Environmental stress influences mitochondrial metabolism in vascular cells: consequences for angiogenesis

While the important and varied roles that vascular cells play in both health and disease is well recognised, the focus on potential therapeutic targets continually shifts as new players emerge. Here, we outline how mitochondria may be viewed as more than simply energygenerating organelles, but instead as important sentinels of metabolic health and effectors of appropriate responses to physiological challenges

Emerging Strategies Targeting Catabolic Muscle Stress Relief

Skeletal muscle wasting represents a common trait in many conditions, including aging, cancer, heart failure, immobilization, and critical illness. Loss of muscle mass leads to impaired functional mobility and severely impedes the quality of life. At present, exercise training remains the only proven treatment for muscle atrophy, yet many patients are too ill, frail, bedridden, or neurologically impaired to perform physical exertion. The development of novel therapeutic strategies that can be applied to an in vivo context and attenuate secondary myopathies represents an unmet medical need. This review discusses recent progress in understanding the molecular pathways involved in regulating skeletal muscle wasting with a focus on pro-catabolic factors, in particular, the ubiquitin-proteasome system and its activating muscle-specific E3 ligase RING-finger protein 1 (MuRF1). Mechanistic progress has provided the opportunity to design experimental therapeutic concepts that may affect the ubiquitin-proteasome system and prevent subsequent muscle wasting, with novel advances made in regards to nutritional supplements, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) inhibitors, myostatin antibodies, β2 adrenergic agonists, and small-molecules interfering with MuRF1, which all emerge as a novel in vivo treatment strategies for muscle wasting

Respiratory Muscle Weakness in Patients with Heart Failure: Time to Make It a Standard Clinical Marker and a Need for Novel Therapeutic Interventions?

Dysfunction of the respiratory muscles (particularly the diaphragm) can compromise ventilation, pulmonary gas exchange, and oxygen delivery to the tissues. This is especially true for patients with heart failure (HF), where a loss in respiratory muscle strength and endurance capacity is common.¹‾⁴ Inspiratory muscle weakness in HF causes heightened breathlessness, exertional intolerance, and reduces health-related quality-of-life.⁵‾⁷ The clinical importance of respiratory muscle weakness has also been clearly demonstrated

Direct observation of a highly spin-polarized organic spinterface at room temperature

The design of large-scale electronic circuits that are entirely spintronics-driven requires a current source that is highly spin-polarised at and beyond room temperature, cheap to build, efficient at the nanoscale and straightforward to integrate with semiconductors. Yet despite research within several subfields spanning nearly two decades, this key building block is still lacking. We experimentally and theoretically show how the interface between Co and phthalocyanine molecules constitutes a promising candidate. Spin-polarised direct and inverse photoemission experiments reveal a high degree of spin polarisation at room temperature at this interface. We measured a magnetic moment on the molecules's nitrogen pi orbitals, which substantiates an ab-initio theoretical description of highly spin-polarised charge conduction across the interface due to differing spinterface formation mechanims in each spin channel. We propose, through this example, a recipe to engineer simple organic-inorganic interfaces with remarkable spintronic properties that can endure well above room temperature

The Spatial Distribution of Absolute Skeletal Muscle Deoxygenation During Ramp-Incremental Exercise Is Not Influenced by Hypoxia.

Time-resolved near-infrared spectroscopy (TRS-NIRS) allows absolute quantitation of deoxygenated haemoglobin and myoglobin concentration ([HHb]) in skeletal muscle. We recently showed that the spatial distribution of peak [HHb] within the quadriceps during moderate-intensity cycling is reduced with progressive hypoxia and this is associated with impaired aerobic energy provision. We therefore aimed to determine whether reduced spatial distribution of skeletal muscle [HHb] was associated with impaired aerobic energy transfer during exhaustive ramp-incremental exercise in hypoxia. Seven healthy men performed ramp-incremental cycle exercise (20 W/min) to exhaustion at 3 fractional inspired O2 concentrations (FIO2): 0.21, 0.16, 0.12. Pulmonary O2 uptake (VO₂) was measured using a flow meter and gas analyser system. Lactate threshold (LT) was estimated non-invasively. Absolute muscle deoxygenation was quantified by multichannel TRS-NIRS from the rectus femoris and vastus lateralis (proximal and distal regions). VO₂peak and LT were progressively reduced (p < 0.05) with hypoxia. There was a significant effect (p < 0.05) of FIO2 on [HHb] at baseline, LT, and peak. However the spatial variance of [HHb] was not different between FIO2 conditions. Peak total Hb ([Hbtot]) was significantly reduced between FIO2 conditions (p < 0.001). There was no association between reductions in the spatial distribution of skeletal muscle [HHb] and indices of aerobic energy transfer during ramp-incremental exercise in hypoxia. While regional [HHb] quantified by TRS-NIRS at exhaustion was greater in hypoxia, the spatial distribution of [HHb] was unaffected. Interestingly, peak [Hbtot] was reduced at the tolerable limit in hypoxia implying a vasodilatory reserve may exist in conditions with reduced FIO2

Human exercise-induced circulating progenitor cell mobilization is nitric oxide-dependent and is blunted in South Asian men

This article is available open access through the publisher’s website. Copyright @ 2010 American Heart Foundation.Objective— Circulating progenitor cells (CPC) have emerged as potential mediators of vascular repair. In experimental models, CPC mobilization is critically dependent on nitric oxide (NO). South Asian ethnicity is associated with reduced CPC. We assessed CPC mobilization in response to exercise in Asian men and examined the role of NO in CPC mobilization per se. Methods and Results— In 15 healthy, white European men and 15 matched South Asian men, CPC mobilization was assessed during moderate-intensity exercise. Brachial artery flow-mediated vasodilatation was used to assess NO bioavailability. To determine the role of NO in CPC mobilization, identical exercise studies were performed during intravenous separate infusions of saline, the NO synthase inhibitor l-NMMA, and norepinephrine.  Flow-mediated vasodilatation (5.8%±0.4% vs 7.9%±0.5%; P=0.002) and CPC mobilization (CD34+/KDR+ 53.2% vs 85.4%; P=0.001; CD133+/CD34+/KDR+ 48.4% vs 73.9%; P=0.05; and CD34+/CD45− 49.3% vs 78.4; P=0.006) was blunted in the South Asian group. CPC mobilization correlated with flow-mediated vasodilatation and l-NMMA significantly reduced exercise-induced CPC mobilization (CD34+/KDR+ −3.3% vs 68.4%; CD133+/CD34+/KDR+ 0.7% vs 71.4%; and CD34+/CD45− −30.5% vs 77.8%; all P<0.001). Conclusion— In humans, NO is critical for CPC mobilization in response to exercise. Reduced NO bioavailability may contribute to imbalance between vascular damage and repair mechanisms in South Asian men.British Heart Foundatio

Reliability and Physiological Interpretation of Pulmonary Gas Exchange by "Circulatory Equivalents" in Chronic Heart Failure

Peak ratios of pulmonary gas-exchange to ventilation during exercise (V˙O2/V˙E and V˙CO2/V˙E, termed "circulatory equivalents") are sensitive to heart failure (HF) severity, likely reflecting low and/or poorly distributed pulmonary perfusion. We tested whether peak V˙O2/V˙E and V˙CO2/V˙E would: (1) distinguish HF patients from controls; (2) be independent of incremental exercise protocol; and (3) correlate with lactate threshold (LT) and ventilatory compensation point (VCP), respectively.Twenty-four HF patients (61±11 years) with reduced ejection fraction (31±8%) and 11 controls (63±7 years) performed ramp-incremental cycle ergometry. Eighteen HF patients also performed slow (5±1 W/min), medium (9±4 W/min), and fast (19±6 W/min) ramps. Peak V˙O2/V˙E and V˙CO2/V˙E from X-Y plot, and LT and VCP from 9-panel plot, were determined by 2 independent, blinded, assessors. Peak V˙O2/V˙E (31.2±4.4 versus 41.8±4.8 mL/L; P<0.0001) and V˙CO2/V˙E (29.3±3.0 versus 36.9±4.0 mL/L; P<0.0001) were lower in HF than controls. Within individuals, there was no difference across 3 ramp rates in peak V˙O2/V˙E (P=0.62) or V˙CO2/V˙E (P=0.97). Coefficient of variation (CV) in peak V˙O2/V˙E was lower than for LT (5.1±2.1% versus 8.2±3.7%; P=0.014), and coefficient of variation in peak V˙CO2/V˙E was lower than for VCP (3.3±1.8% versus 8.7±4.2%; P<0.001). In all participants, peak V˙O2/V˙E was correlated with, but occurred earlier than, LT (r2=0.94; mean bias, -0.11 L/min), and peak V˙CO2/V˙E was correlated with, but occurred earlier than, VCP (r2=0.98; mean bias -0.08 L/min).Peak circulatory equivalents during exercise are strongly associated with (but not identical to) LT and VCP. Peak circulatory equivalents are reliable, objective, effort-independent indices of gas-exchange abnormality in HF

Nanoindentation of Horn River Basin Shales: The Micromechanical Contrast Between Overburden and Reservoir Formations

We present a micromechanical characterization of shales from the Horn River Basin, NW Canada. The shales have contrasting mineralogy and microstructures and play different geomechanical roles in the field: the sample set covers an unconventional gas reservoir and the overburden unit that serves as the upper fracture barrier. Composition and texture were characterized using X-ray diffraction, mercury injection porosimetry, and scanning electron microscopy (SEM). Grid nanoindentation testing was used to obtain the mechanical response of the dominant phases in the shale microstructure. Samples were indented parallel and perpendicular to the bedding plane to assess mechanical anisotropy. Chemical analysis of the grids with SEM-EDS (energy dispersive X-ray spectroscopy) was undertaken and the coupled chemo-mechanical data was used in a statistical clustering procedure (Gaussian mixture model) to reveal the mechanical properties of each phase. The results show that the overburden consists of a soft clay matrix with highly anisotropic elastic stiffness, and stiffer but effectively isotropic inclusions of quartz and feldspar; the significant anisotropy of the overburden has been previously observed on a much larger scale using microseismic data. Creep displacement is concentrated in the clay matrix, which is the key phase for fracture barrier and seal applications. The reservoir units are harder and have more isotropic mechanical responses, primarily due to their lower clay content. Despite varied compositions and microstructures, the major phases of these shales (clay/organic matrix, quartz/feldspar, dolomite, and calcite) have unique mechanical signatures, which will aid identification in future micromechanical characterizations and facilitate their use in upscaling schemes

Firearms-related skeletal muscle trauma: pathophysiology and novel approaches for regeneration

One major cause of traumatic injury is firearm-related wounds (i.e., ballistic trauma), common in both civilian and military populations, which is increasing in prevalence and has serious long-term health and socioeconomic consequences worldwide. Common primary injuries of ballistic trauma include soft-tissue damage and loss, haemorrhage, bone fracture, and pain. The majority of injuries are of musculoskeletal origin and located in the extremities, such that skeletal muscle offers a major therapeutic target to aid recovery and return to normal daily activities. However, the underlying pathophysiology of skeletal muscle ballistic trauma remains poorly understood, with limited evidence-based treatment options. As such, this review will address the topic of firearm-related skeletal muscle injury and regeneration. We first introduce trauma ballistics and the immediate injury of skeletal muscle, followed by detailed coverage of the underlying biological mechanisms involved in regulating skeletal muscle dysfunction following injury, with a specific focus on the processes of muscle regeneration, muscle wasting and vascular impairments. Finally, we evaluate novel approaches for minimising muscle damage and enhancing muscle regeneration after ballistic trauma, which may have important relevance for primary care in victims of violence