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The present study examined and compared the impact of exercise training on redox and molecular properties of human microvascular endothelial cells derived from skeletal muscle biopsies from sedentary recent (RPF, ≤ 5 years as postmenopausal) and late (LPF, ≥ 10 years as postmenopausal) postmenopausal females. Resting skeletal muscle biopsies were obtained before and after 8 weeks of intense aerobic exercise training for isolation of microvascular endothelial cells and determination of skeletal muscle angiogenic proteins and capillarisation. The microvascular endothelial cells were analysed for mitochondrial respiration and production of reactive oxygen species (ROS), glycolysis and proteins related to vascular function, redox balance and oestrogen receptors. Exercise training led to a reduced endothelial cell ROS formation (∼50%; P = 0.009 and P = 0.020 for intact and permeabilized cells (state 3), respectively) in RPF only, with no effect on endothelial mitochondrial capacity in either group. Basal endothelial cell lactate formation was higher (7%; P = 0.028), indicating increased glycolysis, after compared to before the exercise training period in RPF only. Baseline endothelial G protein‐coupled oestrogen receptor (P = 0.028) and muscle capillarisation (P = 0.028) was lower in LPF than in RPF. Muscle vascular endothelial growth factor protein was higher (32%; P = 0.002) following exercise training in LPF only. Exercise training did not influence endothelial cell proliferation or skeletal muscle capillarisation in either group, but the CD31 level in the muscle tissue, indicating endothelial cell content, was higher (>50%; P < 0.05) in both groups. In conclusion, 8 weeks of intense aerobic exercise training reduces ROS formation and enhances glycolysis in microvascular endothelial cells from RPF but does not induce skeletal muscle angiogenesis. Key points: Late postmenopausal females have been reported to achieve limited vascular adaptations to exercise training.There is a paucity of data on the effect of exercise training on isolated skeletal muscle microvascular endothelial cells (MMECs).In this study the formation of reactive oxygen species in MMECs was reduced and glycolysis increased after 8 weeks of aerobic exercise training in recent but not late postmenopausal females.Late postmenopausal females had lower levels of G protein‐coupled oestrogen receptor in MMECs and lower skeletal muscle capillary density at baseline.Eight weeks of intense exercise training altered MMEC properties but did not induce skeletal muscle angiogenesis in postmenopausal females. [ABSTRACT FROM AUTHOR]

Since the 2015 Gorkha earthquake in Nepal, the relationship between the geometry of megathrusts and the control it exerts over the nucleation and propagation of major earthquakes has become an important topic of debate. In this study, we integrate new geologic mapping, a newly interpreted cross section from the Daraundi valley of central Nepal, two published cross sections from the neighboring Marsyangdi and Budhi Gandaki valleys, and a suite of 270 thermochronometric ages to create an integrated and validated three-dimensional kinematic model for the central Nepal Himalaya. We use this model to investigate the assertion that the westward propagation of the Gorkha rupture was restricted by deep-seated structures in the Main Himalayan thrust. The integrated kinematic model based on these cross sections indicates that the ~30 km southward step in the Main Central thrust system mapped in the Daraundi valley, along with the corresponding step in the distribution of reset muscovite (Ar-Ar) ages, is not the result of a lateral structure in the modern Main Himalayan thrust. Instead, the step in the surface geology is the result of a considerably shorter Trishuli thrust sheet in the Daraundi transect (~30 km compared to between 105 and 120 km in the other transects). The corresponding southward step in the distribution of reset muscovite Ar-Ar ages is the result of the Lesser Himalayan duplex being completely translated over the Main Himalayan thrust ramp, elevating and exposing rocks heated to >400 °C farther south in the Daraundi transect. Our integrated model also highlights the 10–15 km of out-of-sequence thrusting that occurs on the Main Central thrust system across central Nepal. Importantly, these out-of-sequence thrusts sole directly into the modern Main Himalayan thrust ramp, and, together with the distribution of reset zircon (U-Th)/He and apatite fission track ages, show that the modern ramp is distinctly linear from east to west, with no support for a lateral structure at the ramp or to the south. [ABSTRACT FROM AUTHOR]

Prosthetic implants, particularly hip endoprostheses, often lead to stress shielding because of a mismatch in compliance between the bone and the implant material, adversely affecting the implant's longevity and effectiveness. Therefore, this work aimed to demonstrate a computationally efficient method for density-based topology optimization of homogenized lattice structures in a patient-specific hip endoprosthesis. Thus, the root mean square error (RMSE) of the stress deviations between the physiological femur model and the optimized total hip arthroplasty (THA) model compared to an unoptimized-THA model could be reduced by 81 % and 66 % in Gruen zone (GZ) 6 and 7. However, the method relies on homogenized finite element (FE) models that only use a simplified representation of the microstructural geometry of the bone and implant. The topology-optimized hip endoprosthesis with graded lattice structures was synthesized using algorithmic design and analyzed in a virtual implanted state using micro-finite element (micro-FE) analysis to validate the optimization method. Homogenized FE and micro-FE models were compared based on averaged von Mises stresses in multiple regions of interest. A strong correlation (CCC > 0.97) was observed, indicating that optimizing homogenized lattice structures yields reliable outcomes. The graded implant was additively manufactured to ensure the topology-optimized result's feasibility., (© 2024. The Author(s).)

Although regular physical activity is known to improve cardiovascular health in men, evidence for its beneficial effects in postmenopausal females is less convincing and it remains unclear whether initiation of exercise training soon after, rather than many years after menopause impacts the magnitude of training-induced adaptations. We evaluated exercise-induced changes in markers of thrombotic risk and conduit artery function in recent ≤5yr compared with late ≥10yr postmenopausal females. Fourteen recent ≤5yr and 13 late ≥10yr healthy postmenopausal females completed 8 wk of regular intensive exercise training, consisting of floorball and cycling. Markers of thrombotic risk and vascular health were assessed before and after the intervention, and data were analyzed using a linear mixed model. Exercise training reduced markers of thrombotic risk, including an 11% reduction ( P = 0.007) in agonist-induced platelet reactivity and a reduction ( P = 0.027) in incipient clot microstructure (∼40% reduction in clot mass) in the recent ≤5yr but not the late ≥10yr ( P = 0.380; P = 0.739, respectively) postmenopausal females. There was no change in conduit artery function, as measured by brachial (recent ≤5yr , P = 0.804; late ≥10yr , P = 0.311) and popliteal artery (recent ≤5yr , P = 0.130; late ≥10yr , P = 0.434) flow-mediated dilation. Only the late ≥10yr postmenopausal females exhibited an increase (by 9.6%, P = 0.022) in intracellular adhesion molecule-1 levels after training, which may have impacted the thrombogenic adaptation in this group. These findings suggest that 8 wk of high-intensity exercise training reduces thrombotic risk in recent ≤5yr , but not late ≥10yr postmenopausal females. Thus, regular physical activity initiated soon after, rather than many years after menopause and at a higher age, may be more efficient for reducing thrombogenic risk. NEW & NOTEWORTHY Eight weeks of high-intensity exercise training reduces platelet reactivity as well as blood clot density and strength in females ≤5 yr past menopause but not in females ≥10 yr past menopause. The divergent response in the late postmenopausal females may be explained by training-induced low-grade systemic inflammation. These findings suggest that regular physical activity initiated soon after menopause, compared with many years after menopause, may be more efficient for reducing the risk of blood clots.

Additive manufacturing (AM) can be used to produce multi-material parts in which the material can be varied voxel-wise in all three spatial directions. This means that the paradigm of the homogeneous material can be abandoned and local effects such as heat conduction or damping can be selectively adjusted in the part. Recently, continuous development of machine technology has allowed the production of multi-metal materials in laser powder bed fusion (PBF-LB/MM). Compared to other additive manufacturing processes for multi-material production, this allows greater design freedom and detail accuracy to be realized. However, due to the novel character of multi-material manufacturing in PBF-LB, the process knowledge for successful and reproducible fabrication is currently lacking. This paper focuses on establishing design guidelines for manufacturing the material pairing of stainless steel 316L (1.4404) and copper alloy CuCrZr (CW106C). The article is accompanied by the development of a specific process chain. As a result of this work, design guidelines for multi-material parts are available for the first time, in regard to arrangement, size, overhangs, economy, powder quality and laser scanning., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: In preclinical models, the pannexin-1 channel has been shown to be involved in blood pressure regulation through an effect on peripheral vascular resistance. Pannexin-1 releases ATP, which can activate constrictive purinergic receptors on the smooth muscle cells. Pannexin-1 opening is proposed to be mediated by α-adrenergic receptors to potentiate sympathetic constriction. This positions pannexin-1 as a putative pharmacological target in blood pressure regulation in humans. The aim was to provide the first translational evidence for a role of pannexin-1 in essential hypertension in humans by use of an advanced invasive mechanistic approach., Methods: Middle-aged stage-1 hypertensive (n=13; 135.7±6.4 over 83.7±3.7 mm Hg) and normotensive men (n=12; 117.3±5.7 over 72.2±3.5 mm Hg) were included. Blood pressure and leg vascular resistance were determined during femoral arterial infusion of tyramine (α-adrenergic receptor stimulation), sodium nitroprusside, and acetylcholine. Measurements were made during control conditions and with pannexin-1 blockade (3000 mg probenecid). Expression of Pannexin-1, purinergic- and α-adrenergic receptors in skeletal muscle biopsies was determined by Western blot., Results: The changes in leg vascular resistance in response to tyramine (+289% versus +222%), sodium nitroprusside (-82% versus -78%) and acetylcholine (-40% versus -44%) infusion were not different between the 2 groups ( P >0.05) and pannexin-1 blockade did not alter these variables ( P >0.05). Expression of pannexin-1 and of purinergic- and α-adrenergic receptors was not different between the 2 groups ( P >0.05)., Conclusions: Contrary to our hypothesis, the data demonstrate that pannexin-1 does not contribute to the elevated blood pressure in essential hypertension, a finding, which also opposes that reported in preclinical models.

Aerobic training can improve vascular endothelial function in-vivo. The aim of this study was to elucidate the mechanisms underlying this improvement in isolated human microvascular endothelial cells. Sedentary males, aged 57 ± 6 years completed 8 weeks of intense aerobic training. Resting muscle biopsies were obtained from the thigh muscle and used for isolation of endothelial cells (pre n = 23, post n = 16). The cells were analyzed for mitochondrial respiration, H 2 O 2 emission, glycolysis, protein levels of antioxidants, NADPH oxidase, endothelial nitric oxide (NO) synthase and prostacyclin synthase (PGI 2 S). In-vivo microvascular function, assessed by acetylcholine infusion and arterial blood pressure were also determined. Endothelial mitochondrial respiration and H 2 O 2 formation were similar before and after training whereas the expression of superoxide dismutase and the expression of glutathione peroxidase were 2.4-fold (p = 0.012) and 2.3-fold (p = 0.006) higher, respectively, after training. In-vivo microvascular function was increased by 1.4-fold (p = 0.036) in parallel with a 2.1-fold increase in endothelial PGI 2 S expression (p = 0.041). Endothelial cell glycolysis was reduced after training, as indicated by a 65% lower basal production of lactate (p = 0.003) and a 30% lower expression of phosphofructokinase (p = 0.011). Subdivision of the participants according to blood pressure at base-line (n = 23), revealed a 2-fold higher (p = 0.049) rate of H 2 O 2 production in endothelial cells from hypertensive participants. Our data show that exercise training increases skeletal muscle microvascular endothelial cell metabolism, antioxidant capacity and the capacity to form prostacyclin. Moreover, elevated blood pressure is associated with increased endothelial mitochondrial ROS formation., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)