding protein (CBP), which was required to regulate osteoblast genetic programs. These findings reveal an in vivo function for p38β and establish that MAPK signaling is essential for bone formation in vivo. These results also suggest that selective p38β agonists may represent attractive therapeutic agents to prevent bone loss associated with osteoporosis and aging

Inverse Regulation of Inflammation and Mitochondrial Function in Adipose Tissue Defines Extreme Insulin Sensitivity in Morbidly Obese Patients

Obesity is associated with insulin resistance, a major risk factor for type 2 diabetes and cardiovascular disease. However, not all obese individuals are insulin resistant, which confounds our understanding of the mechanistic link between these conditions. We conducted transcriptome analyses on 835 obese subjects with mean BMI of 48.8, on which we have previously reported genetic associations of gene expression. Here, we selected ∼320 nondiabetic (HbA1c <7.0) subjects and further stratified the cohort into insulin-resistant versus insulin-sensitive subgroups based on homeostasis model assessment–insulin resistance. An unsupervised informatics analysis revealed that immune response and inflammation-related genes were significantly downregulated in the omental adipose tissue of obese individuals with extreme insulin sensitivity and, to a much lesser extent, in subcutaneous adipose tissue. In contrast, genes related to β-oxidation and the citric acid cycle were relatively overexpressed in adipose of insulin-sensitive patients. These observations were verified by querying an independent cohort of our published dataset of 37 subjects whose subcutaneous adipose tissue was sampled before and after treatment with thiazolidinediones. Whereas the immune response and inflammation pathway genes were downregulated by thiazolidinedione treatment, β-oxidation and citric acid cycle genes were upregulated. This work highlights the critical role that omental adipose inflammatory pathways might play in the pathophysiology of insulin resistance, independent of body weight

Consumption and acceptability of whole grain staples for lowering markers of diabetes risk among overweight and obese Tanzanian adults

Background: Dietary changes characterized by a reduction in carbohydrate quality are occurring in developing countries and may be associated with a higher prevalence of obesity and chronic diseases such as type 2 diabetes mellitus. We assessed the preferences and acceptability of unrefined whole grain carbohydrate staples (i.e., brown rice, unrefined maize and unrefined sorghum ugali) as substitutes for commonly consumed refined carbohydrates in Tanzania. Methods: A questionnaire was used to collect sociodemographic information and dietary habits, and pre-and post-tasting questionnaires were administered for test foods. A 10-point LIKERT scale was used to rate attributes of the three test foods. Results: White rice and refined maize ugali were the most commonly consumed carbohydrate staples in this population; 98% and 91%, respectively. Occasional consumption of unrefined maize and sorghum ugali was reported by 32% and 23% of the participants, respectively. All of the test foods were highly rated for smell, taste, color, appearance and texture. Taste was rated highest for unrefined maize ugali. Almost all of the participants were willing to participate in a future dietary intervention involving regular consumption of these unrefined carbohydrates for at least six months duration. Conclusions: These findings suggest that whole grain carbohydrates are highly acceptable, and that there is a promising potential for their use in future dietary intervention studies in Tanzania

Hydroxyurea differentially modulates activator and repressors of γ-globin gene in erythroblasts of responsive and non-responsive patients with sickle cell disease in correlation with Index of Hydroxyurea Responsiveness

Hydroxyurea (HU), the first of two drugs approved by the US Food and Drug Administration for treating patients with sickle cell disease (SCD), produces anti-sickling effect by re-activating fetal γ-globin gene to enhance production of fetal hemoglobin. However, approximately 30% of the patients do not respond to HU therapy. The molecular basis of non-responsiveness to HU is not clearly understood. To address this question, we examined HU-induced changes in the RNA and protein levels of transcription factors NF-Y, GATA-1, -2, BCL11A, TR4, MYB and NF-E4 that assemble the γ-globin promoter complex and regulate transcription of γ-globin gene. In erythroblasts cultured from peripheral blood CD34+ cells of patients with SCD, we found that HU-induced changes in the protein but not the RNA levels of activator GATA-2 and repressors GATA-1, BCL11A and TR4 correlated with HU-induced changes in fetal hemoglobin (HbF) levels in the peripheral blood of HU high and low responders. However, HU did not significantly induce changes in the protein or RNA levels of activators NF-Y and NF-E4. Based on HU-induced changes in the protein levels of GATA-2, -1 and BCL11A, we calculated an Index of Hydroxyurea Responsiveness (IndexHU-3). Compared to the HU-induced fold changes in the individual transcription factor protein levels, the numerical values of IndexHU-3 statistically correlated best with the HU-induced peripheral blood HbF levels of the patients. Thus, IndexHU-3 can serve as an appropriate indicator for inherent HU responsiveness of patients with SCD

Kir6.1- and SUR2-dependent KATP over-activity disrupts intestinal motility in murine models of Cantu Syndrome

Cantύ Syndrome (CS), caused by gain-of-function (GOF) mutations in pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) ATP-sensitive potassium (KATP) channel subunit genes, is frequently accompanied by gastrointestinal (GI) dysmotility, and we describe one CS patient who required an implanted intestinal irrigation system for successful stooling. We used gene-modified mice to assess the underlying KATP channel subunits in gut smooth muscle, and to model the consequences of altered KATP channels in CS gut. We show that Kir6.1/SUR2 subunits underlie smooth muscle KATP channels throughout the small intestine and colon. Knock-in mice, carrying human KCNJ8 and ABCC9 CS mutations in the endogenous loci, exhibit reduced intrinsic contractility throughout the intestine, resulting in death when weaned onto solid food in the most severely affected animals. Death is avoided by weaning onto a liquid gel diet, implicating intestinal insufficiency and bowel impaction as the underlying cause, and GI transit is normalized by treatment with the KATP inhibitor glibenclamide. We thus define the molecular basis of intestinal KATP channel activity, the mechanism by which overactivity results in GI insufficiency, and a viable approach to therapy