Remote functionalisation via sodium alkylamidozincate intermediates : access to unusual fluorenone and pyridyl ketone reactivity patterns

Treating fluorenone or 2-benzoylpyridine with the sodium zincate [(TMEDA)center dot Na(mu-Bu-t)(mu-TMP)Zn(Bu-t)] in hexane solution, gives efficient Bu-t addition across the respective organic substrate in a highly unusual 1,6-fashion, producing isolable organometallic intermediates which can be quenched and aerobically oxidised to give 3-tert-butyl-9H-fluoren-9-one and 2-benzoyl-5-tert-butylpyridine respectively

Solidarity and Strife After the Atlanta Spa Shootings: A Mixed Methods Study Characterizing Twitter Discussions by Qualitative Analysis and Machine Learning

Background: On March 16, 2021, a white man shot and killed eight victims, six of whom were Asian women at Atlanta-area spa and massage parlors. The aims of the study were to: (1) qualitatively summarize themes of tweets related to race, ethnicity, and racism immediately following the Atlanta spa shootings, and (2) examine temporal trends in expressions hate speech and solidarity before and after the Atlanta spa shootings using a new methodology for hate speech analysis. Methods: A random 1% sample of publicly available tweets was collected from January to April 2021. The analytic sample included 708,933 tweets using race-related keywords. This sample was analyzed for hate speech using a newly developed method for combining faceted item response theory with deep learning to measure a continuum of hate speech, from solidarity race-related speech to use of violent, racist language. A qualitative content analysis was conducted on random samples of 1,000 tweets referencing Asians before the Atlanta spa shootings from January to March 15, 2021 and 2,000 tweets referencing Asians after the shooting from March 17 to 28 to capture the immediate reactions and discussions following the shootings. Results: Qualitative themes that emerged included solidarity (4% before the shootings vs. 17% after), condemnation of the shootings (9% after), racism (10% before vs. 18% after), role of racist language during the pandemic (2 vs. 6%), intersectional vulnerabilities (4 vs. 6%), relationship between Asian and Black struggles against racism (5 vs. 7%), and discussions not related (74 vs. 37%). The quantitative hate speech model showed a decrease in the proportion of tweets referencing Asians that expressed racism (from 1.4% 7 days prior to the event from to 1.0% in the 3 days after). The percent of tweets referencing Asians that expressed solidarity speech increased by 20% (from 22.7 to 27.2% during the same time period) (p \u3c 0.001) and returned to its earlier rate within about 2 weeks. Discussion: Our analysis highlights some complexities of discrimination and the importance of nuanced evaluation of online speech. Findings suggest the importance of tracking hate and solidarity speech. By understanding the conversations emerging from social media, we may learn about possible ways to produce solidarity promoting messages and dampen hate messages

Agency theory and performance appraisal: how bad theory damages learning and contributes to bad management practice

Performance appraisal interviews remain central to how employees are scrutinised, rewarded and sometimes penalised by managers. But they are also often castigated as ineffective, or even harmful, to both individuals and organisations. Exploring this paradox, we highlight the influence of agency theory on the (mal)practice of performance appraisal. The performative nature of human resource management increasingly reflects an economic approach within which its practices are aligned with agency theory. Such theory assumes that actors are motivated mainly or only by economic self-interest. Close surveillance is required to eliminate the risk of shirking and other deviant behaviours. It is a pessimistic mind-set about people that undermines the supportive, co-operative and developmental rhetoric with which appraisal interviews are usually accompanied. Consequently, managers often practice appraisal interviews while holding onto two contradictory mind-sets, a state of Orwellian Doublethink that damages individual learning and organisational performance. We encourage researchers to adopt a more radical critique of appraisal practices that foregrounds issues of power, control and conflicted interests between actors beyond the analyses offered to date

Innate PI3K p110 Regulates Th1/Th17 Development and Microbiota-Dependent Colitis

The p110δ subunit of class IA PI3K modulates signaling in innate immune cells. We previously demonstrated that mice harboring a kinase-dead p110δ subunit (p110δ(KD)) develop spontaneous colitis. Macrophages contributed to the Th1/Th17 cytokine bias in p110δ(KD) mice through increased IL-12 and IL-23 expression. In this study, we show that the enteric microbiota is required for colitis development in germfree p110δ(KD) mice. Colonic tissue and macrophages from p110δ(KD) mice produce significantly less IL-10 compared with wild-type mice. p110δ(KD) APCs cocultured with naive CD4+ Ag-specific T cells also produce significantly less IL-10 and induce more IFN-γ- and IL-17A-producing CD4+ T cells compared with wild-type APCs. Illustrating the importance of APC-T cell interactions in colitis pathogenesis in vivo, Rag1(-/-)/p110δ(KD) mice develop mild colonic inflammation and produced more colonic IL-12p40 compared with Rag1(-/-) mice. However, CD4+ CD45RB(high/low) T cell Rag1(-/-)/p110δ(KD) recipient mice develop severe colitis with increased percentages of IFN-γ- and IL-17A-producing lamina propria CD3+D4+ T cells compared with Rag1(-/-) recipient mice. Intestinal tissue samples from patients with Crohn's disease reveal significantly lower expression of PIK3CD compared with intestinal samples from non-inflammatory bowel disease control subjects (p < 0.05). PIK3CD expression inversely correlates with the ratio of IL12B:IL10 expression. In conclusion, the PI3K subunit p110δ controls homeostatic APC-T cell interactions by altering the balance between IL-10 and IL-12/23. Defects in p110δ expression and/or function may underlie the pathogenesis of human inflammatory bowel disease and lead to new therapeutic strategies

A tale of two towns: A comparative study exploring the possibilities and pitfalls of social capital among people seeking recovery from substance misuse

Background: Social capital has become an influential concept in debating and understanding the modern world. Within the drug and alcohol sector, the concept of ‘recovery capital’ has gained traction with researchers suggesting that people who have access to such capital are better placed to overcome their substance use-related problems than those who do not (Cloud and Granfield, 2008), leading to requests for interventions that focus on building social capital networks (Neale & Stevenson, 2015). While accepting that the concept of social capital has enormous potential for addressing the problems associated with drug use, this paper also considers its ‘dark side’. Methods: Data were drawn from semi-structured interviews with 180 participants including 135 people who use drugs and 45 people who formerly used drugs. Results: High levels of trust, acquired through the establishment of dense social networks, are required to initiate recovery. However, these ‘strong bonds’ may also lead to the emergence of what is perceived by others as an exclusive social network that limits membership to those who qualify and abide by the ‘rules’ of the recovery community, particularly around continuous abstinence. Conclusions: Depending on the nature of the networks and the types of links participants have into them being socially connected can both inhibit and encourage recovery. Therefore, the successful application of social capital within the drugs and alcohol field requires a consideration of not only the presence or absence of social connections but their nature, the value they produce, and the social contexts within which they are developed

Microbiomes of Thalassia testudinum throughout the Atlantic Ocean, Caribbean Sea, and Gulf of Mexico are influenced by site and region while maintaining a core microbiome

Plant microbiomes are known to serve several important functions for their host, and it is therefore important to understand their composition as well as the factors that may influence these microbial communities. The microbiome of Thalassia testudinum has only recently been explored, and studies to-date have primarily focused on characterizing the microbiome of plants in a single region. Here, we present the first characterization of the composition of the microbial communities of T. testudinum across a wide geographical range spanning three distinct regions with varying physicochemical conditions. We collected samples of leaves, roots, sediment, and water from six sites throughout the Atlantic Ocean, Caribbean Sea, and the Gulf of Mexico. We then analyzed these samples using 16S rRNA amplicon sequencing. We found that site and region can influence the microbial communities of T. testudinum, while maintaining a plant-associated core microbiome. A comprehensive comparison of available microbial community data from T. testudinum studies determined a core microbiome composed of 14 ASVs that consisted mostly of the family Rhodobacteraceae. The most abundant genera in the microbial communities included organisms with possible plant-beneficial functions, like plant-growth promoting taxa, disease suppressing taxa, and nitrogen fixers

Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE).

PURPOSE: Gene expression-based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. EXPERIMENTAL DESIGN: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. RESULTS: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations. CONCLUSIONS: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications.See related commentary by McMullen et al., p. 5271.Core funding for this project was provided by the National Institutes of Health (R01-CA172404, PI: S.J. Ramus; and R01-CA168758, PIs: J.A. Doherty and M.A.Rossing), the Canadian Institutes for Health Research (Proof-of-Principle I program, PIs: D.G.Huntsman and M.S. Anglesio), the United States Department of Defense Ovarian Cancer Research Program (OC110433, PI: D.D. Bowtell). A. Talhouk is funded through a Michael Smith Foundation for Health Research Scholar Award. M.S. Anglesio is funded through a Michael Smith Foundation for Health Research Scholar Award and the Janet D. Cottrelle Foundation Scholars program managed by the BC Cancer Foundation. J. George was partially supported by the NIH/National Cancer Institute award number P30CA034196. C. Wang was a Career Enhancement Awardee of the Mayo Clinic SPORE in Ovarian Cancer (P50 CA136393). D.G. Huntsman receives support from the Dr. Chew Wei Memorial Professorship in Gynecologic Oncology, and the Canada Research Chairs program (Research Chair in Molecular and Genomic Pathology). M. Widschwendter receives funding from the European Union’s Horizon 2020 European Research Council Programme, H2020 BRCA-ERC under Grant Agreement No. 742432 as well as the charity, The Eve Appeal (https://eveappeal.org.uk/), and support of the National Institute for Health Research (NIHR) and the University College London Hospitals (UCLH) Biomedical Research Centre. G.E. Konecny is supported by the Miriam and Sheldon Adelson Medical Research Foundation. B.Y. Karlan is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. H.R. Harris is 20 supported by the NIH/National Cancer Institute award number K22 CA193860. OVCARE (including the VAN study) receives support through the BC Cancer Foundation and The VGH+UBC Hospital Foundation (authors AT, BG, DGH, and MSA). The AOV study is supported by the Canadian Institutes of Health Research (MOP86727). The Gynaecological Oncology Biobank at Westmead, a member of the Australasian Biospecimen Network-Oncology group, was funded by the National Health and Medical Research Council Enabling Grants ID 310670 & ID 628903 and the Cancer Institute NSW Grants ID 12/RIG/1-17 & 15/RIG/1-16. The Australian Ovarian Cancer Study Group was supported by the U.S. Army Medical Research and Materiel Command under DAMD17-01-1-0729, The Cancer Council Victoria, Queensland Cancer Fund, The Cancer Council New South Wales, The Cancer Council South Australia, The Cancer Council Tasmania and The Cancer Foundation of Western Australia (Multi-State Applications 191, 211 and 182) and the National Health and Medical Research Council of Australia (NHMRC; ID199600; ID400413 and ID400281). BriTROC-1 was funded by Ovarian Cancer Action (to IAM and JDB, grant number 006) and supported by Cancer Research UK (grant numbers A15973, A15601, A18072, A17197, A19274 and A19694) and the National Institute for Health Research Cambridge and Imperial Biomedical Research Centres. Samples from the Mayo Clinic were collected and provided with support of P50 CA136393 (E.L.G., G.L.K, S.H.K, M.E.S.)