Synthesis of Nitrogenated Heterocycles by Asymmetric Transfer Hydrogenation of N-(tert-Butylsulfinyl)haloimines

Highly optically enriched, protected, nitrogenated heterocycles with different ring sizes have been synthesized by a very efficient methodology consisting of the asymmetric transfer hydrogenation of N-(tert-butylsulfinyl)haloimines followed by treatment with a base to promote an intramolecular nucleophilic substitution process. N-Protected aziridines, pyrrolidines, piperidines, and azepanes bearing aromatic, heteroaromatic, and aliphatic substituents have been obtained in very high yields and diastereomeric ratios up to >99:1. The free heterocycles can be easily obtained by a simple and mild desulfinylation procedure. Both enantiomers of the free heterocycles can be prepared with the same good results by changing the absolute configuration of the sulfur atom of the sulfinyl group.This work was generously supported by the Spanish Ministerio de Ciencia e Innovación (MICINN; grant no. CONSOLIDER INGENIO 2010, CSD2007-00006, CTQ2007-65218 and CTQ2011-24151) and the Generalitat Valenciana (PROMETEO/2009/039 and FEDER). O.P. thanks the Spanish Ministerio de Educación for a predoctoral fellowship (grant no. AP-2008-00989)

The microstructure and hardness of casting a solid brake disc after late graphitizing modification

The features of graphite formation in hypoeutectic and hypereutectic gray cast iron are considered. It is shown that this process in hypoeutectic gray cast irons is easier to control than in hypereutectic, because the formation of a predominantly rectilinear uniformly distributed graphite with a smaller size range and the presence of other distributions is achieved by an one-stage operation of ladle graphitization. The structure of graphite in hypereutectic gray cast irons is characterized by a large variety of its shapes, sizes and distributions, and it is also less technologically stable and controllable. Its characteristics can be approximated to the structure of hypoeutectic gray cast iron due to the obligatory second stage of graphitization. The microstructure and hardness of casting a solid brake disc after late graphitizing modification in a mold are investigated. The content of interdendritic distributions of graphite PGr8, PGr9 and short inclusions of graphite PGd45-90 (GOST 3443-87) was minimized due to the operation of the secondary (late) graphitizing modification. And Brinell hardness of the solid brake disc meets production requirements. © Published under licence by IOP Publishing Ltd.This work is carried out within a framework of the government order (No. FZRU-2020-0011) of the Ministry of Science and Higher Education of the Russian Federation

Epithelial damage and tissue γδ T cells promote a unique tumor-protective IgE response

IgE is an ancient and conserved immunoglobulin isotype with potent immunological function. Nevertheless, the regulation of IgE responses remains an enigma, and evidence of a role for IgE in host defense is limited. Here we report that topical exposure to a common environmental DNA-damaging xenobiotic initiated stress surveillance by γδTCR+ intraepithelial lymphocytes that resulted in class switching to IgE in B cells and the accumulation of autoreactive IgE. High-throughput antibody sequencing revealed that γδ T cells shaped the IgE repertoire by supporting specific variable-diversity-joining (VDJ) rearrangements with unique characteristics of the complementarity-determining region CDRH3. This endogenous IgE response, via the IgE receptor FcεRI, provided protection against epithelial carcinogenesis, and expression of the gene encoding FcεRI in human squamous-cell carcinoma correlated with good disease prognosis. These data indicate a joint role for immunosurveillance by T cells and by B cells in epithelial tissues and suggest that IgE is part of the host defense against epithelial damage and tumor development

Synthesis of γ-, δ-, and ε-Lactams by Asymmetric Transfer Hydrogenation of N-(tert-Butylsulfinyl)iminoesters

Highly enantiomerically enriched γ- and δ-lactams have been prepared by a simple and very efficient procedure that involves the asymmetric transfer hydrogenation of N-(tert-butylsulfinyl)iminoesters followed by desulfinylation of the nitrogen atom and spontaneous cyclization to the desired lactams during the basic workup procedure. Five- and six-membered ring lactams bearing aromatic, heteroaromatic, and aliphatic substituents have been obtained in very high yields and ee’s up to >99%. A slight modification of the procedure also allowed the preparation of ε-lactams in good yields and very high enantioselectivities. Both enantiomers of the final lactams could be prepared with equal efficiency by changing the absolute configuration of the sulfinyl chiral auxiliary

Developing, validating and testing non-vaccine-preventable human papillomavirus to control for differences in sexual behaviour when evaluating HPV vaccination

BACKGROUND: Evaluating impact/effectiveness of human papillomavirus (HPV) vaccination generally assumes stability in factors driving transmission, which might not be valid. We aimed to develop, validate, and test a grouping of non-vaccine-preventable HPV (NVP-HPV) types as a molecular indicator associated with sexual behaviours to control for changes in HPV transmission risk. METHODS: We used data from the National Surveys of Sexual Attitudes and Lifestyles (Natsal-2, 1999-2001, N=1,849; Natsal-3, 2010-2012, N=2,407) to validate the association of NVP-HPV (26/53/66/70/73) with self-reported sexual behaviours. We calculated NVP-HPV-adjusted HPV16/18 vaccine impact/effectiveness estimates in two real-world scenarios: 1) Natsal-2/Natsal-3 (sexually-experienced women in Britain, 18-44yrs) and 2) England's HPV surveillance (women 16-24yrs) (2008, N=3,539; 2010-2020, N=24,707). Samples (urine/vulvo-vaginal swabs) were tested for 21 HPV genotypes (6/11/16/18/26/31/33/35/39/45/51/52/53/56/58/59/66/68/70/73/82) using an in-house multiplex PCR and Luminex-based genotyping assay. RESULTS: NVP-HPV infection was strongly associated with sexual behaviours (e.g., younger age sexual debut, partner numbers). In Natsal data, adjusting for NVP-HPV did not change vaccine impact estimates (unadjusted prevalence ratio (PR: 0.50 (0.27-0.95), adjusted PR: 0.45 (0.25-0.82)). In the second scenario, adjusting for NVP-HPV did not change the prevalence ratio for HPV16/18 comparing 2020 to 2010 (0.07 (0.030.15), unadjusted and adjusted PR). In both scenarios, prevalence of NVP-HPV did not change over time. CONCLUSIONS: We have demonstrated proof-of-concept that NVP-HPV is strongly associated with sexual behaviours. Adjusting for NVP-HPV in two datasets found that original estimates were robust. IMPACT: NVP-HPV might be used to control for changes in HPV transmission risk over time and between groups when evaluating vaccination impact/effectiveness

Late post-operative paraparesis after rib penetration of the spinal canal in a patient with neurofibromatous scoliosis

Rib displacement into the spinal canal is a rare cause of paraplegia or paraparesis in patients affected by neurofibromatous scoliosis. We describe a case of paraparesis in a 14-year-old child affected by neurofibromatous dystrophic kyphoscoliosis, treated with combined posterior and anterior spinal arthrodesis. Seventeen days after the surgical treatment the patient developed clinical signs and symptoms of paraparesis. A CT scan showed the head of the fifth rib protruding into the spinal canal with cord compression. Rib resection and posterior cord decompression were carried out following complete neurological recovery

Cyclin-dependent kinase 18 controls trafficking of aquaporin-2 and its abundance through ubiquitin ligase STUB1, which functions as an AKAP

Arginine-vasopressin (AVP) facilitates water reabsorption in renal collecting duct principal cells through regulation of the water channel aquaporin-2 (AQP2). The hormone binds to vasopressin V2 receptors (V2R) on the surface of the cells and stimulates cAMP synthesis. The cAMP activates protein kinase A (PKA), which initiates signaling that causes an accumulation of AQP2 in the plasma membrane of the cells facilitating water reabsorption from primary urine and fine-tuning of body water homeostasis. AVP-mediated PKA activation also causes an increase in the AQP2 protein abundance through a mechanism that involves dephosphorylation of AQP2 at serine 261 and a decrease in its poly-ubiquitination. However, the signaling downstream of PKA that controls the localization and abundance of AQP2 is incompletely understood. We carried out an siRNA screen targeting 719 kinase-related genes, representing the majority of the kinases of the human genome and analyzed the effect of the knockdown on AQP2 by high-content imaging and biochemical approaches. The screening identified 13 hits whose knockdown inhibited the AQP2 accumulation in the plasma membrane. Amongst the candidates was the so far hardly characterized cyclin-dependent kinase 18 (CDK18). Our further analysis revealed a hitherto unrecognized signalosome comprising CDK18, an E3 ubiquitin ligase, STUB1 (CHIP), PKA and AQP2 that controls the localization and abundance of AQP2. CDK18 controls AQP2 through phosphorylation at serine 261 and STUB1-mediated ubiquitination. STUB1 functions as an A-kinase anchoring protein (AKAP) tethering PKA to the protein complex and bridging AQP2 and CDK18. The modulation of the protein complex may lead to novel concepts for the treatment of disorders which are caused or are associated with dysregulated AQP2 and for which a satisfactory treatment is not available, e.g., hyponatremia, liver cirrhosis, diabetes insipidus, ADPKD or heart failure

Th17-Related Genes and Celiac Disease Susceptibility

Th17 cells are known to be involved in several autoimmune or inflammatory diseases. In celiac disease (CD), recent studies suggest an implication of those cells in disease pathogenesis. We aimed at studying the role of genes relevant for the Th17 immune response in CD susceptibility. A total of 101 single nucleotide polymorphisms (SNPs), mainly selected to cover most of the variability present in 16 Th17-related genes (IL23R, RORC, IL6R, IL17A, IL17F, CCR6, IL6, JAK2, TNFSF15, IL23A, IL22, STAT3, TBX21, SOCS3, IL12RB1 and IL17RA), were genotyped in 735 CD patients and 549 ethnically matched healthy controls. Case-control comparisons for each SNP and for the haplotypes resulting from the SNPs studied in each gene were performed using chi-square tests. Gene-gene interactions were also evaluated following different methodological approaches. No significant results emerged after performing the appropriate statistical corrections. Our results seem to discard a relevant role of Th17 cells on CD risk

A Fluorescent Alcohol Biosensor Using a Simple microPAD Based Detection Scheme

peer reviewedA paper-based microfluidic detection device for the detection of ethanol is demonstrated in this work. The method is based on a fluorophore consisting of short-chain conjugated molecular unit susceptible to the protonation of its terminal pyridine groups, along with a carboxyl-functionalized sidechain that acts as a binder and renders it water-soluble. The resulting fluorescent paper device yields large fluorescence changes when exposed to reactions that yield H 2 O 2 in aqueous solutions. Using an enzyme-catalyzed rection that produces H 2 O 2 from ethanol, we developed a two-zone, cutout paper device containing a reaction zone in which the ethanol-containing analyte is placed, and an adjacent sensor zone where we observe a fluorescence color shift proportional to the ethanol concentration. The limit of detection of the fluidic ethanol biosensor was 0.05 v/v% and the dynamic range was 0.05-2 v/v%. This method was employed to detect the alcohol concentration of consumer vodkas using only a paper sensor and a smartphone camera

Factors affecting medical students in formulating their specialty preferences in Jordan

<p>Abstract</p> <p>Background</p> <p>In recent years there has been a growing appreciation of the issues of career preference in medicine as it may affect student learning and academic performance. However, no such studies have been undertaken in medical schools in Jordan. Therefore, we carried out this study to investigate the career preferences of medical students at Jordan University of Science and Technology and determine factors that might influence their career decisions.</p> <p>Methods</p> <p>A cross-sectional questionnaire-based survey was carried out among second, fourth and sixth year medical students at the Jordan University of Science and Technology, Irbid, Jordan during the academic year 2006/2007. A total of 440 students answered the questionnaire which covered demographic characteristics, specialty preferences, and the factors that influenced these career preferences. Possible influences were selected on the basis of a literature review and discussions with groups of medical students and physicians. Students were asked to consider 14 specialty options and select the most preferred career preference.</p> <p>Results</p> <p>The most preferred specialty expressed by male students was surgery, followed by internal medicine and orthopaedics, while the specialty most preferred by female students was obstetrics and gynaecology, followed by pediatrics and surgery. Students showed little interest in orthopedics, ophthalmology, and dermatology. While 3.1% of females expressed interest in anesthesiology, no male students did. Other specialties were less attractive to most students.</p> <p>Intellectual content of the specialty and the individual's competencies were the most influential on their preference of specialty. Other influential factors were the "reputation of the specialty", "anticipated income", and "focus on urgent care".</p> <p>Conclusion</p> <p>Surgery, internal medicine, pediatrics, and obstetrics and gynaecology were the most preferred specialty preferences of medical students at Jordan University of Science and Technology.</p