Computational studies of Brønsted acid-catalyzed transannular cycloadditions of cycloalkenone hydrazones

The contribution to the energy barrier of a series of tethers in transannular cycloadditions of cycloalkenes with hydrazones has been computationally studied by using DFT. The Houk's distortion model has been employed to evaluate the influence of the tether in the cycloaddition reaction. That model has been extended to determine the contribution of each tether and, more importantly, the effect exerted between them. In addition to the distortion induced by the tethers, the entropy effects caused by them has also been studied. The analysis of the evolution of the electron localization function along the reaction revealed the highly concerted character of the reaction

Mechanistic insights on the enantioselective (4+3) cycloaddition between oxyallylcations and furans catalyzed by binol-based phosphoramides

The mechanism of the enantioselective (4+3) cycloaddition between furan derivatives and oxyallylcations, which are generated from the corresponding oxiranes through in situ oxidation of allenamides, has been studied using DFT methods. The research has revealed that, under acid‐catalysis by a chiral non‐racemic phosphoramide, the epoxide ring‐opening proceeds without any energy barrier, while the rate‐limiting step is the electrophilic attack of the intermediate enaminium ion on the furan ring. The reaction exhibits low energy barriers when dealing with furan derivatives unsubstituted at C2 and C5. Calculations predict the formation of an achiral regioisomer for 2‐substituted furans, a prediction that has been experimentally confirmed. Additionally, the calculations accurately predict the reaction with substituted allenamides

Switchable Brønsted acid-catalyzed ring contraction of Cyclooctatetraene oxide towards the enantioselective synthesis of Cyloheptatrienyl-substituted homoallylic Alcohols and Oxaborinanes

The ability of cyclooctatetraene oxide to undergo two sequential ring contraction events under mild conditions, using Brønsted acid catalysis, has been studied in detail. We have found that the selectivity can be controlled by the acidity of the catalyst and by the temperature, being able to obtain selectively either the cycloheptatriene carbaldehyde product, arising from a single ring-contraction event, or phenylacetaldehyde that is formed after a second ring contraction process. A complete mechanistic picture of the reaction and a rationale behind the influence of the catalyst is provided based on both experimental and computational data. Finally, this acid-catalyzed ring contraction has been coupled with an in situ enantioselective allylation reaction, delivering enantioenriched cycloheptatrienyl-substituted homoallylic alcohols when it is carried out in the presence of a chiral phosphoric acid catalyst. These homoallylic alcohols have also been converted into enantioenriched oxaborinanes through copper-catalyzed nucleophilic borylation/cyclization protocol

A palaeoecological approach to understanding the past and present of Sierra Nevada, a Southwestern European biodiversity hotspot

Mediterranean mountainous environments are biodiversity hotspots and priority areas in conservation agendas. Although they are fragile and threatened by forecasted global change scenarios, their sensitivity to long-term environmental variability is still understudied. The Sierra Nevada range, located in southern Spain on the north-western European flanks of the Mediterranean basin, is a biodiversity hotspot. Consequently, Sierra Nevada provides an excellent model system to apply a palaeoecological approach to detect vegetation changes, explore the drivers triggering those changes, and how vegetation changes link to the present landscape in such a paradigmatic mountain system. A multi-proxy strategy (magnetic susceptibility, grain size, loss-on-ignition, macroremains, charcoal and palynological analyses) is applied to an 8400-year long lacustrine environmental archive from the Laguna de la Mosca (2889 masl). The long-term ecological data show how the Early Holocene pine forests transitioned towards mixed Pinus-Quercus submediterranean forests as a response to a decrease in seasonality at ~7.3 cal. kyr BP. The mixed Pinus-Quercus submediterranean forests collapsed drastically giving way to open evergreen Quercus formations at ~4.2 cal. kyr BP after a well-known aridity crisis. Under the forecasted northward expansion of the Mediterranean area due to global change-related aridity increase, mountain forests inhabiting territories adjacent to the Mediterranean Region could experience analogous responses to those detected in the Sierra Nevada forests to the Mid to Late Holocene aridification, moving from temperate to submediterranean and then Mediterranean formations

Brønsted Acid versus Phase-Transfer Catalysis in the Enantioselective Transannular Aminohalogenation of Enesultams

We have studied the enantioselective transannular aminohalogenation reaction of unsaturated medium-sized cyclic benzosulfonamides by using both chiral Brønsted acid and phase-transfer catalysis. Under optimized conditions, a variety of bicyclic adducts can be obtained with good yields and high enantioselectivities. The mechanism of the reaction was also studied by using computational tools; we observed that the reaction involves the participation of a conformer of the nine-membered cyclic substrate with planar chirality in which the stereochemical outcome is controlled by the relative reactivity of the two pseudorotational enantiomers when interacting with the chiral catalyst

Organocatalytic Enantioselective Vinylcyclopropane-Cyclopentene (VCP-CP) Rearrangement

We have demonstrated that the catalytic and enantioselective vinylcyclopropane-cyclopentene rearrangement can be carried out on (vinylcyclopropyl)acetaldehydes through activation via enamine intermediates. The reaction makes use of racemic starting materials that, upon ring opening facilitated by the catalytic generation of a donor-acceptor cyclopropane, deliver an acyclic iminium ion/dienolate intermediate in which all stereochemical information has been deleted. The final cyclization step forms the rearrangement product, showing that chirality transfer from the catalyst to the final compound is highly effective and leads to the stereocontrolled formation of a variety of structurally different cyclopentenes

Profibrotic role of inducible heat shock protein 90α isoform in systemic sclerosis

Systemic sclerosis (SSc) is an autoimmune disease that affects skin and multiple internal organs. TGF-β, a central trigger of cutaneous fibrosis, activates fibroblasts with the involvement of the stress-inducible chaperone heat shock protein 90 isoform α (Hsp90α). Available evidence supports overexpression and secretion of Hsp90α as a feature in profibrotic pathological conditions. The aim of this work is to investigate the expression and function of Hsp90α in experimental models of skin fibrosis such as human fibroblasts, C57BL/6 mice, and in human SSc. For this purpose, we generated a new experimental model based on doxorubicin administration with improved characteristics with respect to the bleomycin model. We visualized disease progression in vivo by fluorescence imaging. In this work, we obtained Hsp90α mRNA overexpression in human skin fibroblasts, in bleomycin- and doxorubicin-induced mouse fibrotic skin, and in lungs of bleomycin- and doxorubicin-treated mice. Hsp90α-deficient mice showed significantly decreased skin thickness compared with wild-type mice in both animal models. In SSc patients, serum Hsp90α levels were increased in patients with lung involvement and in patients with the diffuse form of SSc (dSSc) compared with patients with the limited form of SSc. The serum Hsp90α levels of patients dSSc were correlated with the Rodnan score and the forced vital capacity variable. These results provide new supportive evidence of the contribution of the Hsp90α isoform in the development of skin fibrosis. In SSc, these results indicated that higher serum levels were associated with dSSc and lung fibrosis.This work was supported by Spanish Ministerio de Economía, Industria y Competitividad, Gobierno de España Grant RTI2018-095214-B-I00, as well as by the Instituto de Formación e Investigación Marqués de Valdecilla IDIVAL (InnVal 17/22; InnVal 20/34), 2020UCI22-PUB-0003 Gobierno de Cantabria (to A.V.V.), SAF2016-75195-R (to J.M.), SAF2017-82905-R (to R.M.), and (NextVal 18/14) to A.P

Multimorbidity management in atrial fibrillation:The Polish perspective in the EHRA-PATHS study

Background: Atrial fibrillation (AF) is the most common arrhythmia which places a significant bur-den on individuals as well as the healthcare system. AF management requires a multidisciplinary approach in which tackling comorbidities is an important aspect. Aims: This study aimed to evaluate how multimorbidity is currently assessed and managed and to determine if interdisciplinary care is undertaken. Methods: A 21-item online survey was undertaken over four weeks as part of the EHRA-PATHS study examining comorbidities in AF and distributed to European Heart Rhythm Association members in Europe. Results: A total of 341 eligible responses were received, of which 35 (10%) were from Polish physi-cians. Compared to other European locations, the rates of specialist services and referrals varied but were not significantly different. However, there were higher numbers of specialized services reported in Poland compared to the rest of Europe for hypertension (57% vs. 37%; P = 0.02) and palpita-tions/arrhythmias (63% vs. 41%; P = 0.01), whereas rates of sleep apnea services and comprehensive geriatric care tended to be lower (20% vs. 34%; P = 0.10 and 14% vs. 36%; P = 0.01, respectively). The only statistical difference in reasons for referral rates between Poland and the rest of Europe was the barrier relating to insurance and financial reasons (31% vs. 11%; P <0.01, respectively). Conclusions: There is a clear need for an integrated approach to patients with AF and associated comorbidities. Preparedness of Polish physicians to deliver such care seems to be similar to other European countries but may be hampered by financial obstacles

Effects of adding post-workout microcurrent in male cross country athletes

Post-exercise microcurrent based treatments have shown to optimise exercise-induced adaptations in athletes. We compared the effects of endurance training in combination with either, a microcurrent or a sham treatment, on endurance performance. Additionally, changes in body composition, post-exercise lactate kinetics and perceived delayed onset of muscle soreness (DOMS) were determined. Eighteen males (32.8±6.3 years) completed an 8-week endurance training programme involving 5 to 6 workouts per week wearing a microcurrent (MIC, n=9) or a sham (SH, n=9) device for 3-h post-workout or in the morning during non-training days. Measurements were conducted at pre- and post-intervention. Compared to baseline, both groups increased (P<0.01) maximal aerobic speed (MIC, pre =17.6±1.3 to post=18.3±1.0; SH, pre=17.8±1.5 to post =18.3±1.3 km.h-1) with no changes in V ̇O2peak. No interaction effect per group and time was observed (P=0.193). Although both groups increased (P<0.05) trunk lean mass (MIC, pre=23.2±2.7 to post=24.2±2.0; SH, pre=23.4±1.7 to post=24.3±1.6 kg) only MIC decreased (pre=4.8±1.5 to post=4.5±1.5, p=0.029) lower body fat. At post-intervention, no main differences between groups were observed for lactate kinetics over the 5 min recovery period. Only MIC decreased (P<0.05) DOMS at 24-h and 48-h, showing a significant average lower DOMS score over 72-h after the completion of the exercise-induced muscle soreness protocol. In conclusion, a 3-h daily application of microcurrent over an 8-week endurance training programme produced no further benefits on performance in endurance-trained males. Nonetheless, the post-workout microcurrent application promoted more desirable changes in body composition and attenuated the perception of DOMS over 72-h post-exercise

Real-World Utilization of the Pill-In-The-Pocket Method for Terminating Episodes of Atrial Fibrillation: Data From the Multinational Antiarrhythmic Interventions for Managing Atrial Fibrillation (AIM-AF) Survey

AIMS: Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice. Episodes may stop spontaneously (paroxysmal AF); may terminate only via intervention (persistent AF); or may persist indefinitely (permanent AF) (see European and American guidelines, referenced below, for more precise definitions). Recently, there has been renewed interest in an approach to terminate AF acutely referred to as \u27pill-in-the-pocket\u27 (PITP). The PITP is recognized in both the US and European guidelines as an effective option using an oral antiarrhythmic drug for acute conversion of acute/recent-onset AF. However, how PITP is currently used has not been systematically evaluated. METHODS AND RESULTS: The recently published Antiarrhythmic Interventions for Managing Atrial Fibrillation (AIM-AF) survey included questions regarding current PITP usage, stratified by US vs. European countries surveyed, by representative countries within Europe, and by cardiologists vs. electrophysiologists. This manuscript presents the data from this planned sub-study. Our survey revealed that clinicians in both the USA and Europe consider PITP in about a quarter of their patients, mostly for recent-onset AF with minimal or no structural heart disease (guideline appropriate). However, significant deviations exist. See the Graphical abstract for a summary of the data. CONCLUSION: Our findings highlight the frequent use of PITP and the need for further physician education about appropriate and optimal use of this strategy