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Herein, we present a highly efficient method for constructing the intricate 5-5-6 fused ring system commonly found in the polycyclic furanobutenolide-derived cembranoid and norcembranoid natural product family with remarkable diastereoselectivity, utilizing an intramolecular Diels-Alder reaction as the cornerstone. Notably, employing a propargyl ether tether as the dienophile yields significant enhancements in the transformation process compared to its propargyl ester counterpart, as demonstrated in our previous total synthesis of havellockate. This advancement holds promising implications for future investigations, offering a streamlined pathway for rapidly assembling the tricyclic core characteristic of this diverse family of natural products.

Objectives: To adapt and develop a reliable and easily administered outcome measure of physical and respiratory function in critically ill children in the PICU., Design: Modified Delphi study to adapt the Chelsea Critical Care Physical Assessment (CPAx) tool for use in children 2-18 years old, with subsequent prospective testing in a single-center cohort., Setting: Single-center tertiary PICU., Subjects: Delphi process in 27 panelists (including physiotherapists, occupational therapists, and pediatric intensivists from seven countries from January 2018 to March 2018). Cohort study in 54 patients admitted to PICU for greater than 24 hours over a 3-month period (April 2018 to June 2018), with median age 5.5 years (interquartile range [IQR], 3-12.75 yr), 33 of 54 male, and 38 of 54 invasively ventilated., Interventions: None., Measurements and Main Results: Three Delphi iterations were required to reach greater than or equal to 80% consensus in all the children's CPAx (cCPAx) items. In the subsequent cohort study, six physiotherapists used the cCPAx tool and scored 54 participants, with a total 106 observations. The median cCPAx tool score was 14.50 (IQR, 3-25) out of a possible total of 50. Inter-rater reliability for 30 randomly selected participants was excellent (intraclass correlation coefficient, 0.998). Completion rate of cCPAx in the 54 patients occurred in 78 of 106 occasions (74%)., Conclusions: The cCPAx tool content that was developed using Delphi methodology provided a feasible and clinically relevant tool for use in assessing physical morbidity in PICU patients 2-18 years old. Overall, the cCPAx scores were low, demonstrating low levels of physical function and high levels of immobility during PICU care., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Volatile methylsiloxanes (VMS) are man-made, nonbiodegradable chemicals produced at a megaton-per-year scale, which leads to concern over their potential for environmental persistence, long-range transport, and bioaccumulation. We used directed evolution to engineer a variant of bacterial cytochrome P450 BM3 to break silicon-carbon bonds in linear and cyclic VMS. To accomplish silicon-carbon bond cleavage, the enzyme catalyzes two tandem oxidations of a siloxane methyl group, which is followed by putative [1,2]-Brook rearrangement and hydrolysis. Discovery of this so-called siloxane oxidase opens possibilities for the eventual biodegradation of VMS.

Purpose: To determine if the speed-duration relationship is altered with age and sex of elite Master's runners., Methods: The world's top 10 performances for men and women in three events (800, 1500, and 5000 m) across six age groups (18-34 yr, 40-49 yr, 50-59 yr, 60-69 yr, 70-79 yr, and 80-89 yr) were analyzed from public data to establish theoretical models of the speed-duration relationship. Critical speed (CS) and the curvature constant ( D ') were estimated by fitting the average speeds and performance times with a two-parameter hyperbolic model., Results: Critical speed expressed relative to the 18- to 34-yr-olds, declined with age (92.2% [40-49] to 55.2% [80-89]; P < 0.001), and absolute CS was higher in men than women within each age group ( P < 0.001). The percent difference in CS between the men and women progressively increased across age groups (10.8% [18-34] to 15.5% [80-89]). D ' was lower in women than men in the 60-69 yr, 70-79 yr, and 80-89 yr age groups ( P < 0.001), but did not differ in the 18-34 yr, 40-49 yr, or 50-59 yr age groups., Conclusions: Critical speed progressively decreased with age, likely due to age-related decrements in several physiological systems that cause reduced aerobic capacity. The mechanism for the larger sex difference in CS in the older age groups is unknown but may indicate physiological differences that occur with aging and/or historical sociological factors that have reduced participation opportunities of older female runners resulting in a more limited talent pool., (Copyright © 2022 by the American College of Sports Medicine.)

Volatile methylsiloxanes (VMS) are a class of non-biodegradable anthropogenic compounds with propensity for long-range transport and potential for bioaccumulation in the environment. As a proof-of-principle for biological degradation of these compounds, we engineered P450 enzymes to oxidatively cleave Si-C bonds in linear and cyclic VMS. Enzymatic reactions with VMS are challenging to screen with conventional tools, however, due to their volatility, poor aqueous solubility, and tendency to extract polypropylene from standard 96-well deep-well plates. To address these challenges, we developed a new biocatalytic reactor consisting of individual 2-mL glass shells assembled in conventional 96-well plate format. In this chapter, we provide a detailed account of the assembly and use of the 96-well glass shell reactors for screening biocatalytic reactions. Additionally, we discuss the application of GC/MS analysis techniques for VMS oxidase reactions and modified procedures for validating improved variants. This protocol can be adopted broadly for biocatalytic reactions with substrates that are volatile or not suitable for polypropylene plates., Competing Interests: Declaration of competing interest The Dow Chemical Company and the California Institute of Technology have filed a patent application describing enzymatic siloxane degradation., (Copyright © 2023. Published by Elsevier Inc.)

The first total synthesis of the furanobutenolide-derived cembranoid diterpenoid havellockate is disclosed. Our convergent strategy employs a Julia-Kocienski olefination to join two enantioenriched fragments to produce a diene that is subsequently used in a propiolic acid esterification/Diels-Alder cascade. This sequence generates the fused carbocyclic core of the natural product in short order. A challenging Zn-mediated Barbier allylation then forges the final C-C bond and also establishes two vicinal stereogenic centers. Finally, a Cu-catalyzed aerobic oxidation facilitates the formation of the β-hydroxybutanolide to complete the total synthesis.

Baranauskas, Marissa N., Timothy J. Fulton, Alyce D. Fly, Bruce J. Martin, Timothy D. Mickleborough, and Robert F. Chapman. High intraindividual variability in the response of serum erythropoietin to multiple simulated altitude exposures. High Alt Med Biol . 23:85-89, 2022. Purpose: To evaluate within-subject variability in the serum erythropoietin (EPO) response to multiple simulated altitude exposures. Methods: Seven physically active men and women (age 27 ± 3 years, body mass index = 24.6 ± 4.0 kg/m 2 ) were exposed to normobaric hypoxia (fraction of inspired oxygen [F i O 2 ] = 0.14) for 12 hours on three separate occasions. Serum EPO concentrations were measured before exposure (0 hour), after 6 hours, and after 12 hours in hypoxia. The EPO response to hypoxia was calculated as percent change from 0 to 12 hours (ΔEPO 0-12 ). Results: Exposure time had a significant effect on EPO ( p  < 0.001) with concentrations increasing 3.2 ± 1.3 mIU/ml from 0 to 6 hours ( p  = 0.034) and 4.7 ± 1.2 mIU/ml from 0 to 12 hours ( p  = 0.001). Group mean ΔEPO 0-12 remained unchanged ( p  = 0.688) between the three exposures; however, there was considerable intraindividual variability in EPO responses. The intrasubject coefficient of variation for ΔEPO 0-12 was 61% ± 28% (range: 17%-103%) with intrasubject associations ranging r  = 0.052 to r  = 0.651 between repeated exposures. Conclusions: Athletes who routinely supplement training with simulated altitude methods (e.g., hypoxic tents) should expect inconsistent EPO responses to intermittent exposures lasting ≤12 hours.

Some track-and-field national governing bodies send athletes to World Championship and Olympic Games (WC/OG) to gain experience that may positively impact future success, even though athletes may not be expected to place high or medal. However, it is unclear if this strategy is advantageous for future medal attainment., Purpose: To determine if participation and/or advancement at a track-and-field athlete's first WC/OG influences the odds of future medaling., Methods: Performances of US track-and-field athletes who made their first WC/OG team during 2000-2013 were tracked through 2016 to stratify athletes into categories. Athletes who medaled on their first team or never made a subsequent team (ie, no experience) were compared with athletes who did not medal on their first team but made subsequent teams (ie, experience). The experience group was further divided into athletes who advanced or did not advance out of the initial round at their first competition for a secondary analysis. Odds ratios (ORs) were calculated using logistic regression to measure the association between experience level and medaling., Results: A significant OR was obtained for advanced versus did not advance (OR = 2.29, 95% confidence interval, 1.07-4.89, P = .03), but not for experience versus no experience (OR = 1.04, 95% confidence interval, 0.60-1.78, P = .91) group., Conclusions: Advancing out of the initial round of competition during an athlete's first WC/OG competition is associated with increased odds of future medaling. National governing bodies should consider this "experience threshold" during team selection processes.

A dual experimental/theoretical investigation of the Ireland-Claisen rearrangement of tetrasubstituted α-phthalimido ester enolates to afford α-tetrasubstituted, β-trisubstituted α-amino acids (generally >20:1 dr) is described. For trans allylic olefins, the Z - and E -enol ethers proceed through chair and boat transition states, respectively. For cis allylic olefins, the trend is reversed. As a result, the diastereochemical outcome of the reaction is preserved regardless of the geometry of the enolate or the accompanying allylic olefin. We term this unique convergence of all possible olefin isomers global diastereoconvergence . This reaction manifold circumvents limitations in present-day technologies for the stereoselective enolization of α,α-disubstituted allyl esters. Density functional theory paired with state-of-the-art local coupled-cluster theory (DLPNO-CCSD(T)) was employed for the accurate determination of quantum mechanical energies.

Purpose: The purpose of this study was to explore relationships between attentional strategies and LRC, running economy, perceived exertion, and dyspnea., Methods: 25 endurance-trained males ([Formula: see text]O 2 max = 68.2 ± 4.7 mL kg -1  min -1 ) ran for 5 min each at two different submaximal speeds, during which LRC and oxygen consumption ([Formula: see text]O 2 ) were measured. The degree of LRC was calculated as the percentage of breaths occurring during the same decile of the step cycle. Attentional focus was assessed at the end of exercise using an Attentional Focusing Questionnaire, with subscales for association, dissociation, and distress., Results: We found no significant relationships between attentional focus measures and LRC. However, dissociation scores were positively correlated with [Formula: see text]O 2 (r = 0.404), as well as  %[Formula: see text]O 2max (r = 0.474), at the slower running speed. Distress scores were the only attentional focus subscale related to perceived exertion and dyspnea (r = 0.378 to 0.654)., Conclusion: These findings suggest attentional focus is not driving the high levels of LRC seen in trained endurance athletes but may relate to running economy and perceptual responses.

Purpose: This study aimed to determine if preexisting respiratory muscle fatigue (RMF) alters motoneuronal output, locomotor muscle fatigue, and cycling performance., Methods: Eight trained male cyclists performed 5-km cycling time trials after a resistive breathing task that induced RMF and under control conditions (CON). Motoneuronal output was estimated using vastus lateralis surface electromyography, and locomotor muscle fatigue was quantified as the change in potentiated quadriceps twitch force from preexercise to postexercise., Results: Time to complete the time trial was 1.9% ± 0.9% longer in RMF compared with CON (P < 0.001). Estimated motoneuronal output was lower in RMF compared with CON during 1 km (45% ± 11% vs 53% ± 13%, P = 0.004) and 2 km (45% ± 14% vs 51% ± 14%, P = 0.008), but was not different thereafter. Ventilation was lower in RMF compared with CON during 1 km (114 ± 19 vs 135 ± 24 L·min, P = 0.003) and 2 km (136 ± 23 vs 152 ± 31 L·min, P = 0.009); however, ratings of dyspnea were similar. After the 5-km time trial, locomotor muscle fatigue was attenuated in RMF compared with CON (-22% ± 6%, vs -28% ± 7%, P = 0.02)., Conclusions: Alterations to dyspnea for a given ventilation seem to have constrained power output during cycling exercise, thereby limiting the development of locomotor muscle fatigue. These findings indicate that the respiratory system is an integral component in a global feedback loop that regulates exercise performance and the development of locomotor muscle fatigue.

Objective: The purpose of this study was to investigate the effects of "train-high sleep-low" (THSL) dietary periodization on ventilatory strategies during cycling exercise at submaximal and maximal intensities. Method: In a randomized crossover design, 8 trained men [age (mean ± SEM) = 28 ± 1 y; peak oxygen uptake = 56.8 ± 2.4 mL kg -1 min -1 ] completed two glycogen-depleting protocols on a cycle ergometer on separate days, with the cycling followed by a low carbohydrate (CHO) meal and beverages containing either no additional CHO (THSL) or beverages containing 1.2 g kg -1 CHO [traditional CHO replacement (TRAD)]. The following morning, participants completed 4 minutes of cycling below (Stage 1), at (Stage 2), and above (Stage 3) gas exchange threshold, followed by a 5-km time trial. Results: Timetrial performance was significantly faster in TRAD compared to THSL (8.7 ± 0.3 minutes and 9.0 ± 0.3 minutes, respectively; p  = 0.02). No differences in ventilation, tidal volume, or carbon dioxide production occurred between conditions at any exercise intensity ( p  > 0.05). During Stage 1, oxygen uptake was 37.9 ± 1.5 mL kg -1 min -1 in the TRAD condition and 39.6 ± 1.8 mL kg -1 min -1 in THSL ( p  = 0.05). During Stage 2, VO2 was 44.6 ± 1.7 mL kg -1 min -1 in the TRAD condition and 47.0 ± 1.9 mL kg -1 min -1 in THSL ( p  = 0.07). No change in operating lung volume was detected between dietary conditions ( p  > 0.05). Conclusions: THSL impairs performance following the dietary intervention, but this occurs with no alteration of ventilatory measures.

A catalytic enantioselective approach to the Myrioneuron alkaloids (-)-myrifabral A and (-)-myrifabral B is described. The synthesis was enabled by a palladium-catalyzed enantioselective allylic alkylation, that generates the C(10) all-carbon quaternary center. A key N -acyl iminium ion cyclization forged the cyclohexane fused tricyclic core, while vinyl boronate cross metathesis and oxidation afforded the lactol ring of (-)-myrifabral A. Adaptation of previously reported conditions allowed for the conversion of (-)-myrifabral A to (-)-myrifabral B., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Here we apply microcrystal electron diffraction (MicroED) to the structural determination of transition-metal complexes. We find that the simultaneous use of 300 keV electrons, very low electron doses, and an ultrasensitive camera allows for the collection of data without cryogenic cooling of the stage. This technique reveals the first crystal structures of the classic zirconocene hydride, colloquially known as "Schwartz's reagent", a novel Pd(II) complex not amenable to solution-state NMR or X-ray crystallography, and five other paramagnetic and diamagnetic transition-metal complexes., Competing Interests: The authors declare no competing financial interest., (Copyright © 2019 American Chemical Society.)

A unique example of Pd-catalyzed decarboxylative dehydrogenation of fully substituted N -acyl allyl enol carbonates is enabled by a new electron deficient phosphinooxazoline (PHOX) ligand. The reaction proceeds from the Z -enol carbonate to provide dehydrogenation products exclusively in high E/Z selectivity, while the E -enol carbonate provides the α-allylation product with only minor dehydrogenation. The reaction proceeds with a broad scope of ( Z )-enol carbonates derived from N -acyl indoles to furnish acyclic formal α,β-unsaturated ester equivalents.

The conjugate addition of organometallic reagents to α,β-unsaturated carbonyls represents an important method to generate C-C bonds in the preparation of all-carbon quaternary centers. Though conjugate additions of organometallic reagents are typically performed utilizing highly reactive organolithium or Grignard reagents, organozinc reagents have garnered attention for their enhanced chemoselectivity and mild reactivity. Despite numerous recent advances with more reactive diorganozinc and mixed diorganozinc reagents, the generation of all-carbon quaternary centers via the conjugate addition of functionalized monoorganozinc reagents remains a challenge. This protocol details a convenient and mild "one-pot" preparation and copper mediated conjugate addition of functionalized monoorganozinc bromides to cyclic α,β-unsaturated carbonyls to afford a broad scope of all-carbon quaternary centers in generally excellent yield and diastereoselectivity. Key to the development of this technology is the utilization of DMA as a reaction solvent with TMSCl as a Lewis acid. Notable advantages to this methodology include the operational simplicity of the organozinc reagent preparation afforded by the utilization of DMA as a solvent, as well as an efficient conjugate addition mediated by various Cu(I) and Cu(II) salts. Moreover, an intermediate silyl enol ether can be isolated utilizing a modified workup procedure. The substrate scope is limited to cyclic unsaturated ketones, and the conjugate addition is impeded by stabilized (e.g., allyl, enolate, homoenolate) and sterically encumbered (e.g., neopentyl, o-aryl) monoorganozinc reagents. Conjugate additions to five- and seven-membered rings were effective, albeit in lower yields compared with six-membered ring substrates.

The first enantioselective palladium-catalyzed decarboxylative allylic alkylation of fully substituted N -acyl indole-derived enol carbonates forming acyclic all-carbon quaternary stereocenters is reported. Excellent yields up to 99% and enantioselectivities up to 98% ee are obtained through the use of a new electron-deficient phosphinoxazoline (PHOX) ligand. Control of substrate enolate geometry is crucial for high selectivity. The obtained α-quaternary N -acyl indoles are formal ester equivalents, and represent a useful handle for further synthetic transformations.

To determine whether acute exposure to moderate hypoxia alters central and peripheral fatigue and to test whether carbohydrate ingestion impacts fatigue characteristics, 12 trained runners completed three running trials lasting 1 h each at 65% of normoxic maximum oxygen uptake. The first trial was performed in normoxia [inspired O 2 fraction ( F i O 2 ) = 0.21], and the last two trials were completed in hypoxia ( F i O 2  = 0.15). Participants ingested a placebo drink in normoxia (NORM-PLA), a placebo drink in hypoxia (HYP-PLA), or a carbohydrate solution in hypoxia (HYP-CHO). HYP conditions were randomized. Peripheral [change in potentiated quadriceps twitch force (ΔQ tw,pot )] and central [change in voluntary activation (ΔVA)] fatigue were assessed via preexercise-to-postexercise changes in magnetically evoked quadriceps twitch. In HYP, blood was drawn to determine the ratio of free-tryptophan (f-TRP) to branched-chain amino acids (BCAA). After exercise, peripheral fatigue was reduced to a similar degree in normoxia and hypoxia (ΔQ tw,pot  = -4.5 ± 1.3% and -4.0 ± 1.5% in NORM-PLA and HYP-PLA, respectively; P = 0.61). Central fatigue was present after normoxic and hypoxic exercise but to a greater degree in HYP-PLA compared with NORM-PLA (ΔVA: -4.7 ± 0.9% vs. -1.9 ± 0.7%; P < 0.01). Carbohydrate ingestion did not influence central fatigue (ΔVA in HYP-CHO: -5.7 ± 1.2%; P = 0.51 vs. HYP-PLA). After exercise, no differences were observed in the ratio of f-TRP to BCAA between HYP-PLA and HYP-CHO ( P = 0.67). Central fatigue increased during prolonged running exercise in moderate hypoxia although the ratio of f-TRP to BCAA remained unchanged. Ingesting carbohydrates while running in hypoxia did not influence fatigue development. NEW & NOTEWORTHY Hypoxic exposure influences the origin of exercise-induced fatigue and the rate of fatigue development depending on the severity of hypoxia. Our data suggest that moderate hypoxia increases central, but not peripheral, fatigue in trained runners exercising at 65% of normoxic maximum oxygen uptake. The increase in central fatigue was unaffected by carbohydrate intake and occurred although the ratio of free tryptophan to branched-chain amino acids remained unchanged.

Monoorganozinc reagents, readily obtained from alkyl bromides, display excellent reactivity with β,β-disubstituted enones and TMSCl in the presence of Cu(I) and Cu(II) salts to synthesize a variety of cyclic functionalized β-quaternary ketones in 38-99% yields and 9:1-20:1 diastereoselectivities. The conjugate addition features a pronounced improvement in DMA using monoorganozinc bromide reagents. A simple one-pot protocol that harnesses in situ generated monoorganozinc reagents delivers comparable product yields.

In the many scientific endeavors that are driven by organic chemistry, unambiguous identification of small molecules is of paramount importance. Over the past 50 years, NMR and other powerful spectroscopic techniques have been developed to address this challenge. While almost all of these techniques rely on inference of connectivity, the unambiguous determination of a small molecule's structure requires X-ray and/or neutron diffraction studies. In practice, however, X-ray crystallography is rarely applied in routine organic chemistry due to intrinsic limitations of both the analytes and the technique. Here we report the use of the electron cryo-microscopy (cryoEM) method microcrystal electron diffraction (MicroED) to provide routine and unambiguous structural determination of small organic molecules. From simple powders, with minimal sample preparation, we could collect high-quality MicroED data from nanocrystals (∼100 nm, ∼10 -15 g) resulting in atomic resolution (<1 Å) crystal structures in minutes., Competing Interests: The authors declare no competing financial interest.

To determine whether acute exposure to simulated moderate altitude alters locomotor-respiratory coupling (LRC) patterns in runners, 13 trained male distance runners performed a running economy and maximal oxygen uptake (V̇o 2max ) test in normoxia (NORM) and hypoxia (HYP) ([Formula: see text]= 15.8%; ~2,400 m/8,000 ft) on separate days. Running economy (RE), the degree of LRC, stride frequency-to-breathing frequency quotients (SF/f b ), ratings of perceived exertion (RPE), and dyspnea were assessed at three common submaximal speeds and V̇o 2max . SF/f b were significantly lower at each submaximal speed in HYP (12.9 km/h: 2.91 ± 0.20 vs. 2.45 ± 0.17, 14.3 km/h: 2.53 ± 0.17 vs. 2.21 ± 0.14, 16.1 km/h: 2.22 ± 0.14 vs. 1.95 ± 0.09; P < 0.05). The degree of LRC (range: 36-99%) in HYP was not significantly different than NORM at any of the three common submaximal speeds. However, the degree of LRC was significantly higher at V̇o 2max in HYP than NORM (43.8 ± 3.4% vs. 57.1 ± 3.8%; P < 0.05). RE and RPE were similar at all running speeds. Dyspnea was significantly greater in HYP compared with NORM at 16.1 km/h ( P < 0.05). Trained distance runners are able to maintain LRC in HYP, despite increases in breathing frequency. Within this unique population, years of training may enhance and optimize the ability to maintain LRC to minimize metabolic costs and dyspnea. NEW & NOTEWORTHY Exposure to acute altitude causes increases in ventilation at rest and any submaximal exercising workload, which may alter locomotor-respiratory coupling (LRC). Our data suggest that trained distance runners can maintain LRC during acute exposure to simulated moderate altitude, even when breathing frequency is increased at any submaximal pace.

Analysis of the instantaneous peak velocity waveform obtained from the common femoral artery can be used to provide an objective assessment of arterial disease in the leg. The calculation of waveform indices pulsatility index and rise time together with principal component analysis has been found to be the ideal method by which to assess the flow data on-line.

Nineteen patients (12 men) mean age, 63.4 years (range, 32 to 78), with stable chronic airflow limitation, mean FEV, 0.55 L (range, 0.3 to 1.05 L), completed an eight-week, double-blind, double cross-over study comparing nebulized salbutamol and salbutamol from a metered-dose inhaler (MDI). Salbutamol from both delivery systems produced bronchodilation. The doses of salbutamol inhaled via the nebulizer and MDI producing maximal bronchodilation were established by cumulative dose-response curves. The contents of the nebulizer and MDI were inhaled four times a day, one system containing salbutamol and the other a placebo. Cross-over of salbutamol from one system to the other occurred every two weeks. There was no significant difference between the two delivery methods in daily peak expiratory flow rate (PEFR), severity of symptoms, or extra bronchodilator usage. Two weekly laboratory assessments of spirometry, PEFR, and exercise tolerance also showed no significant differences. Careful assessment is recommended before the provision of domiciliary nebulizers.

The application of a mini computer to a routine diagnostic vascular laboratory has been assessed in over 4,500 patients over a period of 5 years. The laboratory functions to provide diagnosis of peripheral vascular disease. The computer functions are: scientific, in which it is used for modelling the arterial system and for applying diagnostic algorithms using haemodynamic signals re-input data, data base management, in which it is used to store clinical histories, the results of haemodynamic tests, and data for reconstructive surgery, and administrative, in which it is used for laboratory booking, report generation and management and workload statistics.