Development of cross metathesis for the design of HDAC inhibitors

Epigenetic histones post translational modifications are key players in the regulation of gene expression. Amongst all possible modifications, the N-acetylation of the lysine side chains located at the N-terminal tail of histones is involved in the relaxation of chromatine and contributes to gene transcription. This acetylation status is controlled by histone acetyl transferases (HAT) and histone deacetylases (HDAC and SIRT). The abnormal expression of HDAC has been linked to the progression of several human diseases such as cancers. Therefore, the development of HDAC inhibitors has emerged as a valuable therapeutic strategy, with currently four compounds approved by the FDA and a fifth one in China. Recent data suggested that combination therapies with HDAC inhibitors may contribute to better clinical results. HDACs are zinc-dependant enzymes grouped in a family of 11 proteins (HDAC1-11), grouped in three classes: class I (HDAC1-3,8), class Il (HDAC4-7,9,10) and class IV (HDAC11). The fourth group of deacetylases contains the class Ill NADH+-dependent sirtuins (SIRT1-7). The standard pharmacophore for HDAC inhibitors involves a zinc-binding group (ZBG) linked through a spacer to a “cap” group in interaction with the external solvent accessible surface. We were interested in alternative chemistries to access HDAC inhibitors in which the intermediate spacer could be build out of two similar building blocks, one bearing the ZBG and on bearing the cap group. By selecting linear alkyl-based spacer, cross metathesis appeared to be a short and flexible strategy, provided it supports the presence of highly oxophile functional groups such as carbonyl groups. This poster summarizes our findings in the application of cross metathesis and the biological evaluations of some of the compounds obtained

Regulation of Signaling at Regions of Cell-Cell Contact by Endoplasmic Reticulum-Bound Protein-Tyrosine Phosphatase 1B

Protein-tyrosine phosphatase 1B (PTP1B) is a ubiquitously expressed PTP that is anchored to the endoplasmic reticulum (ER). PTP1B dephosphorylates activated receptor tyrosine kinases after endocytosis, as they transit past the ER. However, PTP1B also can access some plasma membrane (PM)-bound substrates at points of cell-cell contact. To explore how PTP1B interacts with such substrates, we utilized quantitative cellular imaging approaches and mathematical modeling of protein mobility. We find that the ER network comes in close proximity to the PM at apparently specialized regions of cell-cell contact, enabling PTP1B to engage substrate(s) at these sites. Studies using PTP1B mutants show that the ER anchor plays an important role in restricting its interactions with PM substrates mainly to regions of cell-cell contact. In addition, treatment with PTP1B inhibitor leads to increased tyrosine phosphorylation of EphA2, a PTP1B substrate, specifically at regions of cell-cell contact. Collectively, our results identify PM-proximal sub-regions of the ER as important sites of cellular signaling regulation by PTP1B

What is the value and impact of quality and safety teams? A scoping review

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to conduct a scoping review of the literature about the establishment and impact of quality and safety team initiatives in acute care.</p> <p>Methods</p> <p>Studies were identified through electronic searches of Medline, Embase, CINAHL, PsycINFO, ABI Inform, Cochrane databases. Grey literature and bibliographies were also searched. Qualitative or quantitative studies that occurred in acute care, describing how quality and safety teams were established or implemented, the impact of teams, or the barriers and/or facilitators of teams were included. Two reviewers independently extracted data on study design, sample, interventions, and outcomes. Quality assessment of full text articles was done independently by two reviewers. Studies were categorized according to dimensions of quality.</p> <p>Results</p> <p>Of 6,674 articles identified, 99 were included in the study. The heterogeneity of studies and results reported precluded quantitative data analyses. Findings revealed limited information about attributes of successful and unsuccessful team initiatives, barriers and facilitators to team initiatives, unique or combined contribution of selected interventions, or how to effectively establish these teams.</p> <p>Conclusions</p> <p>Not unlike systematic reviews of quality improvement collaboratives, this broad review revealed that while teams reported a number of positive results, there are many methodological issues. This study is unique in utilizing traditional quality assessment and more novel methods of quality assessment and reporting of results (SQUIRE) to appraise studies. Rigorous design, evaluation, and reporting of quality and safety team initiatives are required.</p

Seascape ecology : identifying research priorities for an emerging ocean sustainability science

Seascape ecology, the marine-centric counterpart to landscape ecology, is rapidly emerging as an interdisciplinary and spatially explicit ecological science with relevance to marine management, biodiversity conservation, and restoration. While important progress in this field has been made in the past decade, there has been no coherent prioritisation of key research questions to help set the future research agenda for seascape ecology. We used a 2-stage modified Delphi method to solicit applied research questions from academic experts in seascape ecology and then asked respondents to identify priority questions across 9 interrelated research themes using 2 rounds of selection. We also invited senior management/conservation practitioners to prioritise the same research questions. Analyses highlighted congruence and discrepancies in perceived priorities for applied research. Themes related to both ecological concepts and management practice, and those identified as priorities include seascape change, seascape connectivity, spatial and temporal scale, ecosystem-based management, and emerging technologies and metrics. Highest-priority questions (upper tercile) received 50% agreement between respondent groups, and lowest priorities (lower tercile) received 58% agreement. Across all 3 priority tiers, 36 of the 55 questions were within a ±10% band of agreement. We present the most important applied research questions as determined by the proportion of votes received. For each theme, we provide a synthesis of the research challenges and the potential role of seascape ecology. These priority questions and themes serve as a roadmap for advancing applied seascape ecology during, and beyond, the UN Decade of Ocean Science for Sustainable Development (2021-2030)

Gender differences in the use of cardiovascular interventions in HIV-positive persons; the D:A:D Study

Peer reviewe

Consensus guidelines for the use and interpretation of angiogenesis assays

The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference

More than competition: exploring stakeholder identities at a grassroots cause-related sporting event

The purpose of this paper is to (a) explore stakeholder identities of a grassroots cause-related sporting event; and (b) gain a better understanding of how identities are related to stakeholder development, support of the event, and future intentions. We used a mixed methods research design that consisted of two studies: qualitative followed by quantitative. Study 1 explored stakeholder identities and how they are related to stakeholder development and support of the event, and Study 2 examined how future intentions regarding attendance, donations, and sponsor support differ based on levels of stakeholder identity. Sports marketing and non-profit management literature streams as well as identity theory and social capital theory informed our studies. The National Kidney Foundation Surf Festival was selected because it is a grassroots cause-related sporting event with financial success over the last two decades. In addition, a surf contest, an action sport, is a unique sport setting in the nonprofit sector, which offers insight to marketers seeking to target subcultures. The findings of the qualitative study revealed three identities relevant to participants: sport subculture, community, and cause. A framework emerged from the data that illustrated how these identities unite together to generate social capital, which is linked to effective volunteer and sponsorship management. Quantitative analysis through survey data provided further evidence of the impact of identification with a cause-related sport activity on consumer outcomes. Results indicated attendees with high surf-related identity are more likely to attend future Surf Festivals, have higher intentions to donate to the cause, and have higher sponsor purchase intentions compared to those with low self-identity with the sport subculture. The conclusion discusses implications, framing the findings through the intersection of the sports marketing and non-profit sector industries, and provides suggestions for future research.Ye

Whole-genome sequencing reveals untapped genetic potential in Africa's indigenous cereal crop sorghum

Sorghum is a food and feed cereal crop adapted to heat and drought and a staple for 500 million of the world’s poorest people. Its small diploid genome and phenotypic diversity make it an ideal C4 grass model as a complement to C3 rice. Here we present high coverage (16–45 × ) resequenced genomes of 44 sorghum lines representing the primary gene pool and spanning dimensions of geographic origin, end-use and taxonomic group. We also report the first resequenced genome of S. propinquum, identifying 8 M high-quality SNPs, 1.9 M indels and specific gene loss and gain events in S. bicolor. We observe strong racial structure and a complex domestication history involving at least two distinct domestication events. These assembled genomes enable the leveraging of existing cereal functional genomics data against the novel diversity available in sorghum, providing an unmatched resource for the genetic improvement of sorghum and other grass species

Seascape ecology:identifying research priorities for an emerging ocean sustainability science

Seascape ecology, the marine-centric counterpart to landscape ecology, is rapidly emerging as an interdisciplinary and spatially explicit ecological science with relevance to marine management, biodiversity conservation, and restoration. While important progress in this field has been made in the past decade, there has been no coherent prioritisation of key research questions to help set the future research agenda for seascape ecology. We used a 2-stage modified Delphi method to solicit applied research questions from academic experts in seascape ecology and then asked respondents to identify priority questions across 9 interrelated research themes using 2 rounds of selection. We also invited senior management/conservation practitioners to prioritise the same research questions. Analyses highlighted congruence and discrepancies in perceived priorities for applied research. Themes related to both ecological concepts and management practice, and those identified as priorities include seascape change, seascape connectivity, spatial and temporal scale, ecosystem-based management, and emerging technologies and metrics. Highest-priority questions (upper tercile) received 50% agreement between respondent groups, and lowest priorities (lower tercile) received 58% agreement. Across all 3 priority tiers, 36 of the 55 questions were within a ±10% band of agreement. We present the most important applied research questions as determined by the proportion of votes received. For each theme, we provide a synthesis of the research challenges and the potential role of seascape ecology. These priority questions and themes serve as a roadmap for advancing applied seascape ecology during, and beyond, the UN Decade of Ocean Science for Sustainable Development (2021-2030)