Switching the stereochemical outcome of 6-endo-trig cyclizations; Synthesis of 2,6-Cis-6-substituted 4-oxopipecolic acids

A base-mediated 6-endo-trig cyclization of readily accessible enone-derived α-amino acids has been developed for the direct synthesis of novel 2,6-cis-6- substituted-4-oxo-L-pipecolic acids. A range of aliphatic and aryl side chains were tolerated by this mild procedure to give the target compounds in good overall yields. Molecular modeling of the 6-endo-trig cyclization allowed some insight as to how these compounds were formed, with the enolate intermediate generated via an equilibrium process, followed by irreversible tautomerization/neutralization providing the driving force for product formation. Stereoselective reduction and deprotection of the resulting 2,6-cis-6-substituted 4-oxo-L-pipecolic acids to the corresponding 4-hydroxy-L-pipecolic acids was also performed

Thermoregulatory, metabolic, and cardiovascular responses during 88 min of full-body ice immersion - A case study.

Exposure to extreme cold environments is potentially life-threatening. However, the world record holder of full-body ice immersion has repeatedly demonstrated an extraordinary tolerance to extreme cold. We aimed to explore thermoregulatory, metabolic, and cardiovascular responses during 88 min of full-body ice immersion. We continuously measured gastrointestinal temperature (Tgi ), skin temperature (Tskin), blood pressure, and heart rate (HR). Oxygen consumption (VO2 ) was measured at rest, and after 45 and 88 min of ice immersion, in order to calculate the metabolic heat production. Tskin dropped significantly (28-34°C to 4-15°C) and VO2 doubled (5.7-11.3 ml kg-1  min-1 ), whereas Tgi (37.6°C), HR (72 bpm), and mean arterial pressure (106 mmHg) remained stable during the first 30 min of cold exposure. During the remaining of the trial, Tskin and VO2 remained stable, while Tgi gradually declined to 37.0°C and HR and mean arterial blood pressure increased to maximum values of 101 bpm and 115 mmHg, respectively. Metabolic heat production in rest was 169 W and increased to 321 W and 314 W after 45 and 80 min of ice immersion. Eighty-eight minutes of full-body ice immersion resulted in minor changes of Tgi and cardiovascular responses, while Tskin and VO2 changed markedly. These findings may suggest that our participant can optimize his thermoregulatory, metabolic, and cardiovascular responses to challenge extreme cold exposure

A boundary element analysis on the influence of Krc and e/d on the performance of cyclically loaded single pile in clay

The environment prevalent in oceans necessitates the piles supporting offshore structures to be designed against lateral cyclic loading initiated by wave action. Such quasi-static load reversal induces deterioration in the strength and stiffness of the soil-pile system, introducing progressive reduction in the bearing capacity associated with increased settlement of the pile foundation. To understand the effect of lateral cyclic load on axial response of single piles in soft clay, a numerical model was previously developed and validated by the author. Using the methodology, further analysis has been carried out to investigate how the variation in relative pilesoil stiffness and eccentricity effects the degradation of axial pile capacity due to the effect of lateral cyclic load. This paper presents a brief description of the methodology, analysis and interpretations of the theoretical results obtained from the further analysis and the relevant conclusions drawn there from

Discovery and confirmation of the shortest gamma ray burst from a collapsar [Author Correction to: Nature Astronomy https://doi.org/10.1038/s41550-021-01428-7,]

Gamma-ray bursts (GRBs) are among the brightest and most energetic events in the universe. The duration and hardness distribution of GRBs has two clusters, now understood to reflect (at least) two different progenitors. Short-hard GRBs (SGRBs; T90 2 s) have been attributed to the collapse of peculiar massive stars (collapsars). The discovery of SN 1998bw/GRB 980425 marked the first association of a LGRB with a collapsar and AT 2017gfo/GRB 170817A/GW170817 marked the first association of a SGRB with a binary neutron star merger, producing also gravitational wave (GW). Here, we present the discovery of ZTF20abwysqy (AT2020scz), a fast-fading optical transient in the Fermi Satellite and the InterPlanetary Network (IPN) localization regions of GRB 200826A; X-ray and radio emission further confirm that this is the afterglow. Follow-up imaging (at rest-frame 16.5 days) reveals excess emission above the afterglow that cannot be explained as an underlying kilonova (KN), but is consistent with being the supernova (SN). Despite the GRB duration being short (rest-frame T90 of 0.65 s), our panchromatic follow-up data confirms a collapsar origin. GRB 200826A is the shortest LGRB found with an associated collapsar; it appears to sit on the brink between a successful and a failed collapsar. Our discovery is consistent with the hypothesis that most collapsars fail to produce ultra-relativistic jets

Discovery And Confirmation Of The Shortest Gamma-Ray Burst From A Collapsar

Gamma-ray bursts (GRBs) are among the brightest and most energetic events in the Universe. The duration and hardness distribution of GRBs has two clusters(1), now understood to reflect (at least) two different progenitors(2). Short-hard GRBs (SGRBs; T-90 \u3c 2 s) arise from compact binary mergers, and long-soft GRBs (LGRBs; T-90 \u3e 2 s) have been attributed to the collapse of peculiar massive stars (collapsars)(3). The discovery of SN 1998bw/GRB 980425 (ref. (4)) marked the first association of an LGRB with a collapsar, and AT 2017gfo (ref. (5))/GRB 170817A/GW170817 (ref. (6)) marked the first association of an SGRB with a binary neutron star merger, which also produced a gravitational wave. Here, we present the discovery of ZTF20abwysqy (AT2020scz), a fast-fading optical transient in the Fermi satellite and the Interplanetary Network localization regions of GRB 200826A; X-ray and radio emission further confirm that this is the afterglow. Follow-up imaging (at rest-frame 16.5 days) reveals excess emission above the afterglow that cannot be explained as an underlying kilonova, but which is consistent with being the supernova. Although the GRB duration is short (rest-frame T-90 of 0.65 s), our panchromatic follow-up data confirm a collapsar origin. GRB 200826A is the shortest LGRB found with an associated collapsar; it appears to sit on the brink between a successful and a failed collapsar. Our discovery is consistent with the hypothesis that most collapsars fail to produce ultra-relativistic jets

Stratification of biological therapies by pathobiology in biologic-naive patients with rheumatoid arthritis (STRAP and STRAP-EU): two parallel, open-label, biopsy-driven, randomised trials

Background: Despite highly effective targeted therapies for rheumatoid arthritis, about 40% of patients respond poorly, and predictive biomarkers for treatment choices are lacking. We did a biopsy-driven trial to compare the response to rituximab, etanercept, and tocilizumab in biologic-naive patients with rheumatoid arthritis stratified for synovial B cell status. Methods: STRAP and STRAP-EU were two parallel, open-label, biopsy-driven, stratified, randomised, phase 3 trials done across 26 university centres in the UK and Europe. Biologic-naive patients aged 18 years or older with rheumatoid arthritis based on American College of Rheumatology (ACR)–European League Against Rheumatism classification criteria and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) were included. Following ultrasound-guided synovial biopsy, patients were classified as B cell poor or B cell rich according to synovial B cell signatures and randomly assigned (1:1:1) to intravenous rituximab (1000 mg at week 0 and week 2), subcutaneous tocilizumab (162 mg per week), or subcutaneous etanercept (50 mg per week). The primary outcome was the 16-week ACR20 response in the B cell-poor, intention-to-treat population (defined as all randomly assigned patients), with data pooled from the two trials, comparing etanercept and tocilizumab (grouped) versus rituximab. Safety was assessed in all patients who received at least one dose of study drug. These trials are registered with the EU Clinical Trials Register, 2014-003529-16 (STRAP) and 2017-004079-30 (STRAP-EU). Findings: Between June 8, 2015, and July 4, 2019, 226 patients were randomly assigned to etanercept (n=73), tocilizumab (n=74), and rituximab (n=79). Three patients (one in each group) were excluded after randomisation because they received parenteral steroids in the 4 weeks before recruitment. 168 (75%) of 223 patients in the intention-to-treat population were women and 170 (76%) were White. In the B cell-poor population, ACR20 response at 16 weeks (primary endpoint) showed no significant differences between etanercept and tocilizumab grouped together and rituximab (46 [60%] of 77 patients vs 26 [59%] of 44; odds ratio 1·02 [95% CI 0·47–2·17], p=0·97). No differences were observed for adverse events, including serious adverse events, which occurred in six (6%) of 102 patients in the rituximab group, nine (6%) of 108 patients in the etanercept group, and three (4%) of 73 patients in the tocilizumab group (p=0·53). Interpretation: In this biologic-naive population of patients with rheumatoid arthrtitis, the dichotomic classification into synovial B cell poor versus rich did not predict treatment response to B cell depletion with rituximab compared with alternative treatment strategies. However, the lack of response to rituximab in patients with a pauci-immune pathotype and the higher risk of structural damage progression in B cell-rich patients treated with rituximab warrant further investigations into the ability of synovial tissue analyses to inform disease pathogenesis and treatment response. Funding: UK Medical Research Council and Versus Arthritis

PATRIC: The VBI PathoSystems Resource Integration Center

The PathoSystems Resource Integration Center (PATRIC) is one of eight Bioinformatics Resource Centers (BRCs) funded by the National Institute of Allergy and Infection Diseases (NIAID) to create a data and analysis resource for selected NIAID priority pathogens, specifically proteobacteria of the genera Brucella, Rickettsia and Coxiella, and corona-, calici- and lyssaviruses and viruses associated with hepatitis A and E. The goal of the project is to provide a comprehensive bioinformatics resource for these pathogens, including consistently annotated genome, proteome and metabolic pathway data to facilitate research into counter-measures, including drugs, vaccines and diagnostics. The project's curation strategy has three prongs: ‘breadth first’ beginning with whole-genome and proteome curation using standardized protocols, a ‘targeted’ approach addressing the specific needs of researchers and an integrative strategy to leverage high-throughput experimental data (e.g. microarrays, proteomics) and literature. The PATRIC infrastructure consists of a relational database, analytical pipelines and a website which supports browsing, querying, data visualization and the ability to download raw and curated data in standard formats. At present, the site warehouses complete sequences for 17 bacterial and 332 viral genomes. The PATRIC website () will continually grow with the addition of data, analysis and functionality over the course of the project

Polish children in Norway : between national discourses of belonging and everyday experiences of life abroad

This chapter examines dimensions of self-identification among Polish migrant children in Norway. The arguments are situated within childhood studies and take into account the novel framings of children in mobility/migration scholarship, as well as articularities of Polish context Stemming from the TRANSFAM research project (2013-2016), this work “gives children a voice” through a qualitative research methodology. The study illuminates those national, transnational and global elements that are paramount for daily life family practices and featured in children’s narratives. The paper focuses on the importance of socializing agents (family, peer groups, culture) for the constructions of belonging. It concludes with arguments for acknowledging the contemporary hybrid and relational identities of children who grow up transnationally between Norway and Poland

The Tempered Polymerization of Human Neuroserpin

Neuroserpin, a member of the serpin protein superfamily, is an inhibitor of proteolytic activity that is involved in pathologies such as ischemia, Alzheimer's disease, and Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB). The latter belongs to a class of conformational diseases, known as serpinopathies, which are related to the aberrant polymerization of serpin mutants. Neuroserpin is known to polymerize, even in its wild type form, under thermal stress. Here, we study the mechanism of neuroserpin polymerization over a wide range of temperatures by different techniques. Our experiments show how the onset of polymerization is dependent on the formation of an intermediate monomeric conformer, which then associates with a native monomer to yield a dimeric species. After the formation of small polymers, the aggregation proceeds via monomer addition as well as polymer-polymer association. No further secondary mechanism takes place up to very high temperatures, thus resulting in the formation of neuroserpin linear polymeric chains. Most interesting, the overall aggregation is tuned by the co-occurrence of monomer inactivation (i.e. the formation of latent neuroserpin) and by a mechanism of fragmentation. The polymerization kinetics exhibit a unique modulation of the average mass and size of polymers, which might suggest synchronization among the different processes involved. Thus, fragmentation would control and temper the aggregation process, instead of enhancing it, as typically observed (e.g.) for amyloid fibrillation