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Methods for site-selective sulfamoylation of secondary hydroxyl groups in pyranosides are described. Using a boronic acid catalyst, selective installation of a Boc-protected sulfamoyl group at the equatorial position of

Density functional theory was used to calculate C-H bond dissociation enthalpies (BDEs) at each position of a diverse collection of pyranosides and furanosides differing in relative configuration and substitution patterns. A detailed analysis of the resulting data set (186 BDEs, calculated at the M06-2X/def2-TZVP level of theory) highlights the ways in which stereoelectronic effects, conformational properties, and noncovalent interactions can influence the strengths of C-H bonds in carbohydrates. The results point toward opportunities to alter the radical reactivity of carbohydrate derivatives by variation of their stereochemical configuration or the positions and types of protective groups.

Background: Gastroesophageal reflux disease (GORD) is highly prevalent and often coexists with asthma exacerbation. Divergent findings about the association between the two diseases were reported. We conducted a systematic review and meta-analysis to determine whether there exists an association between GORD and asthma. Methods: We searched MEDLINE, EMBASE, and other databases and then performed a manual search, to identify eligible studies. Pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated using fixed- and random-effect models. We evaluated the quality of included studies, explored heterogeneity between studies, undertook subgroup analyses, assessed publication bias, and performed sensitivity analyses. Results: We identified 32 eligible studies, conducted in 14 countries and including a total of 1,612,361 patients of all ages. Overall, GORD shows a weak association with asthma exacerbation (OR = 1.27; 95% CI 1.18–1.35). This association was observed in cohort, case-control, and cross-sectional designs and in European as well as non-European populations. Subgroup analyses show that GORD is associated with frequent asthma exacerbations (≥3 exacerbations, OR = 1.59; 95% CI 1.13–2.24) and with exacerbations needing oral corticosteroid therapy (OR = 1.24; 95% CI 1.09–1.41). GORD pediatric patients are at higher odds of asthma exacerbation than adults. We did not detect any evidence of publication bias and the association between GORD and asthma exacerbation held in all undertaken sensitivity analyses. Conclusions: Gastroesophageal reflux disease and asthma exacerbation are weakly associated BT's work is funded by a Grant from the Regional Ministry of Education, Universities, and Vocational Training, Santiago de Compostela, Spain, ED431C 2018/20. SI

Diorganotin dihalides act as cocatalysts for site-selective and stereoselective couplings of diol-containing carbohydrates with electron-deficient alkenes in the presence of an Ir(III) photoredox catalyst and quinuclidine, a hydrogen atom transfer mediator. Quantum-chemical calculations support a proposed mechanism involving the formation of a cyclic stannylene acetal intermediate that shows enhanced reactivity toward hydrogen atom abstraction by the quinuclidinium radical cation. Addition of the carbon-centered radical to the alkene partner results in C-alkylation of the carbohydrate substrate.

Traumatic brain injury (TBI) survivors suffer long term from mental illness, neurodegeneration, and neuroinflammation. Studies of 3D tissue models have provided new insights into the pathobiology of many brain diseases. Here, a 3D in vitro contusion model is developed consisting of mouse cortical neurons grown on a silk scaffold embedded in collagen and used outcomes from an in vivo model for benchmarking. Molecular, cellular, and network events are characterized in response to controlled cortical impact (CCI). In this model, CCI induces degradation of neural network structure and function and release of glutamate, which are associated with the expression of programmed necrosis marker phosphorylated Mixed Lineage Kinase Domain Like Pseudokinase (pMLKL). Neurodegeneration is observed first in the directly impacted area and it subsequently spreads over time in 3D space. CCI reduces phosphorylated protein kinase B (pAKT) and Glycogen synthase kinase 3 beta (GSK3β) in neurons in vitro and in vivo, but discordant responses are observed in phosphprylated ribosomal S6 kinase (pS6) and phosphorylated Tau (pTau) expression. In summary, the 3D brain-like culture system mimicked many aspects of in vivo responses to CCI, providing evidence that the model can be used to study the molecular, cellular, and functional sequelae of TBI, opening up new possibilities for discovery of therapeutics.

PurposeAn innovative programme of “Darzi” Fellowships in Clinical Leadership provides doctors in postgraduate training with a unique opportunity to engage in improving systems of health care and develop their capability as future clinical leaders. The purpose of this paper is to report an impact evaluation of the programme, highlighting transferable design principles.Design/methodology/approachQualitative and quantitative data were used iteratively and included a review of literature, analysis of background documents and internal evaluation results, face‐to‐face and telephone interviews, observation of educational events, online questionnaires and representative case studies.FindingsImpact was found at the level of the fellows' learning, their organisations and the wider health system. Identified influencing factors included: clarity of purpose and aims, mutuality of workplace and external learning, learning for transformational change, ambitious but “do‐able” projects, a committed and learning‐oriented sponsor, a supportive organisational culture, high‐quality mentoring, a network of supportive peers, diversity of participants, ongoing monitoring and adaptation, planning for sustainability and the tracking of impact over time.Research limitations/implicationsThe extent to which results are generalisable needs to be considered within the constraints of this programme evaluation.Practical implicationsThe “Darzi” Fellowship programme is effective and impactful, spawning clinical leadership development throughout a wider system. Whole system engagement of trainee doctors in leadership will require more than a Fellowship programme alone, but it is a start.Originality/valueThe evaluation adds to what we know about leadership development generally and provides a rare study in the medical context generating helpful principles for the design of leadership development programmes, particularly in the clinical setting.

Tertiary education has become more competitive in recent years due to reductions in government funding and higher student fees. As the nature of the environment grows more competitive, the role of marketing, previously non‐existent in most universities, has grown significantly. One of the key pieces of information that would assist a university’s marketing effort is an understanding of what determines a student’s university preference. Examines university preference using a form of conjoint analysis, known as adaptive conjoint analysis (ACA), to investigate the importance of a number of attributes to high‐school leavers in Australia. Results indicate that the four most important determinants of university preference were course suitability, academic reputation, job prospects, and teaching quality, which has significance for education managers developing marketing strategies and programs.

Background The Isolation by Distance Web Service (IBDWS) is a user-friendly web interface for analyzing patterns of isolation by distance in population genetic data. IBDWS enables researchers to perform a variety of statistical tests such as Mantel tests and reduced major axis regression (RMA), and returns vector based graphs. The more than 60 citations since 2005 confirm the popularity and utility of this website. Despite its usefulness, the data sets with over 65 populations can take hours or days to complete due to the computational intensity of the statistical tests. This is especially troublesome for web-based software analysis, since users tend to expect real-time results on the order of seconds, or at most, minutes. Moreover, as genetic data continue to increase and diversify, so does the demand for more processing power. In order to increase the speed and efficiency of IBDWS, we first determined which aspects of the code were most time consuming and whether they might be amenable to improvements by parallelization or algorithmic optimization. Results Runtime tests uncovered two areas of IBDWS that consumed significant amounts of time: randomizations within the Mantel test and the RMA calculations. We found that these sections of code could be restructured and parallelized to improve efficiency. The code was first optimized by combining two similar randomization routines, implementing a Fisher-Yates shuffling algorithm, and then parallelizing those routines. Tests of the parallelization and Fisher-Yates algorithmic improvements were performed on a variety of data sets ranging from 10 to 150 populations. All tested algorithms showed runtime reductions and a very close fit to the predicted speedups based on time-complexity calculations. In the case of 150 populations with 10,000 randomizations, data were analyzed 23 times faster. Conclusion Since the implementation of the new algorithms in late 2007, datasets have continued to increase substantially in size and many exceed the largest population sizes we used in our test sets. The fact that the website has continued to work well in "real-world" tests, and receives a considerable number of new citations provides the strongest testimony to the effectiveness of our improvements. However, we soon expect the need to upgrade the number of nodes in our cluster significantly as dataset sizes continue to expand. The parallel implementation can be found at http://ibdws.sdsu.edu/.

The T cell-specific transmembrane glycoprotein CD4 interacts with class II MHC molecules via its external domain and is associated with tyrosine kinase p56lck via a cysteine motif in its cytoplasmic domain. We have assessed the ability of CD4 to synergize with the antigen-specific T cell receptor (TCR) for induction of transmembrane signals that result in lymphokine production. Mutant CD4 molecules were introduced into T cells that lacked endogenous CD4 but expressed TCRs specific for lysozyme peptides or the superantigen SEA bound to Ab or Abm12 class II MHC molecules. With either ligand, T cell activation occurred only when CD4 was associated with p56lck. These results demonstrate that residues within the cytoplasmic domain of CD4 are required for its coreceptor function in TCR-mediated signal transduction and strongly support the notion that the association of CD4 with p56lck is critical in this process.

p56 lck , a lymphocyte-specific member of the src family of cytoplasmic protein-tyrosine kinases, is associated noncovalently with the cell surface glycoproteins CD4 and CD8, which are expressed on functionally distinct subpopulations of T cells. Using transient co-expression of p56 lck with CD4 or CD8α in COS-7 cells, we show that the unique N-terminal region of p56 lck binds to the membrane-proximal 10 and 28 cytoplasmic residues of CD8α and CD4, respectively. Two cysteine residues in each of the critical sequences in CD4, CD8α, and p56 lck are required for association. Our results suggest a novel role for cysteine-mediated interactions between unrelated proteins and provide a model for the association of other src -like cytoplasmic kinases with transmembrane proteins.

A time‐dependent formulation of the boomerang model for resonant electron–molecule scattering is presented in terms of a wave packet propagating on the complex potential surface of the metastable anion. The results of calculations using efficient semiclassical techniques for propagating the wave packet are found to be in excellent agreement with full quantum‐mechanical calculations of vibrational excitation cross sections in e−–N2 scattering. The application of the wave packet formulation as a computational and conceptual approach to the problem of resonant collisions with polyatomic molecules is discussed in the light of recent wave packet calculations on polyatomic photodissociation and Raman spectra.

The application of the method of exterior complex scaling to find complex resonance energies by direct numerical integration is presented. Details of the numerical procedures required are discussed and results are presented for rotational predissociation resonances in H2. The advantage of the exterior-scaling approach is that it requires analytic continuation of the potential to complex values of the coordinates only in the asymptotic or near-asymptotic region. Therefore any representation of the potential is adequate, including piecewise-continuous representations such as cubic splines. In contrast, application of the usual complex-scaling (rotated coordinates) procedure generally requires that the potential be represented by a single analytic function.