The effect of breathing hypoxic gas (15% FIO₂) on physiological and behavioral outcomes during simulated driving in healthy subjects

AbstractHypoxia is mainly caused by cardiopulmonary disease or high‐altitude exposure. We used a driving simulator to investigate whether breathing hypoxic gas influences driving behaviors in healthy subjects. Fifty‐two healthy subjects were recruited in this study, approved by the Science and Engineering Ethical Committee. During simulated driving experiments, driving behaviors, breathing frequency, oxygen saturation (SpO2), and heart rate variability (HRV) were analyzed. Each subject had four driving sessions; a 10‐min practice and three 20‐min randomized interventions: normoxic room air (21% FIO2) and medical air (21% FIO2) and hypoxic air (equal to 15% FIO2), analyzed by repeated measures ANOVA. Driving behaviors and HRV frequency domains showed no significant change. Heart rate (HR; p &lt; 0.0001), standard deviation of the RR interval (SDRR; p = 0.03), short‐term HRV (SD1; p &lt; 0.0001), breathing rate (p = 0.01), and SpO2 (p &lt; 0.0001) were all significantly different over the three gas interventions. Pairwise comparisons showed HR increased during hypoxic gas exposure compared to both normoxic interventions, while SDRR, SD1, breathing rate, and SpO2 were lower. Breathing hypoxic gas (15% FiO2, equivalent to 2710 m altitude) may not have a significant impact on driving behavior in healthy subjects. Furthermore, HRV was negatively affected by hypoxic gas exposure while driving suggesting further research to investigate the impact of breathing hypoxic gas on driving performance for patients with autonomic dysfunction.</jats:p

Janus kinase inhibitors are potential therapeutics for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a poorly treated multifactorial neurodegenerative disease associated with multiple cell types and subcellular organelles. As with other multifactorial diseases, it is likely that drugs will need to target multiple disease processes and cell types to be effective. We review here the role of Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) signalling in ALS, confirm the association of this signalling with fundamental ALS disease processes using the BenevolentAI Knowledge Graph, and demonstrate that inhibitors of this pathway could reduce the ALS pathophysiology in neurons, glia, muscle fibres, and blood cells. Specifically, we suggest that inhibition of the JAK enzymes by approved inhibitors known as Jakinibs could reduce STAT3 activation and modify the progress of this disease. Analysis of the Jakinibs highlights baricitinib as a suitable candidate due to its ability to penetrate the central nervous system and exert beneficial effects on the immune system. Therefore, we recommend that this drug be tested in appropriately designed clinical trials for ALS

Soluble Fas ligand released by colon adenocarcinoma cells induces host lymphocyte apoptosis: an active mode of immune evasion in colon cancer

Expression of membrane-bound Fas ligand (mFasL) on colon cancer cells serves as a potential mechanism to inhibit host immune function by inducing apoptosis of host lymphocytes. Membrane-bound FasL can be cleaved and released as a soluble mediator (sFasL), which may spread the apoptosis induction effect. Our study examined whether colon adenocarcinoma cells release sFasL, and induce apoptosis of host lymphocytes without direct cell–cell contact. In 12 consecutive patients with colon adenocarcinoma mFasL was identified in the tumours, sFasL was measured in the sera and apoptosis identified in tumour-infiltrating and peripheral blood lymphocytes. To analyse the function of sFasL, colon cancer cells were primarily cultured; sFasL was isolated from supernatants, measured, incubated with Fas-bearing Jurkat cells, and the resulting apoptosis was analysed. Serum levels of sFasL were significantly elevated in all colon cancer patients with mFasL expression in tumour tissues (n = 8). In these patients, the number of apoptotic lymphocytes was significantly increased within tumour and peripheral blood. Furthermore, sFasL was present in the corresponding supernatants and induced apoptosis of Jurkat cells in a dose-dependent manner. These findings suggest that mFasL-positive colon cancer cells release sFasL, and thus may induce apoptosis of host lymphocytes as a potential mechanism for immune evasion. © 2001 Cancer Research Campaignhttp://www.bjcancer.co

Bidirectional synthesis of di-t-butyl (2S,6S,8S)- and (2R,6R,8R)-1,7-diazaspiro[5.5]undecane-2,8-dicarboxylate and related spirodiamines

Efficient syntheses of both enantiomers of a spirodiamine diester from (L)- and (D)-aspartic acid are described. The key transformation was the conversion of Boc-protected t-butyl aspartate into the derived aldehyde, two directional Horner Emmons olefination, hydrogenation and selective acid-catalyzed Boc-deprotection and spirocyclization. An alternative, two-directional approaches to derivatives of 1,7-diazaspiro[5.5]undecane is described

Site-selective Suzuki-Miyaura coupling of heteroaryl halides - understanding the trends for pharmaceutically important classes

Suzuki–Miyaura cross-coupling reactions of heteroaryl polyhalides with aryl boronates are surveyed. Drawing on data from literature sources as well as bespoke searches of Pfizer's global chemistry RKB and CAS Scifinder® databases, the factors that determine the site-selectivity of these reactions are discussed with a view to rationalising the trends found

Bed geometry used to test recognition criteria of turbidites and (sandy) debrites

The origin of thick-bedded deep-water sandstones has generated much controversy in recent years. Two fundamentally different models have been proposed for beds with the same internal sedimentary characteristics: (1) progressive particle settling from the base of a turbulent flow—the “turbidity current” model and (2) en-masse freezing of a higher-concentration flow—the “sandy debris flow” model. These models predict beds with very different geometries; turbidites thin gradually whereas debrites have abrupt terminations. Previous studies have relied upon sedimentary recognition criteria (i.e., sedimentary features in small-scale outcrop or core) to interpret depositional mechanism. In this study, depositional mechanism is deduced from bed geometry gained from extensive correlations of individual sandstones preserved in a classic turbidite system (Marnoso-arenacea Formation, Italy). This approach allows recognition criteria for turbidites and submarine debrites to be independently tested. We find that tabular and tapered sandstones (turbidites) have distinctly different internal characteristics to beds with abrupt margins (debrites). Turbidites are relatively well sorted, often exhibit grading and traction structures and have relatively low matrix mud contents. They may also contain massive division, floating clasts and inverse grading. Debrites are moderate-to-poorly sorted, ungraded, structureless, contain floating clasts and have elevated matrix mud contents. These findings have implications for the assessment of submarine gravity flows deposits and reservoir rock characterization

Synthesis and reactions of benzannulated spiroaminals: tetrahydrospirobiquinolines

An efficient two-step synthesis of symmetrical and unsymmetrical tetrahydrospirobiquinolines from o-azidobenzaldehydes is reported. A novel series of tetrahydrospirobiquinolines was prepared by sequential double-aldol condensation with acetone, cyclopentanone, and cyclohexanone to form the corresponding o,o′-diazido-dibenzylidene-acetone, -cyclopentanone, and -cyclohexanone derivatives, respectively, and hydrogenation–spirocyclization. The spirodiamines were further derivatized by electrophilic aromatic bromination, Suzuki coupling, and N-alkylation, all of which proceeded with preservation of the spirocyclic core