Deep Electron Redistributions Induced by Dual Junctions Facilitating Electroreduction of Dilute Nitrate to Ammonia.

The electronic states of metal catalysts can be redistributed by the rectifying contact between metal and semiconductor e.g., N-doped carbon (NC), while the interfacial regulation degree is very limited. Herein, a deep electronic state regulation is achieved by constructing a novel double-heterojunctional Co/Co3O4@NC catalyst containing Co/Co3O4 and Co3O4/NC heterojunctions. When used for dilute electrochemical NO3 - reduction reaction (NO3RR), the as-prepared Co/Co3O4@NC exhibits an outstanding Faradaic efficiency for NH3 formation (FENH3) of 97.9%, -0.4 V versus RHE and significant NH3 yield of 303.5 mmol h-1 gcat -1 at -0.6 V at extremely low nitrate concentrations (100 ppm NO3 --N). Experimental and theoretical results reveal that the dual junctions of Co/Co3O4 and Co3O4/NC drive a unidirectional electron transfer from Co to NC (Co→Co3O4→NC), resulting in electron-deficient Co atoms. The electron-deficient Co promotes NO3 - adsorption, the rate-determining step (RDS) for NO3RR, facilitating the dilute NO3RR to NH3. The design strategy provides a novel reference for unidirectional multistage regulation of metal electronic states boosting electrochemical dilute NO3RR, which opens up an avenue for deep electronic state regulation of electrocatalyst breaking the limitation of the electronic regulation degree by rectifying contact.

Effects of aging on diaphragm hyperemia and blood flow distribution in male and female Fischer 344 rats.

Aging is associated with inspiratory muscle dysfunction; however, the impact of aging on diaphragm blood flow (BF) regulation, and whether sex differences exist, is unknown. We tested the hypotheses in young animals that diaphragm BF and vascular conductance (VC) would be greater in females and that aging would decrease the diaphragm's ability to increase BF with contractions. Young (4-6 mo) and old (22-24 mo) Fischer 344 rats were divided into four groups: young female (YF, n = 7), young male (YM, n = 8), old female (OF, n = 9), and old male (OM, n = 9). Diaphragm BF (mL/min/100 g) and VC (mL/mmHg/min/100 g) were determined, via fluorescent microspheres, at rest and during 1 Hz contractions. In YF versus OF, aging blunted the increase in medial costal diaphragm BF (44 ± 5% vs. 16 ± 12%; P < 0.05) and VC (43 ± 7% vs. 21 ± 12%; P < 0.05). Similarly, in YM versus OM, aging blunted the increase in medial costal diaphragm BF (43 ± 6% vs. 24 ± 12%; P < 0.05) and VC (50 ± 6% vs. 34 ± 10%; P < 0.05). In female rats, age increased dorsal costal diaphragm BF, whereas in male rats, age increased crural diaphragm BF (P < 0.05). Compared with age-matched females, dorsal costal diaphragm BF was lower in YM and OM (P < 0.05). In conclusion, aging results in an inability to augment medial costal diaphragm BF and alters regional diaphragm BF distribution in response to muscular contractions. Furthermore, sex differences in regional diaphragm BF are present in young and old animals.NEW & NOTEWORTHY This is the first study, to our knowledge, to demonstrate that old age impairs the hyperemic response and alters blood flow distribution in the diaphragm of both female and male rats. In addition, this investigation provides novel evidence of sex differences in regional diaphragm blood flow distribution with contractions. The data presented herein suggest that aging compromises diaphragm vascular function and provides a potential mechanism for the diaphragm contractile dysfunction associated with old age.

In vivo cytosolic H2O2 changes and Ca2+ homeostasis in mouse skeletal muscle.

Hydrogen peroxide (H2O2) and calcium ions (Ca2+) are functional regulators of skeletal muscle contraction and metabolism. Although H2O2 is one of the activators of the type-1 ryanodine receptor (RyR1) in the Ca2+ release channel, the interdependence between H2O2 and Ca2+ dynamics remains unclear. This study tested the following hypotheses using an in vivo model of mouse tibialis anterior (TA) skeletal muscle. 1) Under resting conditions, elevated cytosolic H2O2 concentration ([H2O2]cyto) leads to a concentration-dependent increase in cytosolic Ca2+ concentration ([Ca2+]cyto) through its effect on RyR1; and 2) in hypoxia (cardiac arrest) and muscle contractions (electrical stimulation), increased [H2O2]cyto induces Ca2+ accumulation. Cytosolic H2O2 (HyPer7) and Ca2+ (Fura-2) dynamics were resolved by TA bioimaging in young C57BL/6J male mice under four conditions: 1) elevated exogenous H2O2; 2) cardiac arrest; 3) twitch (1 Hz, 60 s) contractions; and 4) tetanic (30 s) contractions. Exogenous H2O2 (0.1-100 mM) induced a concentration-dependent increase in [H2O2]cyto (+55% at 0.1 mM; +280% at 100 mM) and an increase in [Ca2+]cyto (+3% at 1.0 mM; +8% at 10 mM). This increase in [Ca2+]cyto was inhibited by pharmacological inhibition of RyR1 by dantrolene. Cardiac arrest-induced hypoxia increased [H2O2]cyto (+33%) and [Ca2+]cyto (+20%) 50 min postcardiac arrest. Compared with the exogenous 1.0 mM H2O2 condition, [H2O2]cyto after tetanic muscle contractions rose less than one-tenth as much, whereas [Ca2+]cyto was 4.7-fold higher. In conclusion, substantial increases in [H2O2]cyto levels evoke only modest Ca2+ accumulation via their effect on the sarcoplasmic reticulum RyR1. On the other hand, contrary to hypoxia secondary to cardiac arrest, increases in [H2O2]cyto from muscle contractions are small, indicating that H2O2 generation is unlikely to be a primary factor driving the significant Ca2+ accumulation after, especially tetanic, muscle contractions.NEW & NOTEWORTHY We developed an in vivo mouse myocyte H2O2 imaging model during exogenous H2O2 loading, ischemic hypoxia induced by cardiac arrest, and muscle contractions. In this study, the interrelationship between cytosolic H2O2 levels and Ca2+ homeostasis during muscle contraction and hypoxic conditions was revealed. These results contribute to the elucidation of the mechanisms of muscle fatigue and exercise adaptation.

Pulmonary hypertension impairs vasomotor function in rat diaphragm arterioles.

Pulmonary hypertension (PH) is a chronic, progressive condition in which respiratory muscle dysfunction is a primary contributor to exercise intolerance and dyspnea in patients. Contractile function, blood flow distribution, and the hyperemic response are altered in the diaphragm with PH, and we sought to determine whether this may be attributed, in part, to impaired vasoreactivity of the resistance vasculature. We hypothesized that there would be blunted endothelium-dependent vasodilation and impaired myogenic responsiveness in arterioles from the diaphragm of PH rats. Female Sprague-Dawley rats were randomized into healthy control (HC, n = 9) and monocrotaline-induced PH rats (MCT, n = 9). Endothelium-dependent and -independent vasodilation and myogenic responses were assessed in first-order arterioles (1As) from the medial costal diaphragm in vitro. There was a significant reduction in endothelium-dependent (via acetylcholine; HC, 78 ± 15% vs. MCT, 47 ± 17%; P < 0.05) and -independent (via sodium nitroprusside; HC, 89 ± 10% vs. MCT, 66 ± 10%; P < 0.05) vasodilation in 1As from MCT rats. MCT-induced PH also diminished myogenic constriction (P < 0.05) but did not alter passive pressure responses. The diaphragmatic weakness, impaired hyperemia, and blood flow redistribution associated with PH may be due, in part, to diaphragm vascular dysfunction and thus compromised oxygen delivery which occurs through both endothelium-dependent and -independent mechanisms.

A modular, composite framework for the utilization of reduced-scaling Coulomb and exchange construction algorithms: Design and implementation.

Multiple algorithms exist for calculating Coulomb (J) or exchange (K) contributions to Fock-like matrices, and it is beneficial to develop a framework that allows the seamless integration and combination of different J and K construction algorithms. In Psi4, we have implemented the "CompositeJK" formalism for this purpose. CompositeJK allows for the combination of any J and K construction algorithms for any quantum chemistry method formulated in terms of J-like or K-like matrices (including, but not limited to, Hartree-Fock and density functional theory) in a highly modular and intuitive fashion, which is simple to utilize for both developers and users. Using the CompositeJK framework, Psi4 was interfaced to the sn-LinK implementation in the GauXC library, adding the first instance of noncommercial graphics processing unit (GPU) support for the construction of Fock matrix elements to Psi4. On systems with hundreds of atoms, the interface to the CPU sn-LinK implementation displays a higher performance than all the alternative JK construction methods available in Psi4, with up to x2.8 speedups compared to existing Psi4JK implementations. The GPU sn-LinK implementation, harnessing the power of GPUs, improves the observed performance gains to up to x7.0.

Accurate and efficient open-source implementation of domain-based local pair natural orbital (DLPNO) coupled-cluster theory using a t1-transformed Hamiltonian.

We present an efficient, open-source formulation for coupled-cluster theory through perturbative triples with domain-based local pair natural orbitals [DLPNO-CCSD(T)]. Similar to the implementation of the DLPNO-CCSD(T) method found in the ORCA package, the most expensive integral generation and contraction steps associated with the CCSD(T) method are linear-scaling. In this work, we show that the t1-transformed Hamiltonian allows for a less complex algorithm when evaluating the local CCSD(T) energy without compromising efficiency or accuracy. Our algorithm yields sub-kJ mol-1 deviations for relative energies when compared with canonical CCSD(T), with typical errors being on the order of 0.1 kcal mol-1, using our TightPNO parameters. We extensively tested and optimized our algorithm and parameters for non-covalent interactions, which have been the most difficult interaction to model for orbital (PNO)-based methods historically. To highlight the capabilities of our code, we tested it on large water clusters, as well as insulin (787 atoms).

In vivo heat production dynamics during a contraction-relaxation cycle in rat single skeletal muscle fibers.

Skeletal muscle generates heat via contraction-dependent (shivering) and independent (nonshivering) mechanisms. While this thermogenic capacity of skeletal muscle undoubtedly contributes to the body temperature homeostasis of animals and impacts various cellular functions, the intracellular temperature and its dynamics in skeletal muscle in vivo remain elusive. We aimed to determine the intracellular temperature and its changes within skeletal muscle in vivo during contraction and following relaxation. In addition, we tested the hypothesis that sarcoplasmic reticulum Ca2+ ATPase (SERCA) generates heat and increases the myocyte temperature during a transitory Ca2+-induced contraction-relaxation cycle. The intact spinotrapezius muscle of anesthetized adult male Wistar rats (n = 18) was exteriorized and loaded with the fluorescent probe Cellular Thermoprobe for Fluorescence Ratio (49.3 µM) by microinjection over 1 s. The fluorescence ratio (i.e., 580 nm/515 nm) was measured in vivo during 1) temperature increases induced by means of an external heater, and 2) Ca2+ injection (3.9 nL, 2.0 mM). The fluorescence ratio increased as a linear function of muscle surface temperature from 25 °C to 40 °C (r2 = 0.97, P < 0.01). Ca2+ injection (3.9 nL, 2.0 mM) significantly increased myocyte intracellular temperature: An effect that was suppressed by SERCA inhibition with cyclopiazonic acid (CPA, Ca2+: 38.3 ± 1.4 °C vs Ca2++CPA: 28.3 ± 2.8 °C, P < 0.01 at 1 min following injection). While muscle shortening occurred immediately after the Ca2+ injection, the increased muscle temperature was maintained during the relaxation phase. In this investigation, we demonstrated a novel model for measuring the intracellular temperature of skeletal muscle in vivo and further that heat generation occurs concomitant principally with SERCA functioning and muscle relaxation.

Chronic repetitive cooling and caffeine-induced intracellular Ca2+ elevation differentially impact adaptations in slow- and fast-twitch rat skeletal muscles.

Intracellular Ca2+ concentration ([Ca2+]i) is considered important in the regulation of skeletal muscle mass. This study tested the hypothesis that chronic repeated cooling and/or caffeine ingestion would acutely increase [Ca2+]i and hypertrophy muscles potentially in a fiber-type-dependent manner. Control rats and those fed caffeine were subjected to repeated bidiurnal treatments of percutaneous icing, under anesthesia, to reduce the muscle temperature below ∼5°C. The predominantly fast-twitch tibialis anterior (TA) and slow-twitch soleus (SOL) muscles were evaluated after 28 days of intervention. The [Ca2+]i elevating response to icing was enhanced by caffeine loading only in the SOL muscle, with the response present across a significantly higher temperature range than in the TA muscle under caffeine-loading conditions. In both the TA and SOL muscles, myofiber cross-sectional area (CSA) was decreased by chronic caffeine treatment (mean reductions of 10.5% and 20.4%, respectively). However, in the TA, but not the SOL, CSA was restored by icing (+15.4 ± 4.3% vs. noniced, P < 0.01). In the SOL, but not TA, icing + caffeine increased myofiber number (20.5 ± 6.7%, P < 0.05) and satellite cell density (2.5 ± 0.3-fold) in cross sections. These contrasting muscle responses to cooling and caffeine may reflect fiber-type-specific [Ca2+]i responses and/or differential responses to elevated [Ca2+]i.

Assessing cardiorespiratory fitness relative to sex improves surgical risk stratification.

BACKGROUND: To what extent sex-related differences in cardiorespiratory fitness (CRF) impact postoperative patient mortality and corresponding implications for surgical risk stratification remains to be established. METHODS: To examine this, we recruited 640 patients (366 males vs. 274 females) who underwent cardiopulmonary exercise testing prior to elective colorectal surgery. Patients were defined high risk if peak oxygen uptake was <14.3 mL kg-1  min-1 and ventilatory equivalent for carbon dioxide at 'anaerobic threshold' >34. Between-sex CRF and mortality was assessed, and sex-specific CRF thresholds predictive of mortality was calculated. RESULTS: Seventeen percent of deaths were attributed to sub-threshold CRF, which was higher than established risk factors for cardiovascular disease (CVD). The group (independent of sex) exhibited a 5-fold higher mortality (high vs. low risk patients hazard ratio = 4.80, 95% confidence interval 2.73-8.45, p < 0.001). Females exhibited 39% lower CRF (p < 0.001) with more classified high risk than males (36 vs. 23%, p = 0.001), yet mortality was not different (p = 0.544). Upon reformulation of sex-specific CRF thresholds, lower cut-offs for mortality were observed in females, and consequently, fewer (20%) were stratified with sub-threshold CRF compared to the original 36% (p < 0.001). CONCLUSIONS: Low CRF accounted for more deaths than traditional CVD risk factors, and when CRF was considered relative to sex, the disproportionate number of females stratified unfit was corrected. These findings support clinical consideration of 'sex-specific' CRF thresholds to better inform postoperative mortality and improve surgical risk stratification.

An Efficient, Site-Selective and Spontaneous Peptide Macrocyclisation During in†vitro Translation.

Macrocyclisation provides a means of stabilising the conformation of peptides, often resulting in improved stability, selectivity, affinity, and cell permeability. In this work, a new approach to peptide macrocyclisation is reported, using a cyanobenzothiazole-containing amino acid that can be incorporated into peptides by both in vitro translation and solid phase peptide synthesis, meaning it should be applicable to peptide discovery by mRNA display. This cyclisation proceeds rapidly, with minimal by-products, is selective over other amino acids including non N-terminal cysteines, and is compatible with further peptide elaboration exploiting such an additional cysteine in bicyclisation and derivatisation reactions. Molecular dynamics simulations show that the new cyclisation group is likely to influence the peptide conformation as compared to previous thioether-based approaches, through rigidity and intramolecular aromatic interactions, illustrating their complementarity.

A substrate descriptor based approach for the prediction and understanding of the regioselectivity in caged catalyzed hydroformylation.

The use of data driven tools to predict the selectivity of homogeneous catalysts has received considerable attention in the past years. In these studies often the catalyst structure is varied, but the use of substrate descriptors to rationalize the catalytic outcome is relatively unexplored. To study whether this may be an effective tool, we investigated both an encapsulated and a non-encapsulated rhodium based catalyst in the hydroformylation reaction of 41 terminal alkenes. For the non-encapsulated catalyst, CAT2, the regioselectivity of the acquired substrate scope could be predicted with high accuracy using the Δ13C NMR shift of the alkene carbon atoms as a descriptor (R2 = 0.74) and when combined with a computed intensity of the CC stretch vibration (ICC stretch) the accuracy increased further (R2 = 0.86). In contrast, a substrate descriptor approach with an encapsulated catalyst, CAT1, appeared more challenging indicating a confined space effect. We investigated Sterimol parameters of the substrates as well as computer-aided drug design descriptors of the substrates, but these parameters did not result in a predictive formula. The most accurate substrate descriptor based prediction was made with the Δ13C NMR shift and ICC stretch (R2 = 0.52), suggestive of the involvement of CH-π interactions. To further understand the confined space effect of CAT1, we focused on the subset of 21 allylbenzene derivatives to investigate predictive parameters unique for this subset. These results showed the inclusion of a charge parameter of the aryl ring improved the regioselectivity predictions, which is in agreement with our assessment that noncovalent interactions between the phenyl ring of the cage and the aryl ring of the substrate are relevant for the regioselectivity outcome. However, the correlation is still weak (R2 = 0.36) and as such we are investigating novel parameters that should improve the overall regioselectivity outcome.

Exposing Mechanisms for Defect Clearance in Supramolecular Self-Assembly: Palladium-Pyridine Coordination Revisited.

Spherical three-dimensional (3D) cages composed of palladium(II) and pyridyl ligands are a mainstay of supramolecular chemistry with demonstrated catalytic and optoelectronic applications. The widely reported self-assembly of these palladium-based cages exhibits sensitivity to the solvents, reagents, and/or reactants employed. This sensitivity, and the resulting inconsistency between synthetic protocols, hinders the development of desirable palladium-based cages. We have found that pyridyl ligand substitution─the rate-limiting step of self-assembly─is facilitated by endogenous supporting ligands derived from the solvents, reagents, and reactants employed in synthetic protocols of palladium- and platinum-based assemblies. Here, we present a systematic investigation combining 1H-NMR, electrospray ionization mass spectrometry (ESI─MS), and absorption spectroscopy to characterize the intermediates to support the mechanism of pyridyl ligand substitution on a model complex, M(py)2 (M = (N,N,N',N'-tetramethylethylenediamine)palladium(II), py = pyridine), under simulated synthetic conditions for self-assembly. Our investigation exposes mechanisms for pyridyl ligand substitution, featuring intermediates stabilized by solvent, anion, or (in situ formed) alkoxide moieties. Interrogation of destabilizing agents (2,2,2-trifluoroethanol and tetra(n-butyl)ammonium chloride) reveal similar mechanisms that ultimately facilitate the self-assembly of coordination cages. These findings rationalize widely reported solvent and anion effects in the self-assembly of coordination cages (and similar constructs) while highlighting methodologies to understand the role of supporting ligands in coordination chemistry.

Toward an extreme-scale electronic structure system.

Electronic structure calculations have the potential to predict key matter transformations for applications of strategic technological importance, from drug discovery to material science and catalysis. However, a predictive physicochemical characterization of these processes often requires accurate quantum chemical modeling of complex molecular systems with hundreds to thousands of atoms. Due to the computationally demanding nature of electronic structure calculations and the complexity of modern high-performance computing hardware, quantum chemistry software has historically failed to operate at such large molecular scales with accuracy and speed that are useful in practice. In this paper, novel algorithms and software are presented that enable extreme-scale quantum chemistry capabilities with particular emphasis on exascale calculations. This includes the development and application of the multi-Graphics Processing Unit (GPU) library LibCChem 2.0 as part of the General Atomic and Molecular Electronic Structure System package and of the standalone Extreme-scale Electronic Structure System (EXESS), designed from the ground up for scaling on thousands of GPUs to perform high-performance accurate quantum chemistry calculations at unprecedented speed and molecular scales. Among various results, we report that the EXESS implementation enables Hartree-Fock/cc-pVDZ plus RI-MP2/cc-pVDZ/cc-pVDZ-RIFIT calculations on an ionic liquid system with 623 016 electrons and 146 592 atoms in less than 45 min using 27 600 GPUs on the Summit supercomputer with a 94.6% parallel efficiency.

A straightforward graphical/statistical approach to help substantiate cheating on multiple-choice examinations.

Academic dishonesty is prevalent in universities in the form of cheating on examinations, with the problem being much greater in classes that have a large number of students that require close seating arrangements for in-class exams. The scenario described below was experienced during an in-class exam that included the possibility of an Honor Code violation between two students that was observed independently by three different faculty proctors. Herein we detail an objective, statistical approach taken to maintain exam and academic integrity that is compelling and transparent to students and the University Honor Council. Using the established error-similarity analysis for multiple-choice exams, it was determined that the number of identical incorrect answers found on the exams of the two individuals in question was sufficiently greater than the number expected by chance (probability of P < 0.00001). The number of total identical incorrect answers found on the remaining exams (across 65 students, n = 89 comparisons) was plotted as function of the number of total incorrect answers found on these exams (incorrect answers ranged from 1 to 22) and clearly supported that there was an Honor Code violation between the two students in question. The techniques used herein established, beyond a reasonable doubt, that a form of cheating had occurred between these students. However, caution must be taken as further investigation is requisite to establish whether the Honor Code violation was unidirectional (one student copying off the other) or bidirectional (collusion between the two students) in nature.NEW & NOTEWORTHY Academic dishonesty is prevalent in universities, especially on examinations with a large number of students in close seating arrangements. Cheating on a multiple-choice exam was suspected by observations from proctors of the examination. Application of error-similarity analysis associated with identical incorrect answers demonstrated that the probability of cheating was confirmed (P < 0.00001) between two examinees. Further comparisons with the remaining exams provided graphic evidence that a violation of the University's Honor Code had occurred.

Effector Regulated Catalytic Cyclization of Alkynoic Acids Using Pt2 L4 Cages.

Metabolic pathways are highly regulated by effector molecules that influences the rate of enzymatic reactions. Inspired by the catalytic regulation found in living cells, we report a Pt2 L4 cage of which the activity can be controlled by effectors that bind inside the cage. The cage shows catalytic activity in the lactonization of alkynoic acids, with the reaction rates dependent on the effector guest bound in the cage. Some effector guests enhance the rate of the lactonization by up to 19-fold, whereas one decreases it by 5-fold. When mixtures of specific substrates are used, both starting materials and products act as guests for the Pt2 L4 cage, enhancing its catalytic activity for one substrate while reducing its activity for the other. The reported regulatory behavior obtained by the addition of effector molecules paves the way to the development of more complex, metabolic-like catalyst systems.

M6L12 Nanospheres with Multiple C70 Binding Sites for 1O2 Formation in Organic and Aqueous Media.

Singlet oxygen is a potent oxidant with major applications in organic synthesis and medicinal treatment. An efficient way to produce singlet oxygen is the photochemical generation by fullerenes which exhibit ideal thermal and photochemical stability. In this contribution we describe readily accessible M6L12 nanospheres with unique binding sites for fullerenes located at the windows of the nanospheres. Up to four C70 can be associated with a single nanosphere, presenting an efficient method for fullerene extraction and application. Depending on the functionality located on the outside of the sphere, they act as vehicles for 1O2 generation in organic or in aqueous media using white LED light. Excellent productivity in 1O2 generation and consecutive oxidation of 1O2 acceptors using C70⊂[Pd6L12], C60⊂[Pd6L12] or fullerene soot extract was observed. The methodological design principles allow preparation and application of highly effective multifullerene binding spheres.

Ryanodine receptors mediate high intracellular Ca2+ and some myocyte damage following eccentric contractions in rat fast-twitch skeletal muscle.

Eccentric contractions (ECC) facilitate cytosolic calcium ion (Ca2+) release from the sarcoplasmic reticulum (SR) and Ca2+ influx from the extracellular space. Ca2+ is a vital signaling messenger that regulates multiple cellular processes via its spatial and temporal concentration ([Ca2+]i) dynamics. We hypothesized that 1) a specific pattern of spatial/temporal intramyocyte Ca2+ dynamics portends muscle damage following ECC and 2) these dynamics would be regulated by the ryanodine receptor (RyR). [Ca2+]i in the tibialis anterior muscles of anesthetized adult Wistar rats was measured by ratiometric (i.e., ratio, R, 340/380 nm excitation) in vivo bioimaging with Fura-2 pre-ECC and at 5 and 24 h post-ECC (5 × 40 contractions). Separate groups of rats received RyR inhibitor dantrolene (DAN; 10 mg/kg ip) immediately post-ECC (+DAN). Muscle damage was evaluated by histological analysis on hematoxylin-eosin stained muscle sections. Compared with control (CONT, no ECC), [Ca2+]i distribution was heterogeneous with increased percent total area of high [Ca2+]i sites (operationally defined as R ≥ 1.39, i.e., ≥1 SD of mean control) 5 h post-ECC (CONT, 14.0 ± 8.0; ECC5h: 52.0 ± 7.4%, P < 0.01). DAN substantially reduced the high [Ca2+]i area 5 h post-ECC (ECC5h + DAN: 6.4 ± 3.1%, P < 0.01) and myocyte damage (ECC24h, 63.2 ± 1.0%; ECC24h + DAN: 29.1 ± 2.2%, P < 0.01). Temporal and spatially amplified [Ca2+]i fluctuations occurred regardless of DAN (ECC vs. ECC + DAN, P > 0.05). These results suggest that the RyR-mediated local high [Ca2+]i itself is related to the magnitude of muscle damage, whereas the [Ca2+]i fluctuation is an RyR-independent phenomenon.

Post-occlusive reactive hyperemia and skeletal muscle capillary hemodynamics.

Post-occlusive reactive hyperemia (PORH) is an accepted diagnostic tool for assessing peripheral macrovascular function. While conduit artery hemodynamics have been well defined, the impact of PORH on capillary hemodynamics remains unknown, despite the microvasculature being the dominant site of vascular control. Therefore, the purpose of this investigation was to determine the effects of 5 min of feed artery occlusion on capillary hemodynamics in skeletal muscle. We tested the hypothesis that, upon release of arterial occlusion, there would be: 1) an increased red blood cell flux (fRBC) and red blood cell velocity (VRBC), and 2) a decreased proportion of capillaries supporting RBC flow compared to the pre-occlusion condition. METHODS: In female Sprague-Dawley rats (n = 6), the spinotrapezius muscle was exteriorized for evaluation of capillary hemodynamics pre-occlusion, 5 min of feed artery occlusion (Occ), and 5 min of reperfusion (Post-Occ). RESULTS: There were no differences in mean arterial pressure (MAP) or capillary diameter (Dc) between pre-occlusion and post-occlusion (P > 0.05). During 30 s of PORH, capillary fRBC was increased (pre: 59 ± 4 vs. 30 s-post: 77 ± 2 cells/s; P < 0.05) and VRBC was not changed (pre: 300 ± 24 vs. 30 s post: 322 ± 25 µm/s; P > 0.05). Capillary hematocrit (Hctcap) was unchanged across the pre- to post-occlusion conditions (P > 0.05). Following occlusion, there was a 20-30% decrease in the number of capillaries supporting RBC flow at 30 s and 300 s-post occlusion (pre: 92 ± 2%; 30 s-post: 66 ± 3%; 300 s-post: 72 ± 6%; both P < 0.05). CONCLUSION: Short-term feed artery occlusion (i.e. 5 min) resulted in a more heterogeneous capillary flow profile with the presence of capillary no-reflow, decreasing the percentage of capillaries supporting RBC flow. A complex interaction between myogenic and metabolic mechanisms at the arteriolar level may play a role in the capillary no-reflow with PORH. Measurements at the level of the conduit artery mask significant alterations in blood flow distribution in the microcirculation.

Effects of pulmonary hypertension on microcirculatory hemodynamics in rat skeletal muscle.

Pulmonary hypertension (PH) has previously been characterized as a disease of the pulmonary vasculature that subsequently results in myocardial dysfunction. Heart failure compromises skeletal muscle microvascular function, which contributes to exercise intolerance. Therefore, we tested the hypothesis that such changes might be present in PH. Thus, we investigated skeletal muscle oxygen (O2) transport in the rat model of PH to determine if O2 delivery (Q̇O2) is impaired at the level of the microcirculation as evidenced via reduced red blood cell (RBC) flux, velocity, hematocrit, and percentage of capillaries flowing in quiescent muscle. Adult male Sprague-Dawley rats were randomized into healthy (n = 9) and PH groups (n = 9). Progressive PH was induced via a one-time intraperitoneal injection of monocrotaline (MCT; 50 mg/kg) and rats were monitored weekly via echocardiography. Intravital microscopy in the spinotrapezius muscle was performed when echocardiograms confirmed moderate PH (preceding right ventricular (RV) failure). At 25 ± 9 days post-MCT, PH rats displayed RV hypertrophy (RV/(Left ventricle + Septum): 0.28 ± 0.05 vs. 0.44 ± 0.11), pulmonary congestion, and increased right ventricular systolic pressure (21 ± 8 vs. 55 ± 14 mm Hg) compared to healthy rats (all P < 0.05). Reduced capillary RBC velocity (403 ± 140 vs. 227 ± 84 µm/s; P = 0.01), RBC flux (33 ± 12 vs. 23 ± 5 RBCs/s; P = 0.04) and % of capillaries supporting continuous RBC flux at rest (79 ± 8 vs. 56 ± 13%; P = 0.01) were evident in PH rats compared to healthy rats. When Q̇O2 within a given field of view was quantified (RBC flux x % of capillaries supporting continuous RBC flux), PH rats demonstrated lower overall Q̇O2 (↓ 50%; P = 0.002). These data support that microcirculatory hemodynamic impairments (↓ Q̇O2 and therefore altered Q̇O2-to-V̇O2 matching) may compromise blood-myocyte O2 transport in PH. The mechanistic bases for decreased capillary RBC flux, velocity, and percentage of capillaries supporting RBC flow remains an important topic.

'Fit for surgery': the relationship between cardiorespiratory fitness and postoperative outcomes.

NEW FINDINGS: What is the topic of this review? The relationships and physiological mechanisms underlying the clinical benefits of cardiorespiratory fitness (CRF) in patients undergoing major intra-abdominal surgery. What advances does it highlight? Elevated CRF reduces postoperative morbidity/mortality, thus highlighting the importance of CRF as an independent risk factor. The vascular protection afforded by exercise prehabilitation can further improve surgical risk stratification and postoperative outcomes. ABSTRACT: Surgery accounts for 7.7% of all deaths globally and the number of procedures is increasing annually. A patient's 'fitness for surgery' describes the ability to tolerate a physiological insult, fundamental to risk assessment and care planning. We have evolved as obligate aerobes that rely on oxygen (O2 ). Systemic O2 consumption can be measured via cardiopulmonary exercise testing (CPET) providing objective metrics of cardiorespiratory fitness (CRF). Impaired CRF is an independent risk factor for mortality and morbidity. The perioperative period is associated with increased O2 demand, which if not met leads to O2 deficit, the magnitude and duration of which dictates organ failure and ultimately death. CRF is by far the greatest modifiable risk factor, and optimal exercise interventions are currently under investigation in patient prehabilitation programmes. However, current practice demonstrates potential for up to 60% of patients, who undergo preoperative CPET, to have their fitness incorrectly stratified. To optimise this work we must improve the detection of CRF and reduce potential for interpretive error that may misinform risk classification and subsequent patient care, better quantify risk by expressing the power of CRF to predict mortality and morbidity compared to traditional cardiovascular risk factors, and improve patient interventions with the capacity to further enhance vascular adaptation. Thus, a better understanding of CRF, used to determine fitness for surgery, will enable both clinicians and exercise physiologists to further refine patient care and management to improve survival.