Ligand sensitivity in dimeric associations of the serotonin 5HT2c receptor

G-protein-coupled receptors (GPCRs) respond to external stimuli by activating heterotrimeric G proteins inside the cell. There is increasing evidence that many GPCRs exist as dimers or higher oligomers, but the biochemical nature of such dimers and what roles they have, if any, in signal transduction remains unclear. We conducted a comprehensive study of dimerization of the 5HT2c serotonin receptor using disulphide-trapping experiments. We found a dimer interface between transmembrane (TM) helices IV and V that is markedly sensitive to the state of receptor activation. This dimer seems to be quasisymmetrical in interfacial geometry and asymmetrical in its association with its cognate Gα protein. We also found a second interface at TM I helices, which is insensitive to the state of activation

A GMBCG Galaxy Cluster Catalog of 55,424 Rich Clusters from SDSS DR7

We present a large catalog of optically selected galaxy clusters from the application of a new Gaussian Mixture Brightest Cluster Galaxy (GMBCG) algorithm to SDSS Data Release 7 data. The algorithm detects clusters by identifying the red sequence plus Brightest Cluster Galaxy (BCG) feature, which is unique for galaxy clusters and does not exist among field galaxies. Red sequence clustering in color space is detected using an Error Corrected Gaussian Mixture Model. We run GMBCG on 8240 square degrees of photometric data from SDSS DR7 to assemble the largest ever optical galaxy cluster catalog, consisting of over 55,000 rich clusters across the redshift range from 0.1 < z < 0.55. We present Monte Carlo tests of completeness and purity and perform cross-matching with X-ray clusters and with the maxBCG sample at low redshift. These tests indicate high completeness and purity across the full redshift range for clusters with 15 or more members.Comment: Updated to match the published version. The catalog can be accessed from: http://home.fnal.gov/~jghao/gmbcg_sdss_catalog.htm

CATMoS: Collaborative Acute Toxicity Modeling Suite.

BACKGROUND: Humans are exposed to tens of thousands of chemical substances that need to be assessed for their potential toxicity. Acute systemic toxicity testing serves as the basis for regulatory hazard classification, labeling, and risk management. However, it is cost- and time-prohibitive to evaluate all new and existing chemicals using traditional rodent acute toxicity tests. In silico models built using existing data facilitate rapid acute toxicity predictions without using animals. OBJECTIVES: The U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) Acute Toxicity Workgroup organized an international collaboration to develop in silico models for predicting acute oral toxicity based on five different end points: Lethal Dose 50 (LD50 value, U.S. Environmental Protection Agency hazard (four) categories, Globally Harmonized System for Classification and Labeling hazard (five) categories, very toxic chemicals [LD50 (LD50≤50mg/kg)], and nontoxic chemicals (LD50>2,000mg/kg). METHODS: An acute oral toxicity data inventory for 11,992 chemicals was compiled, split into training and evaluation sets, and made available to 35 participating international research groups that submitted a total of 139 predictive models. Predictions that fell within the applicability domains of the submitted models were evaluated using external validation sets. These were then combined into consensus models to leverage strengths of individual approaches. RESULTS: The resulting consensus predictions, which leverage the collective strengths of each individual model, form the Collaborative Acute Toxicity Modeling Suite (CATMoS). CATMoS demonstrated high performance in terms of accuracy and robustness when compared with in vivo results. DISCUSSION: CATMoS is being evaluated by regulatory agencies for its utility and applicability as a potential replacement for in vivo rat acute oral toxicity studies. CATMoS predictions for more than 800,000 chemicals have been made available via the National Toxicology Program's Integrated Chemical Environment tools and data sets (ice.ntp.niehs.nih.gov). The models are also implemented in a free, standalone, open-source tool, OPERA, which allows predictions of new and untested chemicals to be made. https://doi.org/10.1289/EHP8495

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Resident physician recognition of obesity and patient education in a family medicine residency clinic within an underserved community

Background/significance: Obesity is a major problem in Wisconsin. Primary Care Resident Physicians may not be taking the opportunity to address this medical condition and/or offering interventions. Purpose: To assess Resident Physician recognition of obesity and acknowledgment as a medical problem and to further assess the action taken with regard to diet and lifestyle intervention. Methods: A convenience sample of residents was selected and a brief survey was distributed to those selected at two Family Medicine residency clinics to increase awareness of patient obesity. For 8 weeks, participating residents completed the survey by writing the perceived weight, BMI, and weight category. They would add patient age, gender and resident gender prior to reviewing the patient’s vitals. After reviewing the vitals, the resident would then write the actual weight and BMI. A random chart review of 100 charts was completed pre- and post-survey for the participating and non-participating (control) groups to assess obesity recognition and intervention. Pre- and post-survey comparisons utilized chi-square test or Fisher exact for categorical variables and t-test or Mann Whitney test for continuous variables. Binary logistic regression was used for multivariate comparisons. Results: There was no difference in estimated vs. actual BMI regarding patient or resident gender. As expected, BMI was a predictor of whether obesity was addressed. In the participating group there was an increased recognition of obesity among female patients (p= Conclusion: Although there was an increase in acknowledging obesity as a medical problem following an obesity-recognition exercise, there was no increase in intervention. This increase could be secondary to physicians outside of the study having encounters with patients and adding obesity as a problem or medical history. Quality improvement measures will need to be enforced in order to better patient health and outcomes. Specific educational materials targeted toward obesity, diet and lifestyle modifications will need to be created

Obese patients’ compliance and satisfaction with educational intervention: O.N.E. packet

Background: Today, 36% of U.S. adults are obese. Combating obesity is important, as obesity has been shown to increase risk of hypertension, dyslipidemia and type 2 diabetes. The obesity rate in the state of Wisconsin in 2010 was 26%. It is well established that physician counseling is effective in promoting healthy behavior. Although weight loss is asked and advised during clinic visits, physicians rarely assess, assist or arrange interventions. Purpose: To determine if distribution of educational materials to patients with body mass index (BMI) \u3e 30 kg/m2 affects lifestyle modification compliance; and to determine if there is a difference in compliance between physician distribution or peer educator personal summary of educational materials. Methods: Adults with BMI \u3e 30 kg/m2 were randomized before the clinic visits into one of two groups using preprinted envelopes. Physician group patients were handed the packet by the resident physicians. Patient educator group had brief visits with the patient educator who summarized the information and answered questions. Follow-up phone calls were made to patients using a standardized questionnaire. Chi-square or Fisher exact tests were used for categorical data, Mann-Whitney tests for age/BMI; binary logistic regression was used for multivariate analysis. Results: Of the 180 patients eligible to participate, 165 patients were enrolled in the study (80 patient educator, 85 physician) and 15 lost to follow-up. Mean age was 42 ± 14, 76% were female, 81% were African American, and mean visit BMI was 37 ± 7. When asked if they remembered who gave them the packet (patient educator vs. physician), 74% of patients responded correctly. Of the patients who made diet or lifestyle changes since receiving the packet, 68% (54) were from patient educator and 45% (38) from physician (P=0.003). The most common changes were: exercised more (24%, 39), ate healthier (33%, 54), and more aware of what I ate (35%, 57). Visit BMI was not associated with lifestyle change (P=0.07). Univariate analysis determined younger age (35 vs. 50, P=0.0012), brief patient educator visits (P=0.005) and accurate recall of who distributed information (P=0.000) were associated with patient reported lifestyle changes, confirmed by multivariate regression (P=0.03, P=0.007 and P=0.001, respectively). Conclusion: Younger age, brief patient educator visits, and accurate recall of the educational event were significantly associated with patient-reported lifestyle changes in obese patients

A GMBCG galaxy cluster catalog of 55,880 rich clusters from SDSS DR7

We present a large catalog of optically selected galaxy clusters from the application of a new Gaussian Mixture Brightest Cluster Galaxy (GMBCG) algorithm to SDSS Data Release 7 data. The algorithm detects clusters by identifying the red sequence plus Brightest Cluster Galaxy (BCG) feature, which is unique for galaxy clusters and does not exist among field galaxies. Red sequence clustering in color space is detected using an Error Corrected Gaussian Mixture Model. We run GMBCG on 8240 square degrees of photometric data from SDSS DR7 to assemble the largest ever optical galaxy cluster catalog, consisting of over 55,000 rich clusters across the redshift range from 0.1 &lt; z &lt; 0.55. We present Monte Carlo tests of completeness and purity and perform cross-matching with X-ray clusters and with the maxBCG sample at low redshift. These tests indicate high completeness and purity across the full redshift range for clusters with 15 or more members