Adipose mesenchymal stem cells-derived exosomes attenuated hyperoxia-induced lung injury in neonatal rats via inhibiting the NF-κB signaling pathway.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) is the most common chronic morbidity in extremely preterm infants. Mesenchymal stem cells-derived exosomes (MSC-Exos) therapies have shown prospects in animal models of BPD. Our study aimed to evaluate the effect of adipose mesenchymal stem cells-derived exosomes (AMSC-Exos) on BPD and the role of the NF-κB signaling pathway in this process. METHODS: The AMSCs were extracted and AMSC-Exos were isolated by ultracentrifugation method. Newborn rats were exposed to hyperoxia (90% O2) continuously for 7 days to establish a BPD model. The rats were treated with AMSC-Exos by intratracheal administration on postnatal day 4 (P4). Pulmonary morphology, pulmonary vasculature, inflammatory factors, and NF-κB were assessed. Hyperoxia-induced primary type II alveolar epithelial cells (AECIIs) and AMSC-Exos treatment with or without a pan-NF-κB inhibitor (PDTC) were established to explore the potential mechanism. RESULTS: Hyperoxia-exposed rats showed alveolar simplification with decreased radial alveolar count and increased mean linear intercept, low CD31, and vascular endothelial growth factor expression, reduced microvessel density, increased the expression of TNF-α, IL-1ß, and IL-6 and decreased the expression of IL-10, and induced NF-κB phosphorylation. AMSC-Exos protected the neonatal lung from the hyperoxia-induced arrest of alveolar and vascular development, alleviated inflammation, and inhibited NF-κB phosphorylation. Hyperoxia decreased viability, increased apoptosis, enhanced inflammation, and induced NF-κB phosphorylation of AECIIs but improved by AMSC-Exos, PDTC, or AMSC-Exos+PDTC. The effect of AMSC-Exos+PDTC in AECIIs was the same as AMSC-Exos, but more notable than PDTC alone. CONCLUSION: AMSC-Exos attenuated the hyperoxia-induced lung injury in neonatal rats by inhibiting the NF-κB signaling pathway partly.

FTO attenuates TNF-α-induced damage of proximal tubular epithelial cells in acute pancreatitis-induced acute kidney injury via targeting AQP3 in an N6-methyladenosine-dependent manner.

BACKGROUND: Acute kidney injury (AKI) is a frequent complication of severe acute pancreatitis (SAP). Previous investigations have revealed the involvement of FTO alpha-ketoglutarate-dependent dioxygenase (FTO) and aquaporin 3 (AQP3) in AKI. Therefore, the aim of this study is to explore the association of FTO and AQP3 on proximal tubular epithelial cell damage in SAP-induced AKI. METHODS: An in-vitro AKI model was established in human proximal tubular epithelial cells (PTECs) HK-2 via tumor necrosis factor-α (TNF-α) induction (20 ng/mL), after which FTO and AQP3 expression was manipulated and quantified by quantitative real-time PCR and Western blotting. The viability and apoptosis of PTECs under various conditions, and reactive oxygen species (ROS), superoxide dismutase (SOD), and malonaldehyde (MDA) levels within these cells were measured using commercial assay kits and flow cytometry. Methylated RNA immunoprecipitation and mRNA stability assays were performed to elucidate the mechanism of FTO-mediated N6-methyladenosine (m6A) modification. Western blotting was performed to quantify ß-catenin protein levels in the PTECs. RESULTS: FTO overexpression attenuated the TNF-α-induced decrease in viability and SOD levels, elevated apoptosis, increased levels of ROS and MDA, and diminished TNF-α-induced AQP3 expression and reduced ß-catenin expression, but its silencing led to contradictory results. FTO negatively modulates AQP3 levels in RTECs in an m6A-depednent manner and compromises AQP3 stability. In addition, all FTO overexpression-induced effects in TNF-α-induced PTECs were neutralized following AQP3 upregulation. CONCLUSION: FTO alleviates TNF-α-induced damage to PTECs in vitro by targeting AQP3 in an m6A-dependent manner.

The Treatment of Refractory Vitiligo With Autologous Cultured Epithelium Grafting: A Real-World Retrospective Cohort Study.

BACKGROUND: Surgical intervention is the main therapy for refractory vitiligo. We developed a modified autologous cultured epithelial grafting (ACEG) technique for vitiligo treatment. Between January 2015 and June 2019, a total of 726 patients with vitiligo underwent ACEG in China, with patient characteristics and clinical factors being meticulously documented. Using a generalized linear mixed model, we were able to assess the association between these characteristics and the repigmentation rate. RESULTS: ACEG demonstrated a total efficacy rate of 82.81% (1754/2118) in treating 726 patients, with a higher repigmentation rate of 64.87% compared to conventional surgery at 52.69%. Notably, ACEG showed a better response in treating segmental vitiligo, lesions on lower limbs, age ≤ 18, and stable period > 3 years. A keratinocyte:melanocyte ratio below 25 was found to be advantageous too. Single-cell RNA sequencing analysis revealed an increase in melanocyte count and 2 subclusters of keratinocytes after ACEG, which remained higher in repigmented sites even after 1 year. CONCLUSIONS: ACEG is a promising therapy for refractory vitiligo. Patient age, clinical type, lesion site, and stability before surgery influence repigmentation in ACEG. The mechanism of repigmentation after ACEG treatment is likely not confined to the restoration of melanocyte populations. It may also involve an increase in the number of keratinocytes that support melanocyte function within the affected area. These keratinocytes may aid the post-transplant survival and function of melanocytes by secreting cytokines and extracellular matrix components. TRIAL REGISTRATION: registered with Chictr.org.cn (ChiCTR2100051405).

Digital Twin Virtual Welding Approach of Robotic Friction Stir Welding Based on Co-Simulation of FEA Model and Robotic Model.

Robotic friction stir welding has become an important research direction in friction stir welding technology. However, the low stiffness of serial industrial robots leads to substantial, difficult-to-measure end-effector deviations under the welding forces during the friction stir welding process, impacting the welding quality. To more effectively measure the deviations in the end-effector, this study introduces a digital twin model based on the five-dimensional digital twin theory. The model obtains the current data of the robot and six-axis force sensor and calculates the real-time end deviations using the robot model. Based on this, a virtual welding model was realized by integrating the FEA model with the digital twin model using a co-simulation approach. This model achieves pre-process simulation by iteratively cycling through the simulated force from the FEA model and the end displacement from the robot model. The virtual welding model effectively predicts the welding outcomes with a mere 6.9% error in lateral deviation compared to actual welding, demonstrating its potential in optimizing welding parameters and enhancing accuracy and quality. Employing digital twin models to monitor, simulate, and optimize the welding process can reduce risks, save costs, and improve efficiency, providing new perspectives for optimizing robotic friction stir welding processes.

Intravenous thrombolysis in acute ischemic stroke patients with pre-stroke disability: A systematic review and meta-analysis.

BACKGROUND: Intravenous thrombolysis (IVT), which is safe and effective, is the first-line therapy for acute ischemic stroke (AIS). However, its benefit for AIS patients with pre-stroke disability (PSD) is controversial. OBJECTIVE: We determined the association of PSD with the safety and efficacy of IVT among patients with AIS. METHODS: We searched PubMed, Embase, and the Cochrane Library from inception to May 23, 2022. The articles focusing on outcomes of AIS patients with PSD receiving IVT were retrieved. We used the random-effects model to pool outcomes including mortality, 24 h NIHSS improvement, symptomatic intracerebral hemorrhage (sICH), favorable functional outcome (FFO), the favorable outcome, and mortality prevalence. RESULTS: Ten studies (including 245,773 participants) that reported the outcomes of AIS patients with PSD undergoing IVT were included. In unadjusted analyses, PSD was associated with mortality (10 studies; odds ratio [OR] 1.739, 95% confidence interval [CI], 1.336-2.407), FFO (7 studies; OR 1.057, 95% CI, 1.015-1.100), 24 h NIHSS improvement (5 studies; OR .840, 95% CI, .819-.917, p = .000), and sICH (9 studies; OR .773, 95% CI, .481-1.243). In adjusted analyses, PSD was associated with mortality (seven studies; ORadj 1.789, 95% CI, 1.413-2.264), FFO (five studies; ORadj 1.087, 95% CI, 1.002-1.179), 24 h NIHSS improvement (five studies; ORadj .837, 95% CI, .799-.876), and sICH (five studies; ORadj .857, 95% CI, .725-1.012). The prevalence of FFO and mortality in patients with pre-stroke modified Rankin Scale scores of 2-5 were 49% (0.42-0.56) and 37% (0.21-0.53), respectively. CONCLUSIONS: Patients with PSD undergoing IVT had a higher mortality rate than those without PSD. Meanwhile, PSD was associated with FFO, and there was no significant difference in sICH and 24 h NIHSS improvement. High-quality data are needed to clarify the benefits of administering IVT in these patients.

Photocatalytic Sulfonyl Peroxidation of Alkenes via Deamination of N-Sulfonyl Ketimines.

A photocatalytic three-component sulfonyl peroxidation of alkenes with N-sulfonyl ketimines and tert-butyl hydroperoxide is reported. The reaction takes place via the photoinduced EnT process, which allows the efficient synthesis of a variety of ß-peroxyl sulfones under mild reaction conditions in the absence of a transition metal catalyst. The downstream derivatizations of the peroxides were also performed. Furthermore, the utility of this protocol was manifested by the synthesis of 11ß-HSD1 inhibitor and the antiprostate cancer drug bicalutamide.

Extraction, purification, structural characterization, and bioactivities of the genus Schisandra polysaccharides: A review.

The genus Schisandra, a member of the Magnoliaceae family, is a well-known tonic traditional Chinese medicine with a long history of traditional medicinal and functional food used in China. Polysaccharides are one of its main active constituents, which have a wide range of bioactivities, such as anti-inflammatory, anti-tumor, neuroprotection, anti-diabetes, hepatoprotection, immunomodulation, and anti-fatigue. In this paper, we review the extraction, isolation, purification, structural characterization, bioactivities, as well as structure-activity relationship of polysaccharides from the genus Schisandra. In conclusion, we hope that this review could provide reference for the subsequent research on structural, bioactivities, development and application of the genus Schisandra polysaccharides.

Single-cell sequencing reveals increased LAMB3-positive basal keratinocytes and ZNF90-positive fibroblasts in autologous cultured epithelium.

Autologous cultured epithelium grafting (ACEG) presents a promising treatment for refractory vitiligo, yet concerns regarding infections and immunological reactions hinder its surgical use due to serum and feeder dependencies. Addressing this, we culture autologous epithelium under serum- and feeder-free (SFF) conditions, comparing its safety and efficacy with serum- and feeder-dependent (SFD) conditions in stable vitiligo patients, and we discover no significant differences in repigmentation between the SFF and SFD grafts. Single-cell RNA transcriptomics on SFF- and SFD-cultured epithelium alongside healthy skin reveal increased populations of LAMB3+ basal keratinocytes and ZNF90+ fibroblasts in the SFF sheets. Functional analyses showcase active cellular metabolism in LAMB3+ basal keratinocytes, vital in extracellular matrix homeostasis, while ZNF90+ fibroblasts demonstrate increased differentiation, essential in collagen formation for cell adhesion. Importantly, these cell populations in SFF sheets exhibit enhanced interactions with melanocytes compared to SFD sheets. Further, knockdown experiments of LAMB3 in keratinocytes and ZNF90 in fibroblasts lead to a downregulation in melanocyte ligand-receptor-related genes. Overall, SFF sheets demonstrate comparable efficacy to SFD sheets, offering superior safety. LAMB3+ basal keratinocytes and ZNF90+ fibroblasts act as potential drivers behind repigmentation in ACEG under SFF conditions. This study provides translational insights into ACEG repigmentation and potential therapeutic targets for vitiligo.

Real-world safety and efficacy endovascular treatment versus standard medical treatment for basilar artery occlusion: A systematic review and meta-analysis.

PURPOSE: We acknowledge that between endovascular treatment (EVT) has emerged as a promising therapeutic approach, with some evidence of benefits observed in clinical trials. However, there remains a significant gap in the evidence regarding the real-world application and effectiveness of EVT.The objective of this study was to comprehensively evaluate the safety and efficacy differences between EVT and standard medical treatment (SMT) in patients with basilar artery occlusion(BAO). METHODS: Real-world studies (RWSs) on patients with BAO who underwent EVT and SMT were identified through searches in EMBASE, PubMed, and Cochrane Library databases. The efficacy outcomes included good clinical outcomes [defined as modified Rankin Scale (mRS) scores of 0-3 at 90 days], excellence clinical outcomes (defined as mRS scores of 0-2 at 90 days), 90-day mortality rate, and reperfusion status. The safety outcome was symptomatic intracranial hemorrhage (sICH). Subgroup analysis was conducted based on study type (prospective and retrospective studies). The relationship between EVT and SMT with the prognosis of BAO patients was expressed using odds ratios (OR) with a 95% confidence interval (95% CI). RESULTS: The seven studies involved a total of 2885 patients. After conducting sensitivity analysis and excluding articles with high heterogeneity, EVT demonstrated a significant association with good clinical outcomes at 90 days (OR=4.01, 95% CI: 2.60-6.19) and excellence clinical outcomes at 90 days (OR=5.70, 95% CI: 3.18-10.22) compared to SMT. Additionally, EVT showed a lower correlation with 90-day mortality rate compared to the SMT group (OR=0.35, 95% CI: 0.25-0.47). Subgroup analysis based on study type revealed that EVT had higher rates of successful reperfusion (retrospective study group: OR=7.97, 95% CI: 4.83-13.15; prospective study group: OR=51.57, 95% CI: 29.76-89.38) than the SMT group in both subgroups. The presence of sICH was not statistically significant in the retrospective study group (OR=1.20, 95% CI: 0.58-2.48) and showed high heterogeneity. However, in the prospective study group, EVT exhibited a higher risk of bleeding compared to SMT (OR=11.42, 95% CI: 2.65-49.20). CONCLUSIONS: In summary, our real-world study aligns with the conclusions of recently published randomized controlled trials research. When comparing EVT and SMT in the treatment of BAO, EVT shows a higher correlation with favorable clinical outcomes, higher rates of successful reperfusion, and lower mortality rates. However, it does come with an increased risk of sICH.

Surfeit Locus Protein 4 as a Novel Target for Therapeutic Intervention in Cerebral Ischemia-Reperfusion Injury.

Surfeit locus protein 4 (SURF4) functions as a cargo receptor that is capable of transporting newly formed proteins from the lumen of the endoplasmic reticulum into vesicles and Golgi bodies. However, the role of SURF4 in the central nervous system remains unclear. The aim of this study is to investigate the role of SURF4 and its underlying mechanisms in cerebral ischemia/reperfusion (I/R) injury in rats, and whether it can be used effectively for novel therapeutic intervention. We also examined whether transcranial direct-current stimulation (tDCS) can exert a neuroprotective effect via SURF4-dependent signalling. Following cerebral I/R injury in rats, a significant increase was observed in the expression of SURF4. In both I/R injury and oxygen-glucose deprivation (OGD) insult, suppressing the expression of SURF4 demonstrated a neuroprotective effect, while overexpression of SURF4 resulted in increased neuronal death. We further showed that the levels of nerve growth factor precursor (proNGF), p75 neurotrophin receptor (p75NTR), sortilin, and PTEN were increased following cerebral I/R injury, and that SURF4 acted through the PTEN/proNGF signal pathway to regulate neuronal viability. We demonstrated that tDCS treatment reduced SURF4 expression and decreased the infarct volume after cerebral I/R injury. Together, this study indicates that SURF4 plays a critical role in ischemic neuronal injury and may serve as a molecular target for the development of therapeutic strategies in acute ischemic stroke.

Upregulation of mitochondrial PGK1 by ROS-TBC1D15 pathway promotes neuronal death after oxygen-glucose deprivation/reoxygenation injury.

Phosphoglycerate kinase 1 (PGK1) is extensively located in the cytosol and mitochondria. The role of PGK1 in ischemic neuronal injury remains elusive. In the in vitro model of oxygen-glucose deprivation/reoxygenation (OGD/R), we showed that PGK1 expression was increased in cortical neurons. Knockdown of PGK1 led to a reduction of OGD/R-induced neuronal death. The expression of cytosolic PGK1 was reduced, but the levels of mitochondrial PGK1 were increased in OGD/R-insulted neurons. Inhibiting the activity of mitochondrial PGK1 alleviated the neuronal injury after OGD/R insult. We further showed that the protein levels of TBC domain family member 15 (TBC1D15) were decreased in OGD/R-insulted neurons. Knockdown of TBC1D15 led to increased levels of mitochondrial PGK1 after OGD/R insult in cortical neurons. Moreover, increased reactive oxygen species (ROS) resulted in a reduction of TBC1D15 in OGD/R-insulted neurons. These results suggest that the upregulation of mitochondrial PGK1 by ROS-TBC1D15 signaling pathway promotes neuronal death after OGD/R injury. Mitochondrial PGK1 may act as a regulator of neuronal survival and interventions in the PGK1-dependent pathway may be a potential therapeutic strategy.

Mechanisms of Gravitational Influence on Weld Pool Behavior and Weld Bead Performance in Variable Polarity Plasma Arc Welding across Different Welding Position.

This article comprehensively explores the cross-scale effects of gravity on macroscopic flow formation and weld bead formation in variable polarity plasma arc welding. Gravity-induced changes in welding direction were achieved through welding at different spatial positions. The properties of the weld bead were investigated at various spatial locations. Additionally, an elemental tracing technique was employed to study the internal flow behavior of molten metal. In the flat welding position, there is an observable trend of increasing grain size in the welded bead, accompanied by a significant expansion of the coarse grain zone. Consequently, the properties of the weld bead in the flat position are inferior to those achieved in the vertical welding position. This phenomenon can be attributed to the accumulation of molten metal at the exit side of the keyhole, resulting in temperature accumulation. Research indicates that the internal flow within the weld pool plays a critical role in causing this phenomenon. The study's findings reveal the presence of two distinct vortex flow patterns within the weld pool: one aligned with the welding direction and the other directed towards the interior of the weld pool. Particularly noteworthy is the substantial expansion of the flow channel area in the flat welding position, which significantly amplifies the impact of internal flow. This enhanced flow intensity inevitably leads to the increased buildup of molten metal at the keyhole exit side. These studies lay the groundwork for achieving high-quality and controllable spatial-position welding.

Electrochemical Trifluoromethylation and Sulfonylation of N-Allylamides: Synthesis of Oxazoline Derivatives.

We report a new method for the synthesis of trifluoromethylated and sulfonylated oxazolines by electrochemical radical cascade cyclizations of N-allylamides with sodium trifluoromethanesulfinate or sulfonylhydrazines. This protocol provides a green and useful strategy to synthesize trifluoromethylated and sulfonylated oxazolines with a broad substrate scope under ambient conditions.

Decreased syntaxin17 expression contributes to the pathogenesis of acute pancreatitis in murine models by impairing autophagic degradation.

Acute pancreatitis (AP) is an inflammatory disease of the exocrine pancreas. Disruptions in organelle homeostasis, including macroautophagy/autophagy dysfunction and endoplasmic reticulum (ER) stress, have been implicated in human and rodent pancreatitis. Syntaxin 17 (STX17) belongs to the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) subfamily. The Qa-SNARE STX17 is an autophagosomal SNARE protein that interacts with SNAP29 (Qbc-SNARE) and the lysosomal SNARE VAMP8 (R-SNARE) to drive autophagosome-lysosome fusion. In this study, we investigated the role of STX17 in the pathogenesis of AP in male mice or rats induced by repeated intraperitoneal injections of cerulein. We showed that cerulein hyperstimulation induced AP in mouse and rat models, which was characterized by increased serum amylase and lipase activities, pancreatic edema, necrotic cell death and the infiltration of inflammatory cells, as well as markedly decreased pancreatic STX17 expression. A similar reduction in STX17 levels was observed in primary and AR42J pancreatic acinar cells treated with CCK (100 nM) in vitro. By analyzing autophagic flux, we found that the decrease in STX17 blocked autophagosome-lysosome fusion and autophagic degradation, as well as the activation of ER stress. Pancreas-specific STX17 knockdown using adenovirus-shSTX17 further exacerbated pancreatic edema, inflammatory cell infiltration and necrotic cell death after cerulein injection. These data demonstrate a critical role of STX17 in maintaining pancreatic homeostasis and provide new evidence that autophagy serves as a protective mechanism against AP.

Determination of Flavonoid Compounds in Shanxi Aged Vinegars Based on Hydrophobic Deep Eutectic Solvent VALLME-HPLC Method: Assessment of the Environmental Impact of the Developed Method.

This research presents a novel, eco-friendly, vortex-assisted liquid-liquid microextraction (VALLME) approach, integrating hydrophobic deep eutectic solvents (DESs) with HPLC for the identification and quantification of nine specific flavonoids in Shanxi aged vinegar (SAV). The parameters of DES-VALLME, including the ratio of trioctylmethylammonium chloride to 1,4-butanediol (1:6), DES volume (150 µL), vortex duration (5 min), the concentration of NaCl (0.40 g), and centrifugation time (10 min), were optimized to achieve the maximum extraction efficiency of target substances. Under these optimal conditions, quantitative analyses performed via HPLC demonstrated a broad linear range of 0.20-50.00 µg/mL and correlation coefficients (r2) greater than 0.9944 for all nine calibration curves. The limits of detection (LOD) and limits of quantitation (LOQ) were 0.09-0.18 µg/mL and 0.30-0.60 µg/mL, respectively, ensuring high sensitivity. The relative standard deviations for intra-day and inter-day variability were within the acceptable range, 2.34-3.77% and 3.04-4.96%, respectively, demonstrating the method's reliability. The recovery rates ranged from 85.97% to 108.11%, underscoring the method's precision. This technique exhibited a significant enrichment effect (enrichment factor: 43 to 296) on SAV flavonoids. Notably, the eco-friendliness of this procedure was evaluated using the Analytical Eco-Scale, Green Analytical Procedure Index, and Analytical Greenness Metric. The results suggested that this technique is a viable green alternative to traditional flavonoid determination methods in SAV. In summary, this novel method provides a theoretical basis for assessing flavonoid content in SAV samples and tracing SAV products. This contribution has significant implications for enhancing analytical techniques in food chemistry and environmental science and the sustainable development of the food industry.

Different doses of dual orexin receptor antagonists in primary insomnia: a Bayesian network analysis.

Background: Systematic comparisons of the doses of the Food and Drug Administration (FDA)-approved dual orexin receptor antagonists (DORAs) for people with insomnia are limited. Methods: PubMed, Embase, Cochrane Library, and Clinicaltrials. gov were systematically searched to identify relevant studies published before 31 October 2022. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. Results: We pooled 7257 participants from 9 randomized controlled trials (RCTs). Moderate to high certainty evidence demonstrated suvorexant (20 and 40 mg) and daridorexant (10 and 50 mg) as the most effective in latency to persistent sleep (LPS) reduction. Lemborexant at 5 and 10 mg was the most effective in subjective sleep onset time (sTSO) reduction. For wake time after sleep onset (WASO), all drugs except daridorexant 5 mg were more effective than placebo. Lemborexant 5 mg was among the best in subjective WASO (sWASO) (moderate to high certainty) and had the highest surface under the curve ranking area (SUCRA) values for sWASO (100%). For total sleep time (TST), suvorexant and daridorexant, except the respective minimum doses, were more effective than placebo, while suvorexant 40 mg and lemborexant 10 mg may have been the most effective for subjective TST (sTST) (low to very low certainty). Suvorexant 40 mg (RR 1.09), suvorexant 80 mg (RR 1.65), and daridorexant 25 mg (RR 1.16) showed a higher safety risk than placebo. Conclusion: Suvorexant 20 mg, lemborexant 5 mg, lemborexant 10 mg, and daridorexant 50 mg represent suitable approaches for insomnia. Clinical Trial Registration: clinicaltrials.gov, PROSPERO (CRD42022362655).

Effect of Mechanical Stirring on High-Speed GMAW Hump Bead.

High-speed GMAW tends to be accompanied by periodic humping defects, thereby reducing the weld bead quality. A new method was proposed to actively control the weld pool flow for eliminating humping defects. A high-melting point solid pin was designed and inserted into the weld pool to stir the liquid metal during the welding process. The characteristics of the backward molten metal flow were extracted and compared by a high-speed camera. Combined with particle tracing technology, the momentum of the backward metal flow was calculated and analyzed, and the mechanism of hump suppression in high speed GMAW was further revealed. The stirring pin interacted with the liquid molten pool, resulting in a vortex zone behind the stirring pin, which significantly reduced the momentum of the backward molten metal flow, and thus it inhibited the formation of humping beads.

Subthalamic nucleus stimulation attenuates motor seizures via modulating the nigral orexin pathway.

Background: Focal motor seizures that originate in the motor region are a considerable challenge because of the high risk of permanent motor deficits after resection. Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a potential treatment for motor epilepsy that may enhance the antiepileptic actions of the substantia nigra pars reticulata (SNr). Orexin and its receptors have a relationship with both STN-DBS and epilepsy. We aimed to investigate whether and how STN inputs to the SNr regulate seizures and the role of the orexin pathway in this process. Methods: A penicillin-induced motor epileptic model in adult male C57BL/6 J mice was established to evaluate the efficacy of STN-DBS in modulating seizure activities. Optogenetic and chemogenetic approaches were employed to regulate STN-SNr circuits. Selective orexin receptor type 1 and 2 antagonists were used to inhibit the orexin pathway. Results: First, we found that high-frequency ipsilateral or bilateral STN-DBS was effective in reducing seizure activity in the penicillin-induced motor epilepsy model. Second, inhibition of STN excitatory neurons and STN-SNr projections alleviates seizure activities, whereas their activation amplifies seizure activities. In addition, activation of the STN-SNr circuits also reversed the protective effect of STN-DBS on motor epilepsy. Finally, we observed that STN-DBS reduced the elevated expression of orexin and its receptors in the SNr during seizures and that using a combination of selective orexin receptor antagonists also reduced seizure activity. Conclusion: STN-DBS helps reduce motor seizure activity by inhibiting the STN-SNr circuit. Additionally, orexin receptor antagonists show potential in suppressing motor seizure activity and may be a promising therapeutic option in the future.

Multiparametric MRI radiomics fusion for predicting the response and shrinkage pattern to neoadjuvant chemotherapy in breast cancer.

Purpose: During neoadjuvant chemotherapy (NACT), breast tumor morphological and vascular characteristics are usually changed. This study aimed to evaluate the tumor shrinkage pattern and response to NACT by preoperative multiparametric magnetic resonance imaging (MRI), including dynamic contrast-enhanced MRI (DCE-MRI), diffuse weighted imaging (DWI) and T2 weighted imaging (T2WI). Method: In this retrospective analysis, female patients with unilateral unifocal primary breast cancer were included for predicting tumor pathologic/clinical response to NACT (n=216, development set, n=151 and validation set, n=65) and for discriminating the tumor concentric shrinkage (CS) pattern from the others (n=193; development set, n=135 and validation set, n=58). Radiomic features (n=102) of first-order statistical, morphological and textural features were calculated on tumors from the multiparametric MRI. Single- and multiparametric image-based features were assessed separately and were further combined to feed into a random forest-based predictive model. The predictive model was trained in the testing set and assessed on the testing dataset with an area under the curve (AUC). Molecular subtype information and radiomic features were fused to enhance the predictive performance. Results: The DCE-MRI-based model showed higher performance (AUCs of 0.919, 0.830 and 0.825 for tumor pathologic response, clinical response and tumor shrinkage patterns, respectively) than either the T2WI or the ADC image-based model. An increased prediction performance was achieved by a model with multiparametric MRI radiomic feature fusion. Conclusions: All these results demonstrated that multiparametric MRI features and their information fusion could be of important clinical value for the preoperative prediction of treatment response and shrinkage pattern.