Spatiomechanical Modulation of EphB4-Ephrin-B2 Signaling in Neural Stem Cell Differentiation.

Interactions between EphB4 receptor tyrosine kinases and their membrane-bound ephrin-B2 ligands on apposed cells play a regulatory role in neural stem cell differentiation. With both receptor and ligand constrained to move within the membranes of their respective cells, this signaling system inevitably experiences spatial confinement and mechanical forces in conjunction with receptor-ligand binding. In this study, we reconstitute the EphB4-ephrin-B2 juxtacrine signaling geometry using a supported-lipid-bilayer system presenting laterally mobile and monomeric ephrin-B2 ligands to live neural stem cells. This experimental platform successfully reconstitutes EphB4-ephrin-B2 binding, lateral clustering, downstream signaling activation, and neuronal differentiation, all in a configuration that preserves the spatiomechanical aspects of the natural juxtacrine signaling geometry. Additionally, the supported bilayer system allows control of lateral movement and clustering of the receptor-ligand complexes through patterns of physical barriers to lateral diffusion fabricated onto the underlying substrate. The results from this study reveal a distinct spatiomechanical effect on the ability of EphB4-ephrin-B2 signaling to induce neuronal differentiation. These observations parallel similar studies of the EphA2-ephrin-A1 system in a very different biological context, suggesting that such spatiomechanical regulation may be a common feature of Eph-ephrin signaling

Rapamycin directly activates lysosomal mucolipin TRP channels independent of mTOR

Rapamycin (Rap) and its derivatives, called rapalogs, are being explored in clinical trials targeting cancer and neurodegeneration. The underlying mechanisms of Rap actions, however, are not well understood. Mechanistic target of rapamycin (mTOR), a lysosomelocalized protein kinase that acts as a critical regulator of cellular growth, is believed to mediate most Rap actions. Here, we identified mucolipin 1 (transient receptor potential channel mucolipin 1 [TRPML1], also known as MCOLN1), the principle Ca2+ release channel in the lysosome, as another direct target of Rap. Patch-clamping of isolated lysosomal membranes showed that micromolar concentrations of Rap and some rapalogs activated lysosomal TRPML1 directly and specifically. Pharmacological inhibition or genetic inactivation of mTOR failed to mimic the Rap effect. In vitro binding assays revealed that Rap bound directly to purified TRPML1 proteins with a micromolar affinity. In both healthy and disease human fibroblasts, Rap and rapalogs induced autophagic flux via nuclear translocation of transcription factor EB (TFEB). However, such effects were abolished in TRPML1-deficient cells or by TRPML1 inhibitors. Hence, Rap and rapalogs promote autophagy via a TRPML1-dependent mechanism. Given the demonstrated roles of TRPML1 and TFEB in cellular clearance, we propose that lysosomal TRPML1 may contribute a significant portion to the in vivo neuroprotective and anti-aging effects of Rap via an augmentation of autophagy and lysosomal biogenesis

Endovascular Recanalization of Non-acute Symptomatic Middle Cerebral Artery Total Occlusion and Its Short-Term Outcomes

Background and Purpose: The optimal treatment for patients with non-acute symptomatic middle cerebral artery (MCA) total occlusion and a high risk of recurrent ischemic stroke despite medical management is not well-established. We aimed to assess the feasibility, safety, and short-term outcomes of angioplasty and stenting for these patients.Methods: Data of 22 patients with non-acute symptomatic MCA total occlusion who have failed medical management and undergone endovascular recanalization were retrospectively collected in our prospective database. All occlusive lesions were predilated with conventional balloons, followed by paclitaxel-coated coronary balloon inflation or not, and then a remedial stenting was performed or not, depending on the discretion of the operator. The rate of successful recanalization, perioperative outcomes, and short-term outcomes, such as restenosis and stroke recurrence, was analyzed.Results: Successful recanalization was achieved in 95.5% of patients, with 14 patients undergoing balloon angioplasty and 7 patients undergoing remedial stenting. Seven patients developed perioperative complications, including one patient with persistent neurological deficit. Over a median clinical follow-up duration of 5.0 months, only one patient had recurrent ischemic symptoms attributed to the cessation of antiplatelet treatment owing to postoperative intracranial hemorrhage. The proportion of patients who achieved favorable clinical outcome (modified ranking scale score of 0–2) was 85.7%. Post-procedural repeat vascular imaging was performed at 4.5 ± 1.84 months, with nine and one patient undergoing cerebral angiography and magnetic resonance angiography, respectively. One (10%) artery presented with asymptomatic reocclusion.Conclusions: Angioplasty and stenting may be feasible for the patients with non-acute symptomatic atherosclerotic MCA total occlusive disease who have failed medical management

Aberrant Brain Regional Homogeneity and Functional Connectivity of Entorhinal Cortex in Vascular Mild Cognitive Impairment: A Resting-State Functional MRI Study

The aim of this study was to investigate changes in regional homogeneity (ReHo) and the functional connectivity of the entorhinal cortex (EC) in vascular mild cognitive impairment (VaMCI) and to evaluate the relationships between such changes and neuropsychological measures in VaMCI individuals. In all, 31 patients with VaMCI and 32 normal controls (NCs) underwent rs-fMRI. Differences in whole-brain ReHo and seed-based bilateral EC functional connectivity (EC-FC) were determined. Pearson's correlation was used to evaluate the relationships between regions with significant group differences and different neuropsychological measures. Vascular mild cognitive impairment (VaMCI) patients had lower scores in Mini-mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) and higher ones in Activity of Daily Living (ADL) (p < 0.05). Vascular mild cognitive impairment (VaMCI) individuals had significantly lower ReHo in the left cerebellum and right lentiform nucleus than NCs (P < 0.05, TFCE FWE correction). Vascular mild cognitive impairment (VaMCI) subjects showed significant decreases in the FC of the right EC in the right inferior frontal gyrus, right middle frontal gyrus, bilateral pre-central gyrus, and right post-central/superior parietal lobules (P < 0.05, TFCE FWE correction). Significant positive correlations were found between ReHo and MoCA scores for the right lentiform nucleus (r = 0.37, P < 0.05). The right post-central/superior parietal lobules showed a significant positive correlation between right EC-FC and MoCA scores (r = 0.37, P < 0.05). Patterns in ReHo and EC-FC changes in VaMCI patients and their correlations with neuropsychological measures may be a pathophysiological foundation of cognitive impairment, which may aid the early diagnosis of VaMCI

Safety and efficacy of endovascular recanalization for symptomatic non-acute atherosclerotic intracranial large artery occlusion

Background and objectiveThe optimal treatment for patients with symptomatic non-acute atherosclerotic intracranial large artery occlusion (ILAO) despite medical treatment is not well established. We aimed to assess the safety, efficacy, and feasibility of angioplasty and stenting for these patients.MethodsA total of 251 consecutive patients with symptomatic non-acute atherosclerotic ILAO treated with interventional recanalization were retrospectively collected in our center from March 2015 to August 2021. The rate of successful recanalization, perioperative complications, and follow-up outcomes were evaluated.ResultsSuccessful recanalization was achieved in 88.4% (222/251) of the patients. A total of 24 (24/251, 9.6%) symptomatic complications occurred among 251 procedures. In the 193 patients with clinical follow-up during 19.0 ± 14.7 months, 11 (11/193, 5.7%) patients developed ischemic stroke and four (4/193, 2.1%) patients developed transient ischemic attack (TIA). In the 106 patients with vascular imaging follow-up during 6.8 ± 6.6 months, seven (7/106, 6.6%) patients had restenosis and 10 (10/106, 9.4%) patients had reocclusion.ConclusionThis study suggests that interventional recanalization may be a feasible, basically safe, and an effective alternative in carefully selected patients with symptomatic non-acute atherosclerotic ILAO who have failed medical management

Investigation of Wind-Loads Acting on Low-Aspect-Ratio Cylindrical Structures Based on a Wind Tunnel Test

The low-aspect-ratio cylindrical structures represented by oil tanks is a kind of wind sensitive structure, which is prone to buckling under wind-loads. A wind tunnel test was conducted to investigate the properties of wind-loads acting on smooth cylinders with an aspect ratio AR = 0.323 and 0.875, respectively. Some parameters, such as Reynolds number (Re) and turbulence intensity, were taken into account. The results reveal that low-aspect-ratio cylinders have a Re effect, and the effect rises with AR. AR is the main factor affecting the value of the base pressure coefficient and positive pressure range, and the former increases with AR, while the latter decreases with AR. Moreover, due to the influence of the free end and turbulence, which may suppress vortex shedding, the power spectrum of the lift coefficient essentially shows broad spectral peaks with Re and turbulence. Increasing the incoming turbulence made the flow round cylinders at a higher Re state, that is, the supercritical regime is reached at a smaller Re. When turbulence is greater than 4.0%, turbulence and Re have little effect on the mean base force coefficient of low-aspect-ratio cylinders