Novel B(Ar')2(Ar'') hetero-tri(aryl)boranes: a systematic study of Lewis acidity

A series of homo- and hetero-tri(aryl)boranes incorporating pentafluorophenyl, 3,5-bis(trifluoromethyl)phenyl, and pentachlorophenyl groups, four of which are novel species, have been studied as the acidic component of frustrated Lewis pairs for the heterolytic cleavage of H2. Under mild conditions eight of these will cleave H2; the rate of cleavage depending on both the electrophilicity of the borane and the steric bulk around the boron atom. Electrochemical studies allow comparisons of the electrophilicity with spectroscopic measurements of Lewis acidity for different series of boranes. Discrepancies in the correlation between these two types of measurements, combined with structural characterisation of each borane, reveal that the twist of the aryl rings with respect to the boron-centred trigonal plane is significant from both a steric and electronic perspective, and is an important consideration in the design of tri(aryl)boranes as Lewis acids

The role of the RACK1 ortholog Cpc2p in modulating pheromone-induced cell cycle arrest in fission yeast

The detection and amplification of extracellular signals requires the involvement of multiple protein components. In mammalian cells the receptor of activated C kinase (RACK1) is an important scaffolding protein for signal transduction networks. Further, it also performs a critical function in regulating the cell cycle by modulating the G1/S transition. Many eukaryotic cells express RACK1 orthologs, with one example being Cpc2p in the fission yeast Schizosaccharomyces pombe. In contrast to RACK1, Cpc2p has been described to positively regulate, at the ribosomal level, cells entry into M phase. In addition, Cpc2p controls the stress response pathways through an interaction with Msa2p, and sexual development by modulating Ran1p/Pat1p. Here we describe investigations into the role, which Cpc2p performs in controlling the G protein-mediated mating response pathway. Despite structural similarity to Gβ-like subunits, Cpc2p appears not to function at the G protein level. However, upon pheromone stimulation, cells overexpressing Cpc2p display substantial cell morphology defects, disorientation of septum formation and a significantly protracted G1 arrest. Cpc2p has the potential to function at multiple positions within the pheromone response pathway. We provide a mechanistic interpretation of this novel data by linking Cpc2p function, during the mating response, with its previous described interactions with Ran1p/Pat1p. We suggest that overexpressing Cpc2p prolongs the stimulated state of pheromone-induced cells by increasing ste11 gene expression. These data indicate that Cpc2p regulates the pheromone-induced cell cycle arrest in fission yeast by delaying cells entry into S phase

Assessing the order of magnitude of outcomes in single-arm cohorts through systematic comparison with corresponding cohorts: An example from the AMOS study

<p>Abstract</p> <p>Background</p> <p>When a therapy has been evaluated in the first clinical study, the outcome is often compared descriptively to outcomes in corresponding cohorts receiving other treatments. Such comparisons are often limited to selected studies, and often mix different outcomes and follow-up periods. Here we give an example of a systematic comparison to all cohorts with identical outcomes and follow-up periods.</p> <p>Methods</p> <p>The therapy to be compared (anthroposophic medicine, a complementary therapy system) had been evaluated in one single-arm cohort study: the Anthroposophic Medicine Outcomes Study (AMOS). The five largest AMOS diagnosis groups (A-cohorts: asthma, depression, low back pain, migraine, neck pain) were compared to all retrievable corresponding cohorts (C-cohorts) receiving other therapies with identical outcomes (SF-36 scales or summary measures) and identical follow-up periods (3, 6 or 12 months). Between-group differences (pre-post difference in an A-cohort minus pre-post difference in the respective C-cohort) were divided with the standard deviation (SD) of the baseline score of the A-cohort.</p> <p>Results</p> <p>A-cohorts (5 cohorts with 392 patients) were similar to C-cohorts (84 cohorts with 16,167 patients) regarding age, disease duration, baseline affection and follow-up rates. A-cohorts had ≥ 0.50 SD larger improvements than C-cohorts in 13.5% (70/517) of comparisons; improvements of the same order of magnitude (small or minimal differences: -0.49 to 0.49 SD) were found in 80.1% of comparisons; and C-cohorts had ≥ 0.50 SD larger improvements than A-cohorts in 6.4% of comparisons. Analyses stratified by diagnosis had similar results. Sensitivity analyses, restricting the comparisons to C-cohorts with similar study design (observational studies), setting (primary care) or interventions (drugs, physical therapies, mixed), or restricting comparisons to SF-36 scales with small baseline differences between A- and C-cohorts (-0.49 to 0.49 SD) also had similar results.</p> <p>Conclusion</p> <p>In this descriptive analysis, anthroposophic therapy was associated with SF-36 improvements largely of the same order of magnitude as improvements following other treatments. Although these non-concurrent comparisons cannot assess comparative effectiveness, they suggest that improvements in health status following anthroposophic therapy can be clinically meaningful. The analysis also demonstrates the value of a systematic approach when comparing a therapy cohort to corresponding therapy cohorts.</p

From offender to victim-oriented monitoring : a comparative analysis of the emergence of electronic monitoring systems in Argentina and England and Wales

The increasingly psychological terrain of crime and disorder management has had a transformative impact upon the use of electronic monitoring technologies. Surveillance technologies such as electronic monitoring ‑ EM, biometrics, and video surveillance have flourished in commercial environments that market the benefits of asocial technologies in managing disorderly behavior and which, despite often chimerical crime prevention promises, appeal to the ontologically insecure social imagination. The growth of EM in criminal justice has subsequently taken place despite, at best, equivocal evidence that it protects the public and reduces recidivism. Innovative developments in Portugal, Argentina and the United States have re-imagined EM technologies as more personalized devices that can support victims rather than control offenders. These developments represent a re-conceptualization of the use of the technology beyond the neoliberal prism of rational choice theories and offender-oriented thinking that influenced first generation thinking about EM. This paper identifies the socio-political influences that helped conceptualize first generation thinking about EM as, firstly, a community sentence and latterly, as a technique of urban security. The paper reviews attempts to theorize the role and function of EM surveillance technologies within and beyond criminal justice and explores the contribution of victimological perspectives to the use of EM 2.0

On Organizing Algorithms

This short paper acts as a comment on Totaro and Ninno's ‘The Concept of Algorithm as an Interpretative Key of Modern Rationality’ and also introduces some new avenues for exploring the organization of algorithms. In recent discussion of algorithms, concerns have been expressed regarding the apparent power, agential capacity and control that algorithms command of our lives (Beer, 2009; Lash, 2007; Slavin, 2011; Spring, 2011; Stalder and Mayer, 2009). The logic of order, if there is one within these discussions, appears somewhat distinct from the metaphor of recursion suggested by Totaro and Ninno. Using this distinction as a starting point, the paper explores alternative metaphors from which to begin an engagement with political questions of algorithmic ordering. The paper argues for engaging with associative metaphors of: algorithmic account, fluidity, absent-presence and sociality. The paper explores these associative metaphors through an important set of emerging questions regarding organizing algorithms: who and what is included or excluded, on what terms and to what ends

Trypanosomatid RACK1 Orthologs Show Functional Differences Associated with Translation Despite Similar Roles in Leishmania Pathogenesis

RACK1 proteins belong to the eukaryote WD40-repeat protein family and function as spatial regulators of multiple cellular events, including signaling pathways, the cell cycle and translation. For this latter role, structural and genetic studies indicate that RACK1 associates with the ribosome through two conserved positively charged amino acids in its first WD40 domain. Unlike RACK1s, including Trypanosoma brucei RACK1 (TbRACK1), only one of these two positively-charged residues is conserved in the first WD40 domain of the Leishmania major RACK1 ortholog, LACK. We compared virulence-attenuated LACK single copy (LACK/-) L. major, with L. major expressing either two LACK copies (LACK/LACK), or one copy each of LACK and TbRACK1 (LACK/TbRACK1), to evaluate the function of these structurally distinct RACK1 orthologs with respect to translation, viability at host temperatures and pathogenesis. Our results indicate that although the ribosome-binding residues are not fully conserved in LACK, both LACK and TbRACK1 co-sedimented with monosomes and polysomes in LACK/LACK and LACK/TbRACK1 L. major, respectively. LACK/LACK and LACK/TbRACK1 strains differed in their sensitivity to translation inhibitors implying that minor sequence differences between the RACK1 proteins can alter their functional properties. While biochemically distinguishable, both LACK/LACK and LACK/TbRACK1 lines were more tolerant of elevated temperatures, resistant to translation inhibitors, and displayed robust pathogenesis in vivo, contrasting to LACK/- parasites

Transnasal Humidified Rapid Insufflation Ventilatory Exchange in children requiring emergent intubation (Kids THRIVE): a statistical analysis plan for a randomised controlled trial

Published online: 31 May 2023The placement of an endotracheal tube for children with acute or critical illness is a low-frequency and high-risk procedure, associated with high rates of first-attempt failure and adverse events, including hypoxaemia. To reduce the frequency of these adverse events, the provision of oxygen to the patient during the apnoeic phase of intubation has been proposed as a method to prolong the time available for the operator to insert the endotracheal tube, prior to the onset of hypoxaemia. However, there are limited data from randomised controlled trials to validate the efficacy of this technique in children. The technique known as transnasal humidified rapid insufflation ventilatory exchange (THRIVE) uses high oxygen flow rates (approximately 2 L/kg/min) delivered through nasal cannulae during apnoea. It has been shown to at least double the amount of time available for safe intubation in healthy children undergoing elective surgery. The technique and its application in real time have not previously been studied in acutely ill or injured children presenting to the emergency department or admitted to an intensive care unit. The Kids THRIVE trial is a multicentre, international, randomised controlled trial (RCT) in children less than 16 years old undergoing emergent intubation in either the intensive care unit or emergency department of participating hospitals. Participants will be randomised to receive either the THRIVE intervention or standard care (no apnoeic oxygenation) during their intubation. The primary objective of the trial is to determine if the use of THRIVE reduces the frequency of oxygen desaturation and increases the frequency of first-attempt success without hypoxaemia in emergent intubation of children compared with standard practice. The secondary objectives of the study are to assess the impact of the use of THRIVE on the rate of adverse events, length of mechanical ventilation and length of stay in intensive care. In this paper, we describe the detailed statistical analysis plan as an update of the previously published protocol.Shane George, Kristen Gibbons, Tara Williams, Susan Humphreys, Ben Gelbart, Renate Le Marsney, Simon Craig, David Tingay, Arjun Chavan, Andreas Schibler, for the Kids THRIVE Investigators, Paediatric Research in Emergency Departments International Collaborative (PREDICT) and the Australia, New Zealand Intensive Care Society Paediatric Study Group (ANZICS PSG). Kids THRIVE Investigators: Shane George ... Subodh Ganu et al

Genomics and proteomics approaches to the study of cancer-stroma interactions

<p>Abstract</p> <p>Background</p> <p>The development and progression of cancer depend on its genetic characteristics as well as on the interactions with its microenvironment. Understanding these interactions may contribute to diagnostic and prognostic evaluations and to the development of new cancer therapies. Aiming to investigate potential mechanisms by which the tumor microenvironment might contribute to a cancer phenotype, we evaluated soluble paracrine factors produced by stromal and neoplastic cells which may influence proliferation and gene and protein expression.</p> <p>Methods</p> <p>The study was carried out on the epithelial cancer cell line (Hep-2) and fibroblasts isolated from a primary oral cancer. We combined a conditioned-medium technique with subtraction hybridization approach, quantitative PCR and proteomics, in order to evaluate gene and protein expression influenced by soluble paracrine factors produced by stromal and neoplastic cells.</p> <p>Results</p> <p>We observed that conditioned medium from fibroblast cultures (FCM) inhibited proliferation and induced apoptosis in Hep-2 cells. In neoplastic cells, 41 genes and 5 proteins exhibited changes in expression levels in response to FCM and, in fibroblasts, 17 genes and 2 proteins showed down-regulation in response to conditioned medium from Hep-2 cells (HCM). Nine genes were selected and the expression results of 6 down-regulated genes (<it>ARID4A</it>, <it>CALR</it>, <it>GNB2L1</it>, <it>RNF10</it>, <it>SQSTM1</it>, <it>USP9X</it>) were validated by real time PCR.</p> <p>Conclusions</p> <p>A significant and common denominator in the results was the potential induction of signaling changes associated with immune or inflammatory response in the absence of a specific protein.</p