Severe Stroke Patients With Left-Sided Occlusion of the Proximal Anterior Circulation Benefit More From Thrombectomy

Background and Purpose: Endovascular thrombectomy improves the functional independence of patients with proximal anterior circulation occlusion. However, a subset of patients fail to benefit from thrombectomy procedures, the reasons for which remain poorly defined. In this study, we investigated whether the effectiveness of thrombectomy was affected by left- or right-sided occlusion among patients with similar stroke severities.Methods: Patients with proximal anterior circulation occlusion (internal carotid or M1 of middle cerebral artery) treated with the Solitaire stent retriever within 8 h of the onset of acute ischemic stroke were enrolled from the Yijishan Hospital of Wannan Medical College. Stroke severity was measured using the National Institutes of Health Stroke Scale (NIHSS) on admission. The functional outcomes were assessed using the modified Rankin scale (mRS) at 90 days.Results: We enrolled 174 patients including 90 left-sided occlusion and 84 right-sided occlusion. The NIHSS scores on admission were higher in the left-sided (median, 19; interquartile range, 16 to 20) compared to the right-sided occlusion group (median, 15, interquartile range, 13 to 18) (P < 0.001). Following adjustment for potential risk factors, patients with left-sided occlusion had higher rates of functional independence (mRS ≤ 2) and lower rates of mortality (mRS = 6) compared to the right-sided occlusion patients (39.5 vs. 19.6% and 28.9 vs. 47.8%, respectively) in the severe stroke group (NIHSS ≥ 15).Conclusions: In severe stroke patients with proximal anterior circulation occlusion, stent retriever thrombectomy within 8 h of the onset of symptoms provides more benefits to left-sided occlusion

Phosphorylation of Threonine343 Is Crucial for OCT4 Interaction with SOX2 in the Maintenance of Mouse Embryonic Stem Cell Pluripotency

Summary: OCT4 is required to maintain the pluripotency of embryonic stem cells (ESCs); yet, overdose-expression of OCT4 induces ESC differentiation toward primitive endoderm. The molecular mechanism underlying this differentiation switch is not fully understood. Here, we found that substitution of threonine343 by alanine (T343A), but not aspartic acid (T343D), caused a significant loss of OCT4-phosphorylation signal in ESCs. Loss of such OCT4-phosphorylation compromises its interaction with SOX2 but promotes interaction with SOX17. We therefore propose that threonine343-based OCT4-phosphorylation is crucial for the maintenance of ESC pluripotency. This OCT4-phosphorylation-based mechanism may provide insight into the regulation of lineage specification during early embryonic development. : Li and colleagues show that phosphorylation of threonine343 in OCT4 mediates global OCT4-phosphorylation (phos-OCT4T343). Phos-OCT4T343 is crucial for OCT4 to protect embryonic stem cell (ESC) pluripotency. Furthermore, phos-OCT4T343 interacts with SOX2 but non-phos-OCT4T343 interacts with SOX17 in the regulation of ESC pluripotency and differentiation. It also suggests a mechanism for lineage commitment during early embryonic development. Keywords: OCT4-phosphorylation, ESC pluripotency, lineage specification, genome editing, protein interaction, SOX2, SOX17, embryonic developmen

Identification of Crotonylation Metabolism Signature Predicting Overall Survival for Clear Cell Renal Cell Carcinoma

Background. Immunotherapy shows promise in treating cancer by leveraging the immune system to combat cancer cells. However, the influence of crotonylation metabolism on the prognosis and tumor environment in ccRCC patients is not fully understood. Methods. We conducted various systematic analyses, including prognosis and cluster analyses, to investigate the role of KAT2A in immunotherapy. We used qRT-PCR to compare KAT2A expression in cancer and adjacent tissues and among different cell lines. Additionally, we employed Cell Counting Kit-8, wound healing, and Transwell chamber assays to assess changes in the proliferative and metastatic ability of A498 and 786-O cells. Results. We identified three clusters related to crotonylation metabolism, each with distinct prognosis and immune characteristics in ccRCC. We categorized CT1 as immune-inflamed, CT2 as immune-excluded, and CR3 as immune-desert. A new system, CRS, emerged as an effective predictor of patient outcomes with differing immune characteristics. Moreover, qRT-PCR revealed elevated KAT2A levels in ccRCC tissues and cell lines. KAT2A was found to promote ccRCC and correlate significantly with immunosuppressive elements and checkpoints. Reducing KAT2A expression hindered ccRCC cell growth and metastasis. Conclusion. Our study highlights the critical role of crotonylation metabolism in cancer development and progression, particularly its link to poor prognosis. CRS proves to be an accurate predictor of patient outcomes and immune features in ccRCC. KAT2A shows strong associations with clinical factors and the immunosuppressive environment, suggesting potential for innovative immunotherapies in ccRCC treatment

Cancer Cells Evade Stress-Induced Apoptosis by Promoting HSP70-Dependent Clearance of Stress Granules

The formation of stress granules (SG) is regarded as a cellular mechanism to temporarily limit protein synthesis and prevent the unfolding of proteins in stressed cells. It has been noted that SG formation can promote the survival of stressed cells. Paradoxically, however, persistent SGs could cause cell death. The underlying molecular mechanism that affects the relationship between SG dynamics and cellular states is not fully understood. Here we found that SG dynamics in cancer cells differ significantly from those in normal cells. Specifically, prolonged stress caused the formation of persistent SGs and consequently resulted in apoptosis in the normal cells. By contrast, cancer cells resolved SGs and survived the prolonged stress. Regarding the mechanism, the knockdown of HSP70 or the inhibition of the HSP70s’ ATPase activity caused defective SG clearance, leading to apoptosis in otherwise healthy cancer cells. On the other hand, the knockout of G3BPs to block the formation of SGs allowed cancer cells to escape from the HSP70 inhibition-induced apoptosis. Given the observation that SG dynamics were barely affected by the inhibition of autophagy or proteasome, we propose that SG dynamics are regulated mainly by HSP70-mediated refolding of the unfolded proteins or their removal from SGs. As a result, cancer cells evade stress-induced apoptosis by promoting the HSP70-dependent SG clearance

Plasma neutrophil elastase and elafin imbalance is associated with acute respiratory distress syndrome (ARDS) development.

We conducted an exploratory study of genome-wide gene expression in whole blood and found that the expression of neutrophil elastase inhibitor (PI3, elafin) was down-regulated during the early phase of ARDS. Further analyses of plasma PI3 levels revealed a rapid decrease during early ARDS development. PI3 and secretory leukocyte proteinase inhibitor (SLPI) are important low-molecular-weight proteinase inhibitors produced locally at neutrophil infiltration site in the lung. In this study, we tested the hypothesis that an imbalance between neutrophil elastase (HNE) and its inhibitors in blood is related to the development of ARDS.PI3, SLPI, and HNE were measured in plasma samples collected from 148 ARDS patients and 63 critical ill patients at risk for ARDS (controls). Compared with the controls, the ARDS patients had higher HNE, but lower PI3, at the onset of ARDS, resulting in increased HNE/PI3 ratio (mean = 14.5; 95% CI, 10.9-19.4, P<0.0001), whereas plasma SLPI was not associated with the risk of ARDS development. Although the controls had elevated plasma PI3 and HNE, their HNE/PI3 ratio (mean = 6.5; 95% CI, 4.9-8.8) was not significantly different from the healthy individuals (mean = 3.9; 95% CI, 2.7-5.9). Before the onset (7-days period prior to ARDS diagnosis), we only observed significantly elevated HNE, but the HNE-PI3 balance remained normal. With the progress from prior to the onset of ARDS, the plasma level of PI3 declined, whereas HNE was maintained at a higher level, tilting the balance toward more HNE in the circulation as characterized by an increased HNE/PI3 ratio. In contrast, three days after ICU admission, there was a significant drop of HNE/PI3 ratio in the at-risk controls.Plasma profiles of PI3, HNE, and HNE/PI3 may be useful clinical biomarkers in monitoring the development of ARDS

The Pathogenesis of Necroptosis-Dependent Signaling Pathway in Cerebral Ischemic Disease

Necroptosis is the best-described form of regulated necrosis at present, which is widely recognized as a component of caspase-independent cell death mediated by the concerted action of receptor-interacting protein kinase 1 (RIPK1) and receptor-interacting protein kinase 3 (RIPK3). Mixed-lineage kinase domain-like (MLKL) was phosphorylated by RIPK3 at the threonine 357 and serine 358 residues and then formed tetramers and translocated onto the plasma membrane, which destabilizes plasma membrane integrity leading to cell swelling and membrane rupture. Necroptosis is downstream of the tumor necrosis factor (TNF) receptor family, and also interaction with NOD-like receptor pyrin 3 (NLRP3) induced inflammasome activation. Multiple inhibitors of RIPK1 and MLKL have been developed to block the cascade of signal pathways for procedural necrosis and represent potential leads for drug development. In this review, we highlight recent progress in the study of roles for necroptosis in cerebral ischemic disease and discuss how these modifications delicately control necroptosis

Differentiation of adult human retinal pigment epithelial cells into dopaminergic-like cells in vitro and in the recipient monkey brain

Abstract Background Cell therapy is proposed to be a potential treatment for Parkinson’s disease (PD). Although fetal retinal pigment epithelial (RPE) cells have been tested in trials for treating PD patients, controversy has been raised over the issue of whether such cells can be reprogrammed into dopamine-producing cells for therapeutic efficacy. Here, we aim to investigate whether adult human RPE cells can be reprogrammed into dopamine-producing cells both in vitro and in the recipient monkey brain. Methods The RPE layer was isolated from frozen posterior eyeball tissue after penetrating keratoplasty surgery. The tumorigenicity of RPE cells was examined by G-banding and a tumor formation assay in nude mice. Immunogenicity was measured using a one-way mixed lymphocyte reaction (MLR) assay. Dopamine-production in chemically reprogrammed RPE cells was measured by HPLC. Finally, RPE cells were grafted into the brains of monkeys with MPTP-induced PD in order to investigate the potential of such cells treating PD patients in the future. Results RPE cell lines have been successively established from adult human eye tissues. Such cells can be chemically reprogrammed into dopamine-producing cells in vitro. Moreover, after being grafted into the brain caudate putamen of monkeys with MPTP-induced PD, RPE cells became tyrosine hydroxylase-positive cells, and recipient PD monkeys showed significant improvement of clinical conditions. Conclusions This preclinical study using a primate model indicates that human adult RPE cells could be a potential cell source for the treatment of PD in the future

The Research of 30 mm Detecting Distance of Testing Device for Wire Rope Based on Open Magnetizer

Wire rope will have defects such as local faults (LF) and loss of metal area (LMA) during the long-term using process. The nondestructive testing method of magnetic flux leakage (MFL) has been widely used in wire rope defect detection. Currently, the detecting distance between magnetic sensors and wire rope with the MFL method is relatively small (2–5 mm). Considering the inner surface of the sensor head is close to the wire rope, it quickly leads to the sensor head scraping off the surface oil of the wire rope or being stuck by a cut wire in the course of MFL detection. Therefore, it is challenging to realize the sensor with MFL detection of wire rope obtaining the weak signal at a large lift-off (>30 mm). This study used finite element analysis to verify if the MFL signal exists at the large lift-off (>30 mm). Meanwhile, the sensor head was improved using an open magnetizer to make the wire rope reach saturation and excite enough magnetic leakage field. By combining magnetic sensing and coupling and a weak analog signal processing method, not only was the signal effectively detected, but also the signal-to-noise ratio (SNR) was improved. Finally, experiments verify the feasibility of detecting defects at a large distance. The method also has been applied in the high-speed detection of wire rope, which can detect broken wire of 1 mm diameter