Units of Evidence for Analyzing Subdisciplinary Difference in Data Practice Studies

Digital libraries (DLs) are adapting to accommodate research data and related services. The complexities of this new content spans the elements of DL development, and there are questions concerning data selection, service development, and how best to align these with local, institutional initiatives for cyberinfrastructure, data-intensive research, and data stewardship. Small science disciplines are of particular relevance due to the prevalence of this mode of research in the academy, and the anticipated magnitude of data production. To support data acquisition into DLs – and subsequent data reuse – there is a need for new knowledge on the range and complexities inherent in practice-data-curation arrangements for small science research. We present a flexible methodological approach crafted to generate data units to analyze these relationships and facilitate crossdisciplinary comparisons.Library Services (LG-06-07-0032-07) and National Science Foundation (OCI-0830976).is peer reviewe

Benzo-fused Lactams from a Diversity-oriented Synthesis (DOS) Library as Inhibitors of Scavenger Receptor BI (SR-BI)-mediated Lipid Uptake

We report a new series of 8-membered benzo-fused lactams that inhibit cellular lipid uptake from HDL particles mediated by Scavenger Receptor, Class B, Type I (SR-BI). The series was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR), measuring the transfer of the fluorescent lipid DiI from HDL particles to CHO cells overexpressing SR-BI. The series is part of a previously reported diversity-oriented synthesis (DOS) library prepared via a build-couple-pair approach. Detailed structure–activity relationship (SAR) studies were performed with a selection of the original library, as well as additional analogs prepared via solution phase synthesis. These studies demonstrate that the orientation of the substituents on the aliphatic ring have a critical effect on activity. Additionally, a lipophilic group is required at the western end of the molecule, and a northern hydroxyl group and a southern sulfonamide substituent also proved to be optimal. Compound 2p was found to possess a superior combination of potency (av IC50 = 0.10 μM) and solubility (79 μM in PBS), and it was designated as probe ML312

Discovery of Bisamide-heterocycles as Inhibitors of Scavenger Receptor BI (SR-BI)-mediated Lipid Uptake

A new series of potent inhibitors of cellular lipid uptake from HDL particles mediated by scavenger receptor, class B, type I (SR-BI) was identified. The series was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR) that measured the transfer of the fluorescent lipid DiI from HDL particles to CHO cells overexpressing SR-BI. The series is characterized by a linear peptidomimetic scaffold with two adjacent amide groups, as well as an aryl-substituted heterocycle. Analogs of the initial hit were rapidly prepared via Ugi 4-component reaction, and select enantiopure compounds were prepared via a stepwise sequence. Structure–activity relationship (SAR) studies suggest an oxygenated arene is preferred at the western end of the molecule, as well as highly lipophilic substituents on the central and eastern nitrogens. Compound 5e, with (R)-stereochemistry at the central carbon, was designated as probe ML279. Mechanistic studies indicate that ML279 stabilizes the interaction of HDL particles with SR-BI, and its effect is reversible. It shows good potency (IC50 = 17 nM), is non-toxic, plasma stable, and has improved solubility over our alternative probe ML278

Graduate Curriculum for Biological Information Specialists: A Key to Integration of Scale in Biology

Scientific data problems do not stand in isolation. They are part of a larger set of challenges associated with the escalation of scientific information and changes in scholarly communication in the digital environment. Biologists in particular are generating enormous sets of data at a high rate, and new discoveries in the biological sciences will increasingly depend on the integration of data across multiple scales. This work will require new kinds of information expertise in key areas. To build this professional capacity we have developed two complementary educational programs: a Biological Information Specialist (BIS) masters degree and a concentration in Data Curation (DC). We believe that BISs will be central in the development of cyberinfrastructure and information services needed to facilitate interdisciplinary and multi-scale science. Here we present three sample cases from our current research projects to illustrate areas in which we expect information specialists to make important contributions to biological research practice

Indolinyl-Thiazole Based Inhibitors of Scavenger Receptor-BI (SR-BI)-Mediated Lipid Transport

A potent class of indolinyl-thiazole based inhibitors of cellular lipid uptake mediated by scavenger receptor, class B, type I (SR-BI) was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR) in an assay measuring the uptake of the fluorescent lipid DiI from HDL particles. This class of compounds is represented by ML278 (17–11), a potent (average IC50 = 6 nM) and reversible inhibitor of lipid uptake via SR-BI. ML278 is a plasma-stable, noncytotoxic probe that exhibits moderate metabolic stability, thus displaying improved properties for in vitro and in vivo studies. Strikingly, ML278 and previously described inhibitors of lipid transport share the property of increasing the binding of HDL to SR-BI, rather than blocking it, suggesting there may be similarities in their mechanisms of action

Sexual health interventions delivered to participants by mobile technology: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: The use of mobile technologies to prevent STIs is recognised as a promising approach worldwide; however, evidence has been inconclusive, and the field has developed rapidly. With about 1 million new STIs a day globally, up-to-date evidence is urgently needed. OBJECTIVE: To assess the effectiveness of mobile health interventions delivered to participants for preventing STIs and promoting preventive behaviour. METHODS: We searched seven databases and reference lists of 49 related reviews (January 1990-February 2020) and contacted experts in the field. We included randomised controlled trials of mobile interventions delivered to adolescents and adults to prevent sexual transmission of STIs. We conducted meta-analyses and assessed risk of bias and certainty of evidence following Cochrane guidance. RESULTS: After double screening 6683 records, we included 22 trials into the systematic review and 20 into meta-analyses; 18 trials used text messages, 3 used smartphone applications and 1 used Facebook messages as delivery modes. The certainty of evidence regarding intervention effects on STI/HIV occurrence and adverse events was low or very low. There was moderate certainty of evidence that in the short/medium-term text messaging interventions had little or no effect on condom use (standardised mean differences (SMD) 0.02, 95% CI -0.09 to 0.14, nine trials), but increased STI/HIV testing (OR 1.83, 95% CI 1.41 to 2.36, seven trials), although not if the standard-of-care control already contained an active text messaging component (OR 1.00, 95% CI 0.68 to 1.47, two trials). Smartphone application messages also increased STI/HIV testing (risk ratio 1.40, 95% CI 1.22 to 1.60, subgroup analysis, two trials). The effects on other outcomes or of social media or blended interventions is uncertain due to low or very low certainty evidence. CONCLUSIONS: Text messaging interventions probably increase STI/HIV testing but not condom use in the short/medium term. Ongoing trials will report the effects on biological and other outcomes

P2Y receptor regulation of sodium transport in human mammary epithelial cells

Primary human mammary epithelial (HME) cells were immortalized by stable, constitutive expression of the catalytic subunit of human telomerase. Purinergic receptors were identified by RT-PCR and quantitative RT-PCR from mRNA isolated from primary and immortalized cells grown to confluence on membrane filters. Several subtypes of P2Y receptor mRNA were identified including P2Y1, P2Y2, P2Y4, and P2Y6 receptors. RT-PCR experiments also revealed expression of A2b adenosine receptor mRNA in primary and immortalized cells. Confluent monolayers of HME cells exhibited a basal short-circuit current (Isc) that was abolished by amiloride and benzamil. When monolayers were cultured in the presence of hydrocortisone, mRNA expression of Na+ channel (ENaC) -, β-, and -subunits increased approximately threefold compared with that in cells grown without hydrocortisone. In addition, basal benzamil-sensitive Na+ transport was nearly twofold greater in hydrocortisone-treated monolayers. Stimulation with UTP, UDP, or adenosine 5'-O-(3-thiotriphosphate) (ATPS) produced increases in intracellular calcium concentration that were significantly reduced following pretreatment with the calcium-chelating agent BAPTA-AM. Concentration-response relationships indicated that the rank order of potency for these agonists was UTP > UDP > ATPS. Basolateral stimulation with UTP produced a rapid but transient increase in Isc that was significantly reduced if cells were pretreated with BAPTA-AM or benzamil. Moreover, basolateral treatment with either charybdotoxin or clotrimazole significantly inhibited the initial UTP-dependent increase in Isc and eliminated the sustained current response. These results indicate that human mammary epithelial cells express multiple P2 receptor subtypes and that Ca2+ mobilization evoked by P2Y receptor agonists stimulates Na+ absorption by increasing the activity of Ca2+-activated K+ channels located in the basolateral membrane.This work was partly supported by Korea Research Foundation Grant KRF-005-E00076 (to S. Y. Lee) and National Institutes of Health Grants AI-50494 and DK-74010 (to S. M. O'Grady)

Vigorous physical activity and risk of breast cancer in the African American breast cancer epidemiology and risk consortium

The relationship between physical activity and breast cancer risk has been extensively studied among women of European descent, with most studies reporting inverse associations. However, data on American women of African ancestry (AA) and by tumor subtypes are sparse. Thus, we examined associations of vigorous exercise and breast cancer risk overall, and by estrogen receptor (ER) status, in the African American Breast Cancer Epidemiology and Risk Consortium. We pooled data from four large studies on 2482 ER+ cases, 1374 ER− cases, and 16,959 controls. Multivariable logistic regression was used to compute odds ratios (OR) and 95 % confidence intervals (CI) for the risk of breast cancer overall, and polytomous logistic regression was used to model the risk of ER+ and ER− cancer. Recent vigorous exercise was associated with a statistically significant, modestly decreased risk for breast cancer overall (OR 0.88, 95 % CI 0.81–0.96) and for ER+ cancer (OR 0.88, 95 % CI 0.80–0.98), but not for ER− cancer (OR 0.93, 95 % CI 0.82–1.06). Overall, there was no strong evidence of effect modification by age, menopausal status, body mass index, and parity. However, our data were suggestive of modification by family history, such that an inverse association was present among women without a family history but not among those with a relative affected by breast cancer. Results from this large pooled analysis provide evidence that vigorous physical activity is associated with a modestly reduced risk of breast cancer in AA women, specifically ER+ cancer

Family History of Cancer in Relation to Breast Cancer Subtypes in African American Women

Evidence on the relation of family history of cancers other than breast cancer to breast cancer risk is conflicting and most studies have not assessed specific breast cancer subtypes