Statistics for the analysis of molecular dynamics simulations : providing P values for agonist-dependent GPCR activation

Molecular dynamics (MD) is the common computational technique for assessing efficacy of GPCR-bound ligands. Agonist efficacy measures the capability of the ligand-bound receptor of reaching the active state in comparison with the free receptor. In this respect, agonists, neutral antagonists and inverse agonists can be considered. A collection of MD simulations of both the ligand-bound and the free receptor are needed to provide reliable conclusions. Variability in the trajectories needs quantification and proper statistical tools for meaningful and non-subjective conclusions. Multiple-factor (time, ligand, lipid) ANOVA with repeated measurements on the time factor is proposed as a suitable statistical method for the analysis of agonist-dependent GPCR activation MD simulations. Inclusion of time factor in the ANOVA model is consistent with the time-dependent nature of MD. Ligand and lipid factors measure agonist and lipid influence on receptor activation. Previously reported MD simulations of adenosine A2a receptor (A2aR) are reanalyzed with this statistical method. TM6-TM3 and TM7-TM3 distances are selected as dependent variables in the ANOVA model. The ligand factor includes the presence or absence of adenosine whereas the lipid factor considers DOPC or DOPG lipids. Statistical analysis of MD simulations shows the efficacy of adenosine and the effect of the membrane lipid composition. Subsequent application of the statistical methodology to NECA A2aR agonist, with resulting P values in consistency with its pharmacological profile, suggests that the method is useful for ligand comparison and potentially for dynamic structure-based virtual screening

Quantifying conformational changes in GPCRs : glimpse of a common functional mechanism

Background: G-protein-coupled receptors (GPCRs) are important drug targets and a better understanding of their molecular mechanisms would be desirable. The crystallization rate of GPCRs has accelerated in recent years as techniques have become more sophisticated, particularly with respect to Class A GPCRs interacting with G-proteins. These developments have made it possible for a quantitative analysis of GPCR geometrical features and binding-site conformations, including a statistical comparison between Class A GPCRs in active (agonist-bound) and inactive (antagonist-bound) states. Results: Here we implement algorithms for the analysis of interhelical angles, distances, interactions and binding-site volumes in the transmembrane domains of 25 Class A GPCRs (7 active and 18 inactive). Two interhelical angles change in a statistically significant way between average inactive and active states: TM3-TM6 (by -9°) and TM6-TM7 (by +12°). A third interhelical angle: TM5-TM6 shows a trend, changing by -9°. In the transition from inactive to active states, average van der Waals interactions between TM3 and TM7 significantly increase as the average distance between them decreases by >2 Å. Average H-bonding between TM3 and TM6 decreases but is seemingly compensated by an increase in H-bonding between TM5 and TM6. In five Class A GPCRs, crystallized in both active and inactive states, increased H-bonding of agonists to TM6 and TM7, relative to antagonists, is observed. These protein-agonist interactions likely favour a change in the TM6-TM7 angle, which creates a narrowing in the binding pocket of activated receptors and an average ~200 Å3 reduction in volume. Conclusions: In terms of similar conformational changes and agonist binding pattern, Class A GPCRs appear to share a common mechanism of activation, which can be exploited in future drug development

Sex Cord-Gonadal Stromal Tumor of the Rete Testis

A 34-year-old tetraplegic patient with suppurative epididymitis was found on follow-up examination and ultrasonography to have a testicular mass. The radical orchiectomy specimen contained an undifferentiated spindled sex cord-stromal tumor arising in the rete testis. Testicular sex cord-stromal tumors are far less common than germ cell neoplasms and are usually benign. The close relationship between sex cords and ductules of the rete testis during development provides the opportunity for these uncommon tumors to arise anatomically within the rete tesis. This undifferentiated sex cord-stromal tumor, occurring in a previously unreported location, is an example of an unusual lesion mimicking an intratesticular malignant neoplasm

Determining the Effects of Maternal Adiposity on Preterm Neonatal Microbiome and Short Chain Fatty Acid Profiles

The gut microbiota and its metabolites have vast impacts on the human digestive system, immune system, and health outcomes. Short chain volatile fatty acids (SCVFAs) present in feces can be representative of the interactions of the microbiota present in the gut. Low microbiota diversity in the human gut is highly associated with obesity and adverse health outcomes. Furthermore, the maternal microbiome has a direct impact on neonatal microbiota through various pathways such as environment, skin flora, breast milk composition, and vaginal secretions. This study is aimed to further understand the associations between various factors (maternal adiposity, gestational time, length of life, delivery mode, and race/ethnicity ) and neonatal microbiome and its metabolites, SCFA. Data (pre-pregnancy BMI, gestational time, length of life at time of sample collection, delivery mode, race/ethnicity, SCVFA profiles, fecal fermentation profiles, and 16s rRNA sequences, n=75) was obtained from 75 mother-infant dyads. Qiagen CLC Genomics Workbench was used to process 16s RNA data, generate quantitative and qualitative measures of alpha and beta diversity, and generate an analysis of the composition of microbiomes for differential abundances. Multiple metrics were analyzed for alpha and beta diversity and no significant differences were found for acetic acid (A), propionic acid (P), butyric acid (B), or APB combined. Shannon diversity index, a measure of Alpha diversity, showed no significant difference between groups in each subset. BMI differences were significant for no c-section vs. c-section and Black vs. White race/ethnicity. There were no significant differences found in PERMANOVA, a measure of beta diversity, or found in differential abundances among the groups

Redshifts and Velocity Dispersions of Galaxy Clusters in the Horologium-Reticulum Supercluster

We present 118 new optical redshifts for galaxies in 12 clusters in the Horologium-Reticulum supercluster (HRS) of galaxies. For 76 galaxies, the data were obtained with the Dual Beam Spectrograph on the 2.3m telescope of the Australian National University at Siding Spring Observatory. After combining 42 previously unpublished redshifts with our new sample, we determine mean redshifts and velocity dispersions for 13 clusters, in which previous observational data were sparse. In six of the 13 clusters, the newly determined mean redshifts differ by more than 750 km/s from the published values. In the case of three clusters, A3047, A3109, and A3120, the redshift data indicate the presence of multiple components along the line of sight. The new cluster redshifts, when combined with other reliable mean redshifts for clusters in the HRS, are found to be distinctly bi-modal. Furthermore, the two redshift components are consistent with the bi-modal redshift distribution found for the inter-cluster galaxies in the HRS by Fleenor et al. (2005).Comment: 13 pages, 3 figures, Accepted to A

A Profile of the Minnesota Angler

As part of an assessment of the bait leech industry and its market potential, a survey of 5,000 Minnesota anglers was conducted in the spring of 1985. Although the survey instrument was designed to derive information about the bait leech (Nephelopsis obscura) and its use, it also included questions about angler characteristics, preferences, and fishing activities for the 1984 fishing season. Responses to these questions produced a profile of the Minnesota angler. Our survey results show that the typical Minnesota angler is male, middle-aged, has a relatively high household income, and has fished for many years. He fishes from a boat on a lake with other family members mainly for relaxation. He fishes 6 hours a day for 24 days during the summer fishing season. The typical Minnesota angler fishes mainly for walleye and prefers to catch several medium-sized fish as opposed to a limit of small but keeper-sized fish or one large fish. He does not own a cabin and does not belong to fishing clubs or organizations. He is most likely to read Field and Stream magazine but receives a great deal of his fishing information from friends. The household of the typical Minnesota angler has $717 invested in fishing equipment excluding boat(s) and gasoline motor(s) and spends about$165 per year on such equipment. He has access to 5.4 reels and 4.8 rods, is likely to use a depth finder when fishing, and uses a variety of different fishing techniques. He is a member of a household that owns an aluminum- hulled boat 15-16 feet long, powers it with a gasoline-powered outboard motor, and has about $2,400 invested in boat(s), motor(s), and trailer(s). The typical Minnesota angler rated the 1984 fishing experience as average or better

The Relationship Between Minority Business Enterprises and Corporate Purchasing Personnel: Perceptions from Both Sides of the Table

This paper addresses the nature of the difficulties MBEs face when conducting business with large companies through MBE purchasing programs. Data collected from MBEs and purchasing personnel were analyzed with logistic regression to demonstrate that MBEs and their corporate purchasing counterparts have different perceptions across human, environmental, and organizational dimensions of transaction cost economics. These differences help to explain the problems: (1) that MBEs have in selling to large companies and the problems that MBEs and purchasing personnel have in implementing MBE purchasing programs; (2) of reaching agreement in the marketplace; and, (3) of collectively pursuing the economic development of the minority business community. We offer recommendations for improving the relationship between these parties

Recapitulating Parkinson's disease pathology in a three-dimensional human neural cell culture model.

Extensive loss of dopaminergic neurons, and aggregation of the protein α-synuclein into ubiquitin-positive Lewy bodies represents a major neuropathological hallmark of Parkinson's disease. At present the generation of large nuclear-associated Lewy bodies from endogenous wild-type α-synuclein, translationally regulated under its own promoter in human cell culture models requires costly and time-consuming protocols. Here, we demonstrate that fully differentiated human SH-SY5Y neuroblastoma cells grown in three-dimensional cell culture develop Lewy body-like pathology upon exposure to exogenous α-synuclein species. In contrast to most cell- and rodent-based models that exhibit multiple diffuse α-synuclein aggregates throughout the cytoplasm, a single large nuclear inclusion immuno-positive for α-synuclein and ubiquitin is rapidly obtained in our model. This was achieved, without the need for over-expression of α-synuclein or genetic modification of the cell line. However, phosphorylation of α-synuclein within these inclusions was not observed. The system described here provides an ideal tool to screen compounds to therapeutically intervene in Lewy body formation and to investigate the mechanisms involved in disease progression in synucleinopathies

The power of social networks: A model for weaving the Scholarship of Teaching and Learning into institutional culture

This paper offers a guide for those seeking to integrate the Scholarship of Teaching and Learning (SoTL) into higher education institutions to improve the quality of student learning. The authors posit that weaving SoTL into institutional cultures requires the coordinated actions of individuals working in linked social networks rather than individuals acting in isolation. Analyzing both the barriers and potential pathways to integrating SoTL into institutional cultures, the authors provide a conceptual model along with examples of practical strategies for overcoming resistance to change within institutions. The paper provides examples from a variety of different international contexts to show how incentives and other non-coercive measures can motivate faculty and administrators to weave SoTL into institutional fabrics. Drawing on social network theory and the concept of communities of practice, the paper presents a model with attendant strategies for disseminating SoTL values and practices across all three levels of postsecondary institutions: the micro, the meso, and the macro. The authors argue that for SoTL to take root in organizational cultures, there must be 1) effective communication and dissemination of SoTL activity across all levels, 2) well established social networks and links between these levels (nodes), and 3) sustained support by senior administration. The authors conclude by suggesting ways their model could be tested