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Background/Objectives: In connection with previous work on V-shaped polycyclic thiazolo[5,4- f ]quinazolin-9-one and [5,4- f ]quinazoline derivatives that can modulate the activity of various kinases, the synthesis of straight thiazole-fused [4,5- g ] or [5,4- g ]quinazolin-8-ones and quinazoline derivatives hitherto undescribed was envisioned. Methods: An innovative protocol allowed to obtain the target structures. The synthesis of inverted thiazolo[4,5- h ] and [5,4- h ]quinazolin-8-one derivatives was also explored with the aim of comparing biological results. The compounds obtained were tested against a representative panel of eight mammalian protein kinases of human origin: CDK9/CyclinT, Haspin, Pim-1, GSK-3β, CK-1ε, JAK3, CLK1 and DYRK1A. Results and Conclusions: The results obtained show that the novel linear thiazoloquinazolines are not kinase inhibitors. The cytotoxicity of these newly synthesized compounds was assessed against seven representative tumor cell lines (human cancers: Huh7-D12, Caco-2, HCT-116, MCF-7, MDA-MB-231, MDA-MB-468 and PC-3). The majority of these novel molecules proved capable of inhibiting the growth of the tested cells. The 7-Benzyl-8-oxo-7,8-dihydrothiazolo[5,4- g ]quinazolinones 5b and 6b are the most potent, with IC 50 values in the micromolar range. None of these compounds showed toxicity against normal cells. A larger program of investigations will be launched to investigate the real potential interest of such compounds in anticancer applications.

Based on a multitarget approach implementing rivastigmine-INDY hybrids 1, we identified a set of pseudo-irreversible carbamate-type inhibitors of eq BuChE that, after carbamate transfer at the active site serine residue, released the corresponding INDY analogues 2 endowed with h DYRK1A/ h CLK1 kinases inhibitory properties. A SAR study and molecular docking investigation of both series of compounds 1 and 2 revealed that appropriate structural modifications at the carbamate moiety and at the N -appendage of the benzothiazole core led to potent and selective eq BuChE inhibitors with IC 50 up to 27 nM and potent h DYRK1A and h CLK1 inhibitors with IC 50 up to 106 nM and 17 nM respectively. Pleasingly, identification of the matched pair of compounds 1b/2b with a good balance between inhibition of eq BuChE and h DYRK1A/ h CLK1 kinases (IC 50 = 68 nM and IC 50 = 529/54 nM, respectively) further validated our multitarget approach based on a sequential mechanism of action. In addition, target compound 1b exhibited a suitable ADMET profile, including good brain permeability and high stability in PBS, encouraging further biological investigation as a drug candidate., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

Love is a phenomenon that occurs across the world and affects many aspects of human life, including the choice of, and process of bonding with, a romantic partner. Thus, developing a reliable and valid measure of love experiences is crucial. One of the most popular tools to quantify love is Sternberg's 45-item Triangular Love Scale (TLS-45), which measures three love components: intimacy, passion, and commitment. However, our literature review reveals that most studies (64%) use a broad variety of shortened versions of the TLS-45. Here, aiming to achieve scientific consensus and improve the reliability, comparability, and generalizability of results across studies, we developed a short version of the scale-the TLS-15-comprised of 15 items with 5-point, rather than 9-point, response scales. In Study 1 (N = 7,332), we re-analyzed secondary data from a large-scale multinational study that validated the original TLS-45 to establish whether the scale could be truncated. In Study 2 (N = 307), we provided evidence for the three-factor structure of the TLS-15 and its reliability. Study 3 (N = 413) confirmed convergent validity and test-retest stability of the TLS-15. Study 4 (N = 60,311) presented a large-scale validation across 37 linguistic versions of the TLS-15 on a cross-cultural sample spanning every continent of the globe. The overall results provide support for the reliability, validity, and cross-cultural invariance of the TLS-15, which can be used as a measure of love components-either separately or jointly as a three-factor measure., (© 2023. The Author(s).)

Abstract: Besson, T, Pastor, FS, Varesco, G, Berthet, M, Kennouche, D, Dandrieux, P-E, Rossi, J, and Millet, GY. Elite vs. experienced male and female trail runners: comparing running economy, biomechanics, strength, and power. J Strength Cond Res 37(7): 1470-1478, 2023-The increased participation in trail running (TR) races and the emergence of official international races have increased the performance level of the world best trail runners. The aim of this study was to compare cost of running (Cr) and biomechanical and neuromuscular characteristics of elite trail runners with their lower level counterparts. Twenty elite (10 females; ELITE) and 21 experienced (10 females; EXP) trail runners participated in the study. Cr and running biomechanics were measured at 10 and 14 km·h-1 on flat and at 10 km·h-1 with 10% uphill incline. Subjects also performed maximal isometric voluntary contractions of knee and hip extensors and knee flexors and maximal sprints on a cycle ergometer to assess the power-torque-velocity profile (PTVP). Athletes also reported their training volume during the previous year. Despite no differences in biomechanics, ELITE had a lower Cr than EXP (p < 0.05). Despite nonsignificant difference in maximal lower-limb power between groups, ELITE displayed a greater relative torque (p < 0.01) and lower maximal velocity (p < 0.01) in the PTVP. Females displayed shorter contact times (p < 0.01) compared with males, but no sex differences were observed in Cr (p > 0.05). No sex differences existed for the PTVP slope, whereas females exhibited lower relative torque (p < 0.01) and velocity capacities (p < 0.01) compared with males. Although not comprehensively assessing all determining factors of TR performance, those data evidenced level and sex specificities of trail runners in some factors of performance. Strength training can be suggested to lower level trail runners to improve Cr and thus TR performance., (Copyright © 2022 National Strength and Conditioning Association.)

Background and Objective: To determine whether the gap in endurance performance between men and women is reduced as distances increase, i.e. if there is a sex difference in endurance, one can analyse the performance of elite runners, all participants, or one can pair women and men during short-distance events and examine the difference over longer distances. The first two methods have caveats, and the last method has never been performed with a large dataset. This was the goal of the present study., Methods: A dataset including 38,860 trail running races from 1989 to 2021 in 221 countries was used. It provided information on 1,881,070 unique runners, allowing 7251 pairs of men and women with the same relative level of performance to be obtained, i.e. the same percentage of the winner time of the considered race on short races (25-45 km-effort) that were compared during longer races (45-260 km-effort). The effect of distance on sex differences in average speed was determined using a gamma mixed model., Results: The gap between sexes decreased as distance increases, i.e. men's speed decreased by 4.02% (confidence interval 3.80-4.25) for every 10 km-effort increase, whereas it decreased by 3.25% (confidence interval 3.02-3.46) for women. The men-women ratio decreases from 1.237 (confidence interval 1.232-1.242) for a 25 km-effort to 1.031 (confidence interval 1.011-1.052) for a 260 km-effort. This interaction was modulated by the level of performance, i.e. the greater the performance level of the runner, the lower the difference in endurance between sexes., Conclusions: This study shows for the first time that the gap between men and women shrinks when trail running distance increases, which demonstrates that endurance is greater in women. Although women narrow the performance gap with men as race distance increases, top male performers still outperform the top women., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Abstract: Sabater Pastor, FS, Besson, T, Berthet, M, Varesco, G, Kennouche, D, Dandrieux, P-E, Rossi, J, and Millet, GY. Elite road vs. trail runners: comparing economy, biomechanics, strength, and power. J Strength Cond Res 37(1): 181-186, 2023-The purpose of this study was to determine the differences between road (ROAD) vs. trail (TRAIL) elite runners in terms of force-velocity profile (FVP), running biomechanics, lower-limb maximal isometric strength, cost of running (Cr), and training. Seventeen male elite athletes (10 TRAIL and 7 ROAD) participated in this study. Force-velocity profile was measured using a 2-sprint test on a cycle ergometer. Strength was assessed with a dynamometer measuring isometric maximum voluntary torque of the knee extensors and knee flexors. Biomechanics parameters (running kinematics and stiffness) were measured, and Cr was calculated at 10 and 14 km·h-1 at 0% slope and at 10 km·h-1 on a 10% slope on a treadmill. Athletes also reported their training duration during the previous year. Theoretical maximal torque (F0) and maximal power (Pmax) in the FVP were higher for TRAIL vs. ROAD (122 ± 13 vs. 99 ± 7 N·m, p = 0.001; and 726 ± 89 vs. 626 ± 44 W; p = 0.016). Cost of running was higher for TRAIL compared with ROAD on flat at 14 km·h-1 (4.32 ± 0.22 vs. 4.06 ± 0.29 J·kg-1·m-1; p = 0.047) but similar at 10 km·h-1 and uphill. No differences were found in maximal isometric strength or running biomechanics. ROAD spent 81% more time training than TRAIL (p = 0.0003). The specific training (i.e., "natural" resistance training) performed during graded running in trail runners and training on level surface at high speed may explain our results. Alternatively, it is possible that trail running selects stronger athletes because of the greater strength requirements of graded running., (Copyright © 2022 National Strength and Conditioning Association.)

The DYRK (Dual-specificity tyrosine phosphorylation-regulated kinase) family of protein kinases is involved in the pathogenesis of several neurodegenerative diseases. Among them, the DYRK1A protein kinase is thought to be implicated in Alzheimer's disease (AD) and Down syndrome, and as such, has emerged as an appealing therapeutic target. DYRKs are a subset of the CMGC (CDK, MAPKK, GSK3 and CLK) group of kinases. Within this group of kinases, the CDC2-like kinases (CLKs), such as CLK1, are closely related to DYRKs and have also sparked great interest as potential therapeutic targets for AD. Based on inhibitors previously described in the literature (namely TG003 and INDY), we report in this work a new class of dihydroquinolines exhibiting inhibitory activities in the nanomolar range on h DYRK1A and h CLK1. Moreover, there is overwhelming evidence that oxidative stress plays an important role in AD. Pleasingly, the most potent dual kinase inhibitor 1p exhibited antioxidant and radical scavenging properties. Finally, drug-likeness and molecular docking studies of this new class of DYRK1A/CLK1 inhibitors are also discussed in this article.

We report herein on a catalytic system involving palladium and copper to achieve the cyclization of N -arylcyanothioformamides and the synthesis of 2-cyanobenzothiazoles. The C-H functionalization/intramolecular C-S bond formation reaction was achieved in the presence of air, using 2.0 equiv of an inorganic additive (KI). In many cases, the reaction led to a sole product regioselectively obtained in good yields, allowing the synthesis of a wide range of substituted 2-cyanobenzothiazole derivatives, providing valuable building blocks for the design of more complex heterocyclic or molecular labeling systems.

Infantile (fetal and neonatal) megakaryocytes (Mks) have a distinct phenotype consisting of hyperproliferation, limited morphogenesis, and low platelet production capacity. These properties contribute to clinical problems that include thrombocytopenia in neonates, delayed platelet engraftment in recipients of cord blood stem cell transplants, and inefficient ex vivo platelet production from pluripotent stem cell-derived Mks. The infantile phenotype results from deficiency of the actin-regulated coactivator, MKL1, which programs cytoskeletal changes driving morphogenesis. As a strategy to complement this molecular defect, we screened pathways with the potential to affect MKL1 function and found that DYRK1A inhibition dramatically enhanced Mk morphogenesis in vitro and in vivo. Dyrk1 inhibitors rescued enlargement, polyploidization, and thrombopoiesis in human neonatal Mks. Mks derived from induced pluripotent stem cells responded in a similar manner. Progenitors undergoing Dyrk1 inhibition demonstrated filamentous actin assembly, MKL1 nuclear translocation, and modulation of MKL1 target genes. Loss-of-function studies confirmed MKL1 involvement in this morphogenetic pathway. Expression of Ablim2, a stabilizer of filamentous actin, increased with Dyrk1 inhibition, and Ablim2 knockdown abrogated the actin, MKL1, and morphogenetic responses to Dyrk1 inhibition. These results delineate a pharmacologically tractable morphogenetic pathway whose manipulation may alleviate clinical problems associated with the limited thrombopoietic capacity of infantile Mks.

The purpose of the study was to assess sex-related differences in resting mechanical properties and adaptations of skeletal muscles and tendons in response to trail running races of different distances using multi-site shear wave elastography assessments of the lower limb, force capacity and blood analyses. Sex differences in resting mechanical properties of knee extensor and plantar flexor muscles and tendons were characterized by shear wave velocity (SWV) measurements in healthy males (N = 42) and females (N = 25) trained in long-distance running. Effects of running distance on muscle and tendon properties were assessed in short (<60 km, N = 23) vs. long (>100 km, N = 26) distance races. Changes in isometric maximal voluntary contraction torque, serum C-reactive protein and creatine kinase activity were also quantified after running races. Higher SWV of relaxed triceps surae muscle was detected in females as compared to males before running races (+4.8%, p = 0.006), but the significant increases in triceps surae muscle group (+7.0%, p = 0.001) and patellar tendon SWV (+15.4%, p = 0.001) after short-distance races were independent of sex. A significant decrease in triceps surae muscle SWV was found after long-distance races in the whole experimental population (-3.1%, p = 0.049). Post-races increase in C-reactive protein and creatine kinase activity were significantly correlated to the relative decreases in triceps surae and quadriceps femoris skeletal muscle SWV (ρ = -0.56, p = 0.001 and ρ = -0.51, p = 0.001, respectively). Resting mechanical properties of muscles and tendons are affected by sex, and adaptations to trail races are related to running distance. Exercise-induced changes in resting skeletal muscle mechanical properties are associated with enhanced indirect markers of inflammation and muscle damage., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In this study we show that glycosylation is relevant for immune recognition of therapeutic antibodies, and that defined glycan structures can modulate immunogenicity. Concerns regarding immunogenicity arise from the high heterogeneity in glycosylation that is difficult to control and can deviate from human glycosylation if produced in non-human cell lines. While non-human glycosylation is thought to cause hypersensitivity reactions and immunogenicity, less is known about effects of Fc-associated glycan structures on immune cell responses. We postulated that glycosylation influences antigen recognition and subsequently humoral responses to therapeutic antibodies by modulating 1) recognition and uptake by dendritic cells (DCs), and 2) antigen routing, processing and presentation. Here, we compared different glycosylation variants of the antibody rituximab (RTX) in in vitro assays using human DCs and T cells as well as in in vivo studies. We found that human DCs bind and internalize unmodified RTX stronger compared to its aglycosylated form suggesting that glycosylation mediates uptake after recognition by glycan-specific receptors. Furthermore, we show that DC-uptake of RTX increases or decreases if glycosylation is selectively modified to recognize activating (by mannosylation) or inhibitory lectin receptors (by sialylation). Moreover, glycosylation seems to influence antigen presentation by DCs because specific glycovariants tend to induce either stronger or weaker T cell activation. Finally, we demonstrate that antibody glycosylation impacts anti-drug antibody (ADA) responses to RTX in vivo. Hence, defined glycan structures can modulate immune recognition and alter ADA responses. Glyco-engineering may help to decrease clinical immunogenicity and ADA-associated adverse events such as hypersensitivity reactions., (© 2022 John Wiley & Sons Ltd.)

In recent years, there has been a significant expansion in female participation in endurance (road and trail) running. The often reported sex differences in maximal oxygen uptake (VO 2max ) are not the only differences between sexes during prolonged running. The aim of this narrative review was thus to discuss sex differences in running biomechanics, economy (both in fatigue and non-fatigue conditions), substrate utilization, muscle tissue characteristics (including ultrastructural muscle damage), neuromuscular fatigue, thermoregulation and pacing strategies. Although males and females do not differ in terms of running economy or endurance (i.e. percentage VO 2max sustained), sex-specificities exist in running biomechanics (e.g. females have greater non-sagittal hip and knee joint motion compared to males) that can be partly explained by anatomical (e.g. wider pelvis, larger femur-tibia angle, shorter lower limb length relative to total height in females) differences. Compared to males, females also show greater proportional area of type I fibres, are more able to use fatty acids and preserve carbohydrates during prolonged exercise, demonstrate a more even pacing strategy and less fatigue following endurance running exercise. These differences confer an advantage to females in ultra-endurance performance, but other factors (e.g. lower O 2 carrying capacity, greater body fat percentage) counterbalance these potential advantages, making females outperforming males a rare exception. The present literature review also highlights the lack of sex comparison in studies investigating running biomechanics in fatigue conditions and during the recovery process., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: While the physiological determinants of road running have been widely studied, there is a lack of research in trail-running racing performance. The aim of our study was to determine the physiological predictors of trail-running performance in races of different distances in similar terrain and weather conditions., Methods: Seventy-five trail runners participating in one of the races of the Ultra-Trail du Mont-Blanc were recruited. Previous to the race, each runner was evaluated with (1) an incremental treadmill test to determine maximal oxygen uptake, ventilatory thresholds, cost of running, and substrate utilization; (2) a power-force-velocity profile on a cycle ergometer; (3) maximal voluntary contractions of the knee extensors and plantar flexors; and (4) anthropometric characteristics. Neuromuscular fatigue was evaluated after the races. Twenty-four runners finished a SHORT (<55 km), 16 finished a MEDIUM (101 km), and 14 finished a LONG (>145 km) race. Correlations and multiple linear regressions were used to find the determinants of performance in each race distance., Results: Performance in SHORT was explained by maximal oxygen uptake and lipid utilization at 10 km/h (r2 = .825, P < .001). Performance in MEDIUM was determined by maximal oxygen uptake, maximal isometric strength, and body fat percentage (r2 = .917, P < .001). A linear model could not be applied in LONG, but performance was correlated to peak velocity during the incremental test., Conclusions: Performance in trail running is mainly predicted by aerobic capacity, while lipid utilization also influences performance in races <60 km and performance in approximately 100 km is influenced by muscle strength and body composition.

In a permanent quest for profit, employees can be reduced to a mere function or instrument, dissociated from their quality as individuals for the organization's ends. Experiencing such a feeling as an employee has been called organizational dehumanization. Scholars have recently suggested that organizational dehumanization may play a key role in the development of emotional labor. However, how organizational dehumanization and two main emotional labor strategies (i.e., surface and deep acting) are causally related remains unclear in this literature. In the present research, we argue that employees who experience organizational dehumanization and whose self is thus threatened then engage in surface acting to "conserve" their self or in deep acting to "give up" their self in service of the role. Overall, the combined results of three studies offer strong evidence that organizational dehumanization leads employees to perform more surface acting, but not more deep acting. Unexpectedly, our findings also indicate that deep acting reduces the perception of being dehumanized by the organization. In showing this, the present research sheds light on the potential dark side of deep acting, by suggesting that this strategy can change employees' perspectives in a way that may encourage them to stay in an organization that treats them as a means to an end. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Right-wing authoritarianism (RWA) and social dominance orientation (SDO) both predict generalized prejudice, dehumanization, intergroup discrimination, oppression, violence, right-wing political party preference, and generally punitive attitudes. Authoritarian attitudes have been theorized to involve maladaptive emotional, cognitive, and social self-regulation. However, there is no study of authoritarianism using the functioning of the parasympathetic nervous system (PNS) as a physiological index of self-regulation, thus leaving it unclear whether regulation is "impaired" with authoritarian attitudes per se. PNS functioning is commonly assessed by examining tonic and phasic heart rate variability (HRV). These two components are recognized to be important in terms of adaptation to stress. Decreased HRV has been associated with hypoactive prefrontal regulation, hyperactive subcortical structures, maladaptive self-regulation, hyper-vigilance, decreased prosocial tendencies, defensiveness, impulsive behaviors, and aggression. Previous research suggests that self-regulatory failure may favor hostile attitudes and prejudicial intergroup behaviors. In a first study, we found that high RWA was associated with lower tonic HRV at rest. In a second study, stress-induced autonomic reactivity and poststress autonomic recovery were examined as potential pathways linking authoritarian attitudes to self-regulation. We found that high RWA and high SDO were associated with (i) lower tonic HRV during stress, (ii) greater autonomic reactivity during stress, and (iii) lower autonomic recovery. Overall, our results suggest that autonomic dysregulation during and following stress is a plausible physiological pathway connecting RWA and SDO to self-regulation. Implications of such results for research on political attitudes are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The objective of this review is to list the structures composed of a pyridopyrimidine moiety which have shown a therapeutic interest or have already been approved for use as therapeutics. We consider all the synthetic protocols to prepare these pyridopyrimidine derivatives. The review is organized into four sections, successively pyrido[2,3- d ]pyrimidines, pyrido[3,4- d ]pyrimidines, pyrido[4,3- d ]pyrimidines and pyrido[3,2- d ]pyrimidines. For each compound we present the biological activity and the synthetic route reported. To produce this manuscript, the bibliographic research was done using Reaxys and Scifinder for each kind of pyridopyrimidine.

Purpose: Fatigue has previously been investigated in trail running by comparing maximal isometric force before and after the race. Isometric contractions may not entirely reflect fatigue-induced changes, and therefore dynamic evaluation is warranted. The aim of the present study was to compare the magnitude of the decrement of maximal isometric force versus maximal power, force, and velocity after trail running races ranging from 40 to 170 km., Methods: Nineteen trail runners completed races shorter than 60 km, and 21 runners completed races longer than 100 km. Isometric maximal voluntary contractions (IMVCs) of knee extensors and plantar flexors and maximal 7-second sprints on a cycle ergometer were performed before and after the event., Results: Maximal power output (Pmax; -14% [11%], P < .001), theoretical maximum force (F0; -11% [14%], P < .001), and theoretical maximum velocity (-3% [8%], P = .037) decreased significantly after both races. All dynamic parameters but theoretical maximum velocity decreased more after races longer than 100 km than races shorter than 60 km (P < .05). Although the changes in IMVCs were significantly correlated (P < .05) with the changes in F0 and Pmax, reductions in IMVCs for knee extensors (-29% [16%], P < .001) and plantar flexors (-26% [13%], P < .001) were larger (P < .001) than the reduction in Pmax and F0., Conclusions: After a trail running race, reductions in isometric versus dynamic forces were correlated, yet they are not interchangeable because the losses in isometric force were 2 to 3 times greater than the reductions in Pmax and F0. This study also shows that the effect of race distance on fatigue measured in isometric mode is true when measured in dynamic mode.

Introduction: Women have been shown to experience less neuromuscular fatigue than men in knee extensors (KE) and less peripheral fatigue in plantar flexors (PF) after ultratrail running, but it is unknown if these differences exist for shorter trail running races and whether this may impact running economy. The purpose of this study was to characterize sex differences in fatigability over a range of running distances and to examine possible differences in the postrace alteration of the cost of running (Cr)., Methods: Eighteen pairs of men and women were matched by performance after completing different races ranging from 40 to 171 km, divided into SHORT versus LONG races (<60 and >100 km, respectively). Neuromuscular function and Cr were tested before and after each race. Neuromuscular function was evaluated on both KE and PF with voluntary and evoked contractions using electrical nerve (KE and PF) and transcranial magnetic (KE) stimulation. Oxygen uptake, respiratory exchange ratio, and ventilation were measured on a treadmill and used to calculate Cr., Results: Compared with men, women displayed a smaller decrease in maximal strength in KE (-36% vs -27%, respectively, P < 0.01), independent of race distance. In SHORT only, women displayed less peripheral fatigue in PF compared with men (Δ peak twitch: -10% vs -24%, respectively, P < 0.05). Cr increased similarly in men and women., Conclusions: Women experience less neuromuscular fatigue than men after both "classic" and "extreme" prolonged running exercises but this does not impact the degradation of the energy Cr., (Copyright © 2021 by the American College of Sports Medicine.)

The etiology of changes in lower-limb neuromuscular function, especially to the central nervous system, may be affected by exercise duration. Direct evidence is lacking as few studies have directly compared different race distances. This study aimed to investigate the etiology of deficits in neuromuscular function following short versus long trail-running races. Thirty-two male trail runners completed one of five trail-running races as LONG (>100 km) or SHORT (<60 km). Pre- and post-race, maximal voluntary contraction (MVC) torque and evoked responses to electrical nerve stimulation during MVCs and at rest were used to assess voluntary activation and muscle contractile properties of knee-extensor (KE) and plantar-flexor (PF) muscles. Transcranial magnetic stimulation (TMS) was used to assess evoked responses and corticospinal excitability in maximal and submaximal KE contractions. Race distance correlated with KE MVC (ρ = -0.556) and twitch (ρ = -0.521) torque decreases (p ≤ .003). KE twitch torque decreased more in LONG (-28 ± 14%) than SHORT (-14 ± 10%, p = .005); however, KE MVC time × distance interaction was not significant (p = .073). No differences between LONG and SHORT for PF MVC or twitch torque were observed. Maximal voluntary activation decreased similarly in LONG and SHORT in both muscle groups (p ≥ .637). TMS-elicited silent period decreased in LONG (p = .021) but not SHORT (p = .912). Greater muscle contractile property impairment in longer races, not central perturbations, contributed to the correlation between KE MVC loss and race distance. Conversely, PF fatigability was unaffected by race distance., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Transition-metal-free direct arylation of C-H or N-H bonds is one of the key emerging methodologies that is currently attracting tremendous attention. Diaryliodonium salts serve as a stepping stone on the way to alternative environmentally friendly and straightforward pathways for the construction of C-C and C-heteroatom bonds. In this review, we emphasize the recent synthetic advances of late-stage C(sp2)-N and C(sp2)-C(sp2) bond-forming reactions under metal-free conditions using diaryliodonium salts as arylating reagent and its applications to the synthesis of new arylated bioactive heterocyclic compounds.

This paper reports a convenient sequential one-pot approach for the synthesis of an array of 14 pyrazolo[1,5- a ][1,3,5]triazines, substituted in C8 by halogen (Br), various functions (CN and CO 2 Et) and alkyl or (het)aryl groups. This study confirms the interest of combining the efficient heating obtained under dielectric microwave heating and the achievement of sequential one-pot reactions, avoiding the tedious work-up and purification of intermediate compounds, achieving sustainable synthesis processes. Considering usual conventional methods, this microwave protocol is featured by advantages in terms of yields, reaction times, and convenient gram scale synthesis.

New Findings: What is the central question of this study? Are spinal and/or supraspinal perturbations implicated in central fatigue induced in the plantar flexor muscles following prolonged trail running races? What is the main finding and its importance? The study confirmed the presence of central fatigue following various trail running distances from 40 to 170 km. The reduction in the V-wave in conjunction with the lack of change in the H-reflex suggests that a major component of this central fatigue may arise from supraspinal mechanisms in the plantar flexor muscles., Abstract: Trail running races are known to induce considerable impairments in neuromuscular function of which central mechanisms are a substantial component. However, the loci of this central fatigue (i.e. supraspinal and/or spinal) is not well identified. The aim of this study was to better understand central fatigue aetiology induced in the plantar flexor muscles by various trail running distances from 40 to 170 km. Eighteen runners participated in the study and neuromuscular function of their plantar flexors was tested before (PRE) and after (POST) various races during the Ultra-Trail du Mont Blanc. Neuromuscular function was evaluated with voluntary and evoked contractions using electrical tibial nerve stimulation. H-reflex and V-wave responses were also measured during submaximal and maximal voluntary contraction, respectively. Reductions in maximal voluntary contraction torque (-29%; P < 0.001) and voluntary activation level (-12%; P < 0.001) were observed after trail running races. The V-wave was reduced in soleus (-35%; P = 0.003) and gastrocnemius medialis (-28%; P = 0.031), with no changes for the H-reflex in soleus (P = 0.577). The present study confirmed the presence of central fatigue following trail running exercise. The reduction in the V-wave in conjunction with the lack of change in the H-reflex suggests that a major component of this central fatigue may arise from supraspinal mechanisms., (© 2021 The Authors. Experimental Physiology © 2021 The Physiological Society.)

The development of new and greener approaches to organic synthesis has been a trend in recent years. Continuing the latest publications of our team, in this work, we demonstrate the efficiency of three solvents: eucalyptol (1,8-cineole), cyclopentyl methyl ether (CPME), and 2-methyltetrahydrofuran (2-MeTHF) for the synthesis of O,S,N-heterocyclic compounds.

DYRK1A is a serine/threonine kinase encoded on human chromosome 21 (HSA21) that has been implicated in several pathologies of Down syndrome (DS), including cognitive deficits and Alzheimer's disease. Although children with DS are predisposed to developing leukemia, especially B cell acute lymphoblastic leukemia (B-ALL), the HSA21 genes that contribute to malignancies remain largely undefined. Here, we report that DYRK1A is overexpressed and required for B-ALL. Genetic and pharmacologic inhibition of DYRK1A decreased leukemic cell expansion and suppressed B-ALL development in vitro and in vivo. Furthermore, we found that FOXO1 and STAT3, transcription factors that are indispensable for B cell development, are critical substrates of DYRK1A. Loss of DYRK1A-mediated FOXO1 and STAT3 signaling disrupted DNA damage and ROS regulation, respectively, leading to preferential cell death in leukemic B cells. Thus, we reveal a DYRK1A/FOXO1/STAT3 axis that facilitates the development and maintenance of B-ALL.

Introduction: Nerve ultrasound has been used increasingly in clinical practice as a complementary test for diagnostic assessment of neuropathies, but nerve biopsy remains invaluable in certain cases. The aim of this study was to compare ultra-high-frequency ultrasound (UHF-US) to histologic findings in progressive polyneuropathies., Methods: Ten patients with severe, progressive neuropathies underwent ultrasound evaluation of the sural nerve before nerve biopsy. Ultrasound data were compared with histologic results in a retrospective manner., Results: Sural nerves were easily identified on UHF-US. Nerve hyperechogenicity correlated with inflammatory infiltrates on biopsy. Nerve fascicles could be identified and measured on ultrasound in the majority of patients., Discussion: Hyperechogenicity on UHF-US may be a marker of nerve inflammation in neuropathies. Furthermore, the UHF-US probe allows for evaluation of sensory nerves in spite of their small size, providing valuable information on their size and on their internal structure., (© 2020 Wiley Periodicals LLC.)

Efficient microwave-assisted chemical processes were applied to the synthesis of an array of novel N -(4-methoxyphenylamino)-2-methyl benzo-, pyrido- or pyrazino-thieno[3,2- d ]pyrimidin-4-amine derivatives. These heteroaromatic systems were envisioned as potent bioisosteric analogues of MPC-6827 , an anticancer agent previously developed until phase II clinical studies. A brief evaluation and comparison of their antiproliferative activity on HT-29 and Caco-2, two human colorectal cancer cell lines, were also reported. At the tested concentrations (5 and 10 µM), thieno[3,2- d ]pyrimidin-4-amines 4a and 4c exhibited an inhibitory effect similar to MPC-6827 on human colorectal cancer cell proliferation.

Purpose: Ultramarathon running includes two main types of events: single-stage race (SSR) and multistage races (MSR). Direct comparison of neuromuscular fatigue and recovery after SSR versus MSR race of comparable distance and elevation has never been performed. The aim of this study was to assess neuromuscular fatigue and recovery after two ultramarathons of equal distance performed either (i) in a single stage or (ii) in four successive days., Methods: Thirty-one runners participated in the study: 17 ran 169 km in a single-stage race and 14 performed around 40 km·d over 4 d. The two races were performed on the same course. Neuromuscular function was tested before (PRE), after (POST), and 2 (D + 2), 5 (D + 5) and 10 (D + 10) days after the races. Neuromuscular function was evaluated on both knee extensors (KE) and plantar flexors (PF) with voluntary and evoked contractions using electrical (femoral and tibial, respectively) nerve stimulation., Results: Reduction of voluntary activation measured in the KE was greater (i.e., central fatigue) for SSR than MSR directly after the race (-23% vs -7%), P < 0.01). Reductions in evoked mechanical KE and PF responses on relaxed muscle (i.e., peripheral fatigue) of both KE and PF took longer to recover in MSR than in SSR., Conclusions: Performing prolonged running exercise over several days, each separated by rest, elicits more prolonged impairments in contractile function compared with single-stage ultramarathon, whereas single-stage mountain ultramarathon ran on the same course is associated with greater central fatigue.

We previously highlighted the interest in 6,5,6-fused tricyclic analogues of 4-aminoquinazolines as kinase inhibitors in the micromolar to the nanomolar range of IC 50 values. For the generation of chemical libraries, the formamide-mediated cyclization of the cyanoamidine precursors was carried out under microwave irradiation in an eco-friendly approach. In order to explore more in-depth the pharmacological interest in such tricyclic skeletons, the central five member ring, i.e., thiophène or furan, was replaced by a pyrrole to afford 9H-pyrimido[5,4-b]- and [4,5-b]indol-4-amine derivatives inspired from harmine. The inhibitory potency of the final products was determined against four protein kinases (CDK5/p25, CK1/ε, GSK3 and DYRK1A). As a result, we have identified promising compounds targeting CK1/ε and DYRK1A and displaying micromolar and submicromolar IC 50 values., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Two superposed layers of transparent cylindrical lenslet gratings create classical moiré fringes when illuminated from behind. We rely on this observation to conceive special devices made of superposed lenslet gratings that produce compelling beating shapes when tilted against the light. Level-line moirés are created by superposing gratings of cylindrical lenslets of the same period on both sides of a substrate and by locally shifting some of the cylindrical lenses according to the moiré theory. Depending on the illumination and the viewing conditions, constant light intensities or colors move across graphical elements or faces. Such level-line moiré samples have been fabricated and characterized to determine the optimal fabrication parameters. Thanks to their striking visual appeal and their relatively challenging fabrication, moirés created by superposition of lenslets have a high potential for document security, art, and decoration.

In the last few years, vegetarian products have become a widespread dietary option in food industry to the point that large retail chains such as McDonald's has offered a vegetarian burger to their customers (e.g., the Grand Veggie). In the present research, two studies investigated the influence of a vegetarian label on calorie perception, frequency consumption and food choices. In the first study (N = 211) participants were randomly assigned to an experimental design 2 (burger type: Grand Veggie vs Big Mac). In the second study (N = 915), participants were either exposed to a similar burger labeled vegetarian or a meat-based. Both studies show that vegetarian products are perceived as being less caloric than their non-vegetarian equivalents. However, participants do not report more intention to eat more vegetarian products and do not lead to differences in menu composition.