Rhodium-catalysed vinyl 1,4-conjugate addition coupled with Sharpless asymmetric dihydroxylation in the synthesis of the CDE ring fragment of pectenotoxin-4.

Our synthesis of the CDE ring fragment of pectenotoxin-4 utilised two key steps to make the complex bicyclic ketal unit: (i) a rhodium-catalysed vinyl group 1,4-addition as the major C-C bond forming step; (ii) a stereoselective Sharpless Asymmetric Dihydroxylation (SAD) of the resulting 1,1-disubstituted homoallylic alcohol. Subsequent acid-catalysed cyclisation afforded the desired [5,6]-bicyclic ketal of the target molecule. This methodology was shown to be compatible with the desired E ring fragment in order to construct the CDE fragment of pectenotoxin-4.

Time perception and autistic spectrum condition: A systematic review.

Problems with timing and time perception have been suggested as key characteristics of autism spectrum condition (ASC). Studies and personal accounts from clinicians, parents, caregivers, and self-reports from autistic people themselves often refer to problems with time. Although a number of empirical studies have examined aspects relating to time in autistic individuals, there remains no clear consensus on whether or how timing mechanisms may be affected in autism.

The Effect of Ageing on Optimal Integration of Conflicting and Non-Conflicting Visual-Haptic Stimuli.

Multisensory integration typically follows the predictions of a statistically optimal model whereby the contribution of each sensory modality is weighted according to its reliability. Previous research has shown that multisensory integration is affected by ageing, however it is less certain whether older adults follow this statistically optimal model. Additionally, previous studies often present multisensory cues which are conflicting in size, shape or location, yet naturally occurring multisensory cues are usually non-conflicting.

Brain Ultrasonography Consensus on Skill Recommendations and Competence Levels Within the Critical Care Setting.

Background: To report a consensus on the different competency levels for the elaboration of skill recommendations in performing brain ultrasonography within the neurocritical care setting.

Methods: Four brain ultrasound experts, supported by a methodologist, performed a preselection of indicators and skills based on the current literature and clinical expertise. An international panel of experts was recruited and subjected to web-based questionnaires according to a Delphi method presented in three separate rounds.

Evidence for Mannitol as an Effective Agent Against Intracranial Hypertension: An Individual Patient Data Meta-analysis.

Mannitol is currently used to reduce intracranial pressure (ICP), but the evidence supporting its usefulness has been questioned. We aim to meta-analyze the effectiveness of mannitol in reducing ICP in adult patients with cerebral injuries and its dependency on baseline ICP values, comparing findings from individual patient data (IPD) and aggregated data (AD) meta-analysis performed on the same studies. We searched the Medline database, with no time limitation, through March 1, 2019.

Impact of Ergot Alkaloids on Female Reproduction in Domestic Livestock Species.

Fescue toxicosis is a multifaceted syndrome that elicits many negative effects on livestock consuming ergot alkaloids produced by endophyte-infected tall fescue. The economic losses associated with fescue toxicosis are primarily due to reproductive failure including altered cyclicity, suppressed hormone secretion, reduced pregnancy rates, agalactia, and reduced offspring birth weights. For decades, a multitude of research has investigated the physiological and cellular mechanisms of these reproductive failures associated with fescue toxicosis.

Central and peripheral factors mechanistically linked to exercise intolerance in heart failure with reduced ejection fraction.

Exercise intolerance is a primary symptom of heart failure (HF); however, the specific contribution of central and peripheral factors to this intolerance is not well described. The hyperbolic relationship between exercise intensity and time to exhaustion (speed-duration relationship) defines exercise tolerance but is underused in HF. We tested the hypotheses that critical speed (CS) would be reduced in HF, resting central functional measurements would correlate with CS, and the greatest HF-induced peripheral dysfunction would occur in more oxidative muscle.

Impaired diaphragm resistance vessel vasodilation with prolonged mechanical ventilation.

Mechanical ventilation (MV) is a life-saving intervention, yet with prolonged MV (i.e., ≥6 h) there are time-dependent reductions in diaphragm blood flow and an impaired hyperemic response of unknown origin.

Protein kinase D and Gβγ mediate sustained nociceptive signaling by biased agonists of protease-activated receptor-2.

Proteases sustain hyperexcitability and pain by cleaving protease-activated receptor-2 (PAR) on nociceptors through distinct mechanisms. Whereas trypsin induces PAR coupling to Gα, Gα, and β-arrestins, cathepsin-S (CS) and neutrophil elastase (NE) cleave PAR at distinct sites and activate it by biased mechanisms that induce coupling to Gα, but not to Gα or β-arrestins. Because proteases activate PAR by irreversible cleavage, and activated PAR is degraded in lysosomes, sustained extracellular protease-mediated signaling requires mobilization of intact PAR from the Golgi apparatus or synthesis of new receptors by incompletely understood mechanisms.

The maximal metabolic steady state: redefining the 'gold standard'.

The maximal lactate steady state (MLSS) and the critical power (CP) are two widely used indices of the highest oxidative metabolic rate that can be sustained during continuous exercise and are often considered to be synonymous. However, while perhaps having similarities in principle, methodological differences in the assessment of these parameters typically result in MLSS occurring at a somewhat lower power output or running speed and exercise at CP being sustainable for no more than approximately 20-30 min. This has led to the view that CP overestimates the 'actual' maximal metabolic steady state and that MLSS should be considered the 'gold standard' metric for the evaluation of endurance exercise capacity.

Edward F. Adolph Distinguished Lecture. Contemporary model of muscle microcirculation: gateway to function and dysfunction.

This review strikes at the very heart of how the microcirculation functions to facilitate blood-tissue oxygen, substrate, and metabolite fluxes in skeletal muscle. Contemporary evidence, marshalled from animals and humans using the latest techniques, challenges iconic perspectives that have changed little over the past century. Those perspectives include the following: the presence of contractile or collapsible capillaries in muscle, unitary control by precapillary sphincters, capillary recruitment at the onset of contractions, and the notion of capillary-to-mitochondrial diffusion distances as limiting O delivery.

Clathrin and GRK2/3 inhibitors block δ-opioid receptor internalization in myenteric neurons and inhibit neuromuscular transmission in the mouse colon.

Endocytosis is a major mechanism through which cellular signaling by G protein-coupled receptors (GPCRs) is terminated. However, recent studies demonstrate that GPCRs are internalized in an active state and continue to signal from within endosomes, resulting in effects on cellular function that are distinct to those arising at the cell surface. Endocytosis inhibitors are commonly used to define the importance of GPCR internalization for physiological and pathophysiological processes.

Unaltered V̇o kinetics despite greater muscle oxygenation during heavy-intensity two-legged knee extension versus cycle exercise in humans.

Relative perfusion of active muscles is greater during knee extension ergometry (KE) than cycle ergometry (CE). This provides the opportunity to investigate the effects of increased O delivery (Q̇o) on deoxygenation heterogeneity among quadriceps muscles and pulmonary oxygen uptake (V̇o) kinetics. Using time-resolved near-infrared spectroscopy, we hypothesized that compared with CE the superficial vastus lateralis (VL), superficial rectus femoris, and deep VL in KE would have ) a smaller amplitude of the exercise-induced increase in deoxy[Hb + Mb] (related to the balance between V̇o and Q̇o); ) a greater amplitude of total[Hb + Mb] (related to the diffusive O conductance); ) a greater homogeneity of regional muscle deoxy[Hb + Mb]; and ) no difference in pulmonary V̇o kinetics.

Concerted Nucleophilic Aromatic Substitution Reactions.

Recent developments in experimental and computational chemistry have identified a rapidly growing class of nucleophilic aromatic substitutions that proceed by concerted (cS Ar) rather than classical, two-step, S Ar mechanisms. Whereas traditional S Ar reactions require substantial activation of the aromatic ring by electron-withdrawing substituents, such activating groups are not mandatory in the concerted pathways.

Agonist-dependent development of delta opioid receptor tolerance in the colon.

The use of opioid analgesics is severely limited due to the development of intractable constipation, mediated through activation of mu opioid receptors (MOR) expressed by enteric neurons. The related delta opioid receptor (DOR) is an emerging therapeutic target for chronic pain, depression and anxiety. Whether DOR agonists also promote sustained inhibition of colonic transit is unknown.

Sexual dimorphism in the control of skeletal muscle interstitial Po of heart failure rats: effects of dietary nitrate supplementation.

Sex differences in the mechanisms underlying cardiovascular pathophysiology of O transport in heart failure (HF) remain to be explored. In HF, nitric oxide (NO) bioavailability is reduced and contributes to deficits in O delivery-to-utilization matching. Females may rely more on NO for cardiovascular control and as such experience greater decrements in HF.

Intercostal muscle blood flow is elevated in old rats during submaximal exercise.

Background: Respiratory muscle blood flows (BF) increase substantially during exercise in younger adult rats. As aging is associated with altered pulmonary function, we hypothesized that old rats will have greater intercostal muscle BF and vascular conductances (VC) than young rats during submaximal exercise.

Methods: Mean arterial pressure and respiratory muscle BFs (via carotid artery catheter and radiolabeled microspheres, respectively) were measured at rest and during submaximal exercise in young (n = 9) and old (n = 7) Fischer 344 X Brown Norway rats.

Impact of slick hair trait on physiological and reproductive performance in beef heifers consuming ergot alkaloids from endophyte-infected tall fescue1.

Fescue toxicosis is a multifaceted syndrome common in cattle grazing endophyte-infected tall fescue. The objective of this study was to evaluate the impact of the slick hair trait on physiological and reproductive parameters in heifers experiencing fescue toxicosis. Angus × Senepol heifers (n = 31) were blocked by weight (393.

G-Protein-Coupled Receptors Are Dynamic Regulators of Digestion and Targets for Digestive Diseases.

G-protein-coupled receptors (GPCRs) are the largest family of transmembrane signaling proteins. In the gastrointestinal tract, GPCRs expressed by epithelial cells sense contents of the lumen, and GPCRs expressed by epithelial cells, myocytes, neurons, and immune cells participate in communication among cells. GPCRs control digestion, mediate digestive diseases, and coordinate repair and growth.

Exercise intensity and middle cerebral artery dynamics in humans.

Despite its necessity for understanding healthy brain aging, the influence of exercise intensity on cerebrovascular kinetics is currently unknown. We, therefore characterized middle cerebral artery blood flow velocity (MCAv) kinetics associated with two exercise intensities: low and moderate. We hypothesized that increasing exercise intensity would increase the MCAv amplitude response (Amp) and that age and estimated fitness (V̇O2max) would be related to Amp.

G protein-coupled receptor trafficking and signaling: new insights into the enteric nervous system.

G protein-coupled receptors (GPCRs) are essential for the neurogenic control of gastrointestinal (GI) function and are important and emerging therapeutic targets in the gut. Detailed knowledge of both the distribution and functional expression of GPCRs in the enteric nervous system (ENS) is critical toward advancing our understanding of how these receptors contribute to GI function during physiological and pathophysiological states. Equally important, but less well defined, is the complex relationship between receptor expression, ligand binding, signaling, and trafficking within enteric neurons.

Accumulation of intramyocyte TRPV1-mediated calcium during heat stress is inhibited by concomitant muscle contractions.

Heat stress promotes intramyocyte calcium concentration ([Ca]) accumulation via transient receptor potential vanilloid 1 (TRPV1) channels. We tested the hypothesis that muscle contractile activity concomitant with heat stress would accelerate the increase in [Ca] via TRPV1, further impairing [Ca] homeostasis. Spinotrapezius muscles of adult Wistar rats were exteriorized in vivo and loaded with the fluorescent Ca probe fura 2-AM.

A two-injection prostaglandin F presynchronization treatment decreases pregnancy rates of cycling replacement beef heifers.

Improving artificial insemination (AI) pregnancy rates in replacement heifers improves the genetic advancement within a herd. Heifers that have completed at least three estrous cycles prior to breeding have greater pregnancy rates compared to acyclic females. Therefore, it was hypothesized that a presynchronization treatment program consisting of two injections of prostaglandin F (PGF) prior to the start of the CO-Synch + 5 d CIDR protocol would initiate earlier attainment of puberty and more estrous cycles prior to AI, thus increasing AI pregnancy rates.