Efficient preparation of TMSCCl2Br and its use in dichlorocyclopropanation of electron deficient alkenes

The reaction of excess TMSCl and LiCCl2Br at low temperature is a technically simple high yield route to TMSCCl2Br. The latter is a stable source of the dichlorobromomethide carbanion, which undergoes 1,4-addition with cyclic nitroalkenes and (E)-fumarates leading to dichlorocyclopropanes after bromide explusion. For nitrostyrenes the reaction arrests at the 1,4-addition product. Low temperature NMR studies and DFT calculations suggest the formation of an ‘ate’ species [(nitronate)SiFMe3]- which, upon boil off of TMSF at 10 - 20 °C, yields the cyclopropane. DFT calculations also support the experimental differences between fluoride and acetate as promotors

Anionic sigmatropic-electrocyclic-Chugaev cascades: accessing 12-aryl-5-(methylthiocarbonylthio)tetracenes and a related anthra[2,3-b]thiophene

1,4-Diols resulting from the double addition of ArCCLi (Ar = Ph, substituted phenyl, 2-thienyl) to ortho-C6H4(CHO)2 undergo cascades to tetracenes on simple admixture of LiHDMS, CS2 and MeI. Acene formation proceeds by [3,3]-sigmatropic rearrangement of xanthate anions followed by 6π electrocyclisations. The reactions are terminated by E2 or anionic Chugaev-type eliminations. Structural packing motifs and electronic properties are reported for the tetracenes

Understanding anionic Chugaev elimination in pericyclic tetracene formation

The reaction pathway for the formation of tetracenes from the diols 1,2-C6H4(CHOHC≡CAr)2 , LiHDMS, CS2 and MeI has been modelled by computational methods at the CBS-QB3 level of theory. Comparison of PhCHOC(=S)YCCPh (Y = S- or SMe) indicates a slight kinetic advantage for the anionic system towards [3,3]-sigmatropic rearrangement [Eact(calc.) 19.7 vs 21.8 kcal mol-1]. Using anthracene-based models, 10-{SC(=O)Y}-4a,10-dihydroanthracene (Y = S- or SMe), allows direct comparison of both syn and anti-manifolds in the neutral vs. anionic Chugaev elimination. Syn elimination of [HSC(=O)S]- is distinctly favoured [Eact(calc.) 11.4 kcal mol-1] vs. syn elimination of neutral methylated HSC(=O)SMe [Eact(calc.) 27.5 kcal mol-1]. The smaller barrier to syn elimination of the anionic leaving group is in accord with the low temperature conditions required for this Chugaev reaction (60 oC) and suggests a general advantage in carrying out Chugaev eliminations in anionic manifolds

An efficient synthesis of substituted chrysenes

Substituted chrysenes have been swiftly synthesised by the 6-endo-dig cyclisation of ethynylnaphthalenes using platinum(II) chloride. Cyclisation precursors were directly prepared from commercially available 2-bromoaldehydes in a telescoped synthetic procedure involving a Cannizzaro triggered cascade and subsequent dehydration and desilylation. This short synthetic procedure allows rapid access to derivatives of biologically active molecules with useful electronic properties

A crisis of protection and safe passage: violence experienced by migrants/refugees travelling along the Western Balkan corridor to Northern Europe.

BACKGROUND: Pushed by ongoing conflicts and pulled by the desire for a better life, over one million migrants/refugees transited Balkan countries and arrived in Europe during 2015 and early 2016. To curb this influx, European countries instituted restrictive migration policies often characterized by building of razor-wire border fences and border closures. Among migrants/refugees who received mental health care in Serbia while travelling through Balkan countries to Northern Europe, we assessed the prevalence and patterns of violent events experienced including physical trauma. METHODS: A mixed methods study among migrants/refugees attending mobile mental health clinics run by Médecins sans Frontières (MSF) between July 2015 and June 2016, in Serbia - a main transit hub to European countries. Clinics were conducted according to MSF guidelines by experienced psychologists who were supported by cultural mediators. The main outcome measures were violent events and associated physical trauma. RESULTS: Of 992 migrants/refugees attending MSF mental health clinics, the majority (72%) were from Syria and Afghanistan and included vulnerable groups (14%) such as unaccompanied minors and pregnant women. The most frequent mental health symptoms/signs were anxiety (29%) and adjustment reactions (26%). Of the 992 migrants/refugees, 270 (27%) had experienced violent events during their journey. Signs of physical trauma due to acts of violence were seen in 223(22%) of the 992 individuals, 144 (65%) being perpetrated by State authorities and involving women (11%) and children (13%). Border closures along the Balkan route were associated with a dramatic decrease in registered migrants/refugee arrivals in Serbia. Conversely, among those that made it across the borders, an increasing linear trend in reported violent events was observed at MSF mental health clinics (X2 for linear trend, P <0 · 001). Qualitative evidence corroborated with quantitative findings. CONCLUSIONS: Nearly one-in-three migrants/refugees seen in MSF clinics experienced violent events including physical trauma along their journey. State authorities, including those in European countries were the perpetrators in over half of such events which were associated with border closures. There is "a crisis of protection and safe passage" which needs to change towards one of respect for the principles of international human rights and refugee law

Discovery of (meth)acrylate polymers that resist colonization by fungi associated with pathogenesis and biodeterioration

© 2020 The Authors. Fungi have major, negative socioeconomic impacts, but control with bioactive agents is increasingly restricted, while resistance is growing. Here, we describe an alternative fungal control strategy via materials operating passively (i.e., no killing effect). We screened hundreds of (meth)acrylate polymers in high throughput, identifying several that reduce attachment of the human pathogen Candida albicans, the crop pathogen Botrytis cinerea, and other fungi. Specific polymer functional groups were associated with weak attachment. Low fungal colonization materials were not toxic, supporting their passive, anti-attachment utility. We developed a candidate monomer formulation for inkjet-based 3D printing. Printed voice prosthesis components showed up to 100% reduction in C. albicans biofilm versus commercial materials. Furthermore, spray-coated leaf surfaces resisted fungal infection, with no plant toxicity. This is the first high-throughput study of polymer chemistries resisting fungal attachment. These materials are ready for incorporation in products to counteract fungal deterioration of goods, food security, and health

Plague and the Human Flea, Tanzania

Pulex irritans fleas were more common in villages with high plague incidence

Non-traditional support workers delivering a brief psychosocial intervention for older people with anxiety and depression: the NOTEPAD feasibility study

ackground: Anxiety and depression often coexist in older people. These disorders are often underdiagnosed and undertreated, and are associated with increased use of health and social care services, and raised mortality. Barriers to diagnosis include the reluctance of older people to present to their general practitioner (GP) with mood symptoms because of the stigma they perceive about mental health problems, and because the treatments offered are not acceptable to them. Objectives: To refine a community-based psychosocial intervention for older people with anxiety and/or depression so that it can be delivered by non-traditional providers such, as support workers (SWs), in the third sector. To determine whether or not SWs can be trained to deliver this intervention to older people with anxiety and/or depression. To test procedures and determine if it is feasible to recruit and randomise patients, and to conduct a process evaluation to provide essential information to inform a randomised trial. Design: Three phases, all informed by a patient and public involvement and engagement group. Qualitative work with older people and third-sector providers, plus a consensus group to refine the intervention, training, SW manuals and patient participant materials (phase 1). Recruitment and training of SWs (phase 2). Feasibility study to test recruitment procedures and assess fidelity of delivery of the intervention; and interviews with study participants, SWs and GPs to assess acceptability of the intervention and impact on routine care (phase 3). Setting: North Staffordshire, in collaboration with Age UK North Staffordshire. © Queen’s Printer and Controller of HMSO 2019. This work was produced by Burroughs et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. vii ABSTRACT viii Intervention: A psychosocial intervention, comprising one-to-one contact between older people with anxiety and/or depression and a SW employed by Age UK North Staffordshire, based on the principles of behavioural activation (BA), with encouragement to participate in a group activity. Results: Initial qualitative work contributed to refinement of the psychosocial intervention. Recruitment (and retention) of the SWs was possible; the training, support materials and manual were acceptable to them, and they delivered the intervention as intended. Recruitment of practices from which to recruit patients was possible, but the recruitment target (100 patients) was not achieved, with 38 older adults randomised. Retention at 4 months was 86%. The study was not powered to demonstrate differences in outcomes. Older people in the intervention arm found the sessions with SWs acceptable, although signposting to, and attending, groups was not valued by all participants. GPs recognised the need for additional care for older people with anxiety and depression, which they could not provide. Participation in the study did not have an impact on routine care, other than responding to the calls from the study team about risk of self-harm. GPs were not aware of the work done by SWs with patients. Limitations: Target recruitment was not achieved. Conclusions: Support workers recruited from Age UK employees can be recruited and trained to deliver an intervention, based on the principles of BA, to older people with anxiety and/or depression. The training and supervision model used in the study was acceptable to SWs, and the intervention was acceptable to older people. Future work: Further development of recruitment strategies is needed before this intervention can be tested in a fully powered randomised controlled trial. Trial registration: Current Controlled Trials ISRCTN16318986. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 7, No. 25. See the NIHR Journals Library website for further project information

Initiation of T cell signaling by CD45 segregation at 'close contacts'.

It has been proposed that the local segregation of kinases and the tyrosine phosphatase CD45 underpins T cell antigen receptor (TCR) triggering, but how such segregation occurs and whether it can initiate signaling is unclear. Using structural and biophysical analysis, we show that the extracellular region of CD45 is rigid and extends beyond the distance spanned by TCR-ligand complexes, implying that sites of TCR-ligand engagement would sterically exclude CD45. We also show that the formation of 'close contacts', new structures characterized by spontaneous CD45 and kinase segregation at the submicron-scale, initiates signaling even when TCR ligands are absent. Our work reveals the structural basis for, and the potent signaling effects of, local CD45 and kinase segregation. TCR ligands have the potential to heighten signaling simply by holding receptors in close contacts.The authors thank R.A. Cornall, M.L. Dustin and P.A. van der Merwe for comments on the manuscript and S. Ikemizu for useful discussions about the structure. We also thank W. Lu and T. Walter for technical support with protein expression and crystallization, the staff at Diamond Light Source beamlines I02, I03 and I04-1 (proposal mx10627) and European Synchrotron Radiation Facility beamlines ID23EH1 and ID23EH2 for assistance at the synchrotrons, G. Sutton for assistance with MALS experiments, and M. Fritzsche for advice on the calcium analysis. This work was funded by the Wellcome Trust (098274/Z/12/Z to S.J.D.; 090532/Z/09/Z to R.J.C.G.; 090708/Z/09/Z to D.K.), the UK Medical Research Council (G0700232 to A.R.A.), the Royal Society (UF120277 to S.F.L.) and Cancer Research UK (C20724/A14414 to C.S.; C375/A10976 to E.Y.J.). The Oxford Division of Structural Biology is part of the Wellcome Trust Centre for Human Genetics, Wellcome Trust Core Award Grant Number 090532/Z/09/Z. We acknowledge financial support from Instruct, an ESFRI Landmark Project. The OPIC electron microscopy facility was funded by a Wellcome Trust JIF award (060208/Z/00/Z).This is the author accepted manuscript. The final version is available from Nature Publishing Group via https://doi.org/10.1038/ni.339