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Background and objectives: The effects of noninvasive focused magnetothermal brain stimulation using magnetic nanoparticles (MNPs) on post-stroke motor deficits and metabolic dormancy in subacute ischemic injury are not well-established. This study examined if magnetothermal brain stimulation using magnetic nanoparticles (Nano-MS) enhances motor recovery after stroke. Methods: We randomly distributed rats into Sham, Control, MNP injection only, and Nano-MS groups. We administered focused magnetic stimulation for 30 min daily following an MNP injection (15 mg/mL) into the targeted motor cortex via the carotid artery three weeks after the transient (90 min) middle cerebral artery occlusion. We assessed motor functionality via behavioral tests and conducted positron emission tomography (PET) imaging to verify cerebral metabolic activity. We assessed neuronal excitability, neuroinflammation, blood-brain barrier (BBB) integrity, and neurogenesis four weeks post-stroke. Results: The Nano-MS group exhibited significantly improved motor deficits and cerebral metabolic activity compared to the Control and MNP groups (p

The widespread dissemination of the COVID-19 pandemic precipitated a transition from traditional, in-person pedagogy to online methods within higher vocational education. The inherent limitations of online learning have become progressively conspicuous. Given its pivotal role amidst the pandemic, numerous institutions have endeavored to integrate technology with traditional classroom pedagogies. Consequently, blended learning has emerged as a focal point within vocational education, garnering notable attention and interest. The question arises: which learning method proves most effective for vocational skills development? This study endeavored to ascertain the comparative effectiveness of various learning methods for vocational skills training. Specifically, employing a quantitative approach, the study conducted a comprehensive questionnaire survey of graduates of higher vocational institutions in China. Participants have undergone training via exclusively physical, thoroughly online, and blended learning formats, respectively. The objective was to evaluate the efficacy of these three methods as perceived by higher vocational graduates. In addition, the study aimed to analyze the personal and pedagogical factors that influence the effectiveness of these learning methods. The collected data underwent analysis utilizing SPSS software. One-way analysis of variance (ANOVA) tests, correlation analyses, and subsequent least significant difference (LSD) post-hoc analyses were employed to investigate the correlations between demographic variables and factors related to teachers and educational resources across the three learning methods. These findings indicate that blended learning is the most efficient approach, with a notable preference among vocational graduates. Physical learning demonstrated superior effectiveness, particularly in functional skills training. In divergence, online learning ranked the lowest among graduates' preference, efficiency, and efficacy in functional skills training. Among the demographic factors examined, gender and duration of graduation exhibited notable variances across the effectiveness of different learning methods. However, there are no significant differences in the area of origin, economic region, type of higher vocational institution, and majors. These insights provide valuable guidance for higher vocational institutions in selecting the most suitable learning methods for enhancing functional skills training.

Abstract Microbubbles (MBs) combined with focused ultrasound (FUS) has emerged as a promising noninvasive technique to permeabilize the blood–brain barrier (BBB) for drug delivery into the brain. However, the safety and biological consequences of BBB opening (BBBO) remain incompletely understood. This study aims to investigate the effects of two parameters mediating BBBO: microbubble volume dose (MVD) and mechanical index (MI). High-resolution MRI-guided FUS was employed in mouse brains to assess BBBO by manipulating these two parameters. Afterward, the sterile inflammatory response (SIR) was studied 6 h post-FUS treatment. Results demonstrated that both MVD and MI significantly influenced the extent of BBBO, with higher MVD and MI leading to increased permeability. Moreover, RNA sequencing revealed upregulation of major inflammatory pathways and immune cell infiltration after BBBO, indicating the presence and extent of SIR. Gene set enrichment analysis identified 12 gene sets associated with inflammatory responses that were significantly upregulated at higher MVD or MI. A therapeutic window was established between therapeutically relevant BBBO and the onset of SIR, providing operating regimes to avoid damage from stimulation of the NFκB pathway via TNFɑ signaling to apoptosis. These results contribute to the optimization and standardization of BBB opening parameters for safe and effective drug delivery to the brain and further elucidate the underlying molecular mechanisms driving sterile inflammation.

Flavin adenine dinucleotide (FAD) interacts with flavoproteins to mediate oxidation-reduction reactions required for cellular energy demands. Not surprisingly, mutations that alter FAD binding to flavoproteins cause rare inborn errors of metabolism (IEMs) that disrupt liver function and render fasting intolerance, hepatic steatosis, and lipodystrophy. In our study, depleting FAD pools in mice with a vitamin B2-deficient diet (B2D) caused phenotypes associated with organic acidemias and other IEMs, including reduced body weight, hypoglycemia, and fatty liver disease. Integrated discovery approaches revealed B2D tempered fasting activation of target genes for the nuclear receptor PPARα, including those required for gluconeogenesis. We also found PPARα knockdown in the liver recapitulated B2D effects on glucose excursion and fatty liver disease in mice. Finally, treatment with the PPARα agonist fenofibrate activated the integrated stress response and refilled amino acid substrates to rescue fasting glucose availability and overcome B2D phenotypes. These findings identify metabolic responses to FAD availability and nominate strategies for the management of organic acidemias and other rare IEMs.

ObjectiveMitophagy removes damaged mitochondria to maintain cellular homeostasis. Aryl hydrocarbon receptor (AhR) expression in the liver plays a crucial role in supporting normal liver functions, but its impact on mitochondrial function is unclear. Here, we identified a new role of AhR in the regulation of mitophagy to control hepatic energy homeostasis.MethodsIn this study, we utilized primary hepatocytes from AhR knockout (KO) mice and AhR knockdown AML12 hepatocytes. An endogenous AhR ligand, kynurenine (Kyn), was used to activate AhR in AML12 hepatocytes. Mitochondrial function and mitophagy process were comprehensively assessed by MitoSOX and mt-Keima fluorescence imaging, Seahorse XF-based oxygen consumption rate measurement, and Mitoplate S-1 mitochondrial substrate utilization analysis.ResultsTranscriptomic analysis indicated that mitochondria-related gene sets were dysregulated in AhR KO liver. In both primary mouse hepatocytes and AML12 hepatocyte cell lines, AhR inhibition strongly suppressed mitochondrial respiration rate and substrate utilization. AhR inhibition also blunted the fasting response of several essential autophagy genes and the mitophagy process. We further identified BCL2 interacting protein 3 (BNIP3), a mitophagy receptor that senses nutrient stress, as an AhR target gene. AhR is directly recruited to the Bnip3 genomic locus, and Bnip3 transcription was enhanced by AhR endogenous ligand treatment in wild-type liver and abolished entirely in AhR KO liver. Mechanistically, overexpression of Bnip3 in AhR knockdown cells mitigated the production of mitochondrial reactive oxygen species (ROS) and restored functional mitophagy.ConclusionsAhR regulation of the mitophagy receptor BNIP3 coordinates hepatic mitochondrial function. Loss of AhR induces mitochondrial ROS production and impairs mitochondrial respiration. These findings provide new insight into how endogenous AhR governs hepatic mitochondrial homeostasis.

Abstract The polymeric gel electrolytes are attractive owing to their higher ionic conductivities than those of dry polymer electrolytes and lowered water activity for enlarged potential window. However, the ionic conductivity and mechanical strength of the Na‐ion conducting polymeric gel electrolytes are limited by below 20 mS cm−1 and 2.2 MPa. Herein, we demonstrate Na‐ion conducting and flexible polymeric hydrogel electrolytes of the chemically coupled poly(diallyldimethylammonium chloride)‐dextrin‐N,N′‐methylene‐bis‐acrylamide film immersed in NaClO4 solution (ex‐DDA‐Dex + NaClO4) for flexible sodium‐ion hybrid capacitors (f‐NIHC). In particular, the anion exchange reaction and synergistic interaction of ex‐DDA‐Dex with the optimum ClO4− enable to greatly improve the ionic conductivity up to 27.63 mS cm−1 at 25°C and electrochemical stability window up to 2.6 V, whereas the double networking structure leads to achieve both the mechanical strength (7.48 MPa) and softness of hydrogel electrolytes. Therefore, the f‐NIHCs with the ex‐DDA‐Dex + NaClO4 achieved high specific and high‐rate capacities of 192.04 F g−1 at 500 mA g−1 and 116.06 F g−1 at 10 000 mA g−1, respectively, delivering a large energy density of 120.03 W h kg−1 at 906 W kg−1 and long cyclability of 70% over 500 cycles as well as demonstrating functional operation under mechanical stresses.

Research shows teacher influence in school decision-making is related to improving individual job satisfaction and professional commitment. However, few empirical studies investigate how different domains of school decision-making may have a distinct relationship with both individual teacher job satisfaction and professional commitment. Using the Schools and Staffing Survey 2011-2012 and the National Teacher and Principal Survey 2015-2016 which are national samples of U.S. primary and secondary schools, this study examines teacher influence in managerial and instruction domains of school decision-making and whether both are associated with job satisfaction and professional commitment. Results showed that teacher influence in the instruction domain has a statistically stronger relationship with teacher professional commitment than job satisfaction. In contrast, teacher influence in the managerial domain of school decision-making has a statistically stronger relationship with teacher job satisfaction than professional commitment. The results have policy implications for involving teachers in school decision-making and improving their overall job satisfaction.

Abstract Magnesium‐ion batteries (MIBs) have promising applications because of their high theoretical capacity and the natural abundance of magnesium Mg. However, the kinetic performance and cyclic stability of cathode materials are limited by the strong interactions between Mg ions and the crystal lattice. Here, we demonstrate the unique Mg2+‐ion storage mechanism of a hierarchical accordion‐like vanadium oxide/carbon heterointerface (V2O3@C), where the V2O3 crystalline structure is reconstructed into a MgV3O7∙H2O phase through an anodic hydration reaction upon first cycle, for the improved kinetic and cyclic performances. As verified by in situ/ex situ spectroscopic and electrochemical analyses, the fast charge transfer kinetics of the V2O3@C cathode were due to the crystal‐reconstruction and chemically coupled heterointerface. The V2O3@C demonstrated an ultrahigh rate capacity of 130.4 mAh g−1 at 50 000 mA g−1 and 1000 cycles, achieving a Coulombic efficiency of 99.6%. The high capacity of 381.0 mA h g−1 can be attributed to the reversible Mg2+‐ion intercalation mechanism observed in the MgV3O7∙H2O phase using a 0.3 M Mg(TFSI)2/ACN(H2O) electrolyte. Additionally, within the voltage range of 2.25 V versus Mg/Mg2+, the V2O3@C exhibited a capacity of 245.1 mAh g−1 when evaluated with magnesium metal in a 0.3 M Mg(TFSI)2 + 0.25 M MgCl2/DME electrolyte. These research findings have important implications for understanding the relationship between the Mg‐ion storage mechanism and reconstructed crystal phase of vanadium oxides as well as the heterointerface reconstruction for the rational design of MIB cathode materials.

BackgroundPreclinical data suggest circadian variation in ischemic stroke progression, with more active cell death and infarct growth in rodent models with inactive phase (daytime) than active phase (nighttime) stroke onset. We aimed to examine the association of stroke onset time with presenting severity, early neurological deterioration (END), and long-term functional outcome in human ischemic stroke.Methods and findingsIn a Korean nationwide multicenter observational cohort study from May 2011 to July 2020, we assessed circadian effects on initial stroke severity (National Institutes of Health Stroke Scale [NIHSS] score at admission), END, and favorable functional outcome (3-month modified Rankin Scale [mRS] score 0 to 2 versus 3 to 6). We included 17,461 consecutive patients with witnessed ischemic stroke within 6 hours of onset. Stroke onset time was divided into 2 groups (day-onset [06:00 to 18:00] versus night-onset [18:00 to 06:00]) and into 6 groups by 4-hour intervals. We used mixed-effects ordered or logistic regression models while accounting for clustering by hospitals. Mean age was 66.9 (SD 13.4) years, and 6,900 (39.5%) were women. END occurred in 2,219 (12.7%) patients. After adjusting for covariates including age, sex, previous stroke, prestroke mRS score, admission NIHSS score, hypertension, diabetes, hyperlipidemia, smoking, atrial fibrillation, prestroke antiplatelet use, prestroke statin use, revascularization, season of stroke onset, and time from onset to hospital arrival, night-onset stroke was more prone to END (adjusted incidence 14.4% versus 12.8%, p = 0.006) and had a lower likelihood of favorable outcome (adjusted odds ratio, 0.88 [95% CI, 0.79 to 0.98]; p = 0.03) compared with day-onset stroke. When stroke onset times were grouped by 4-hour intervals, a monotonic gradient in presenting NIHSS score was noted, rising from a nadir in 06:00 to 10:00 to a peak in 02:00 to 06:00. The 18:00 to 22:00 and 22:00 to 02:00 onset stroke patients were more likely to experience END than the 06:00 to 10:00 onset stroke patients. At 3 months, there was a monotonic gradient in the rate of favorable functional outcome, falling from a peak at 06:00 to 10:00 to a nadir at 22:00 to 02:00. Study limitations include the lack of information on sleep disorders and patient work/activity schedules.ConclusionsNight-onset strokes, compared with day-onset strokes, are associated with higher presenting neurologic severity, more frequent END, and worse 3-month functional outcome. These findings suggest that circadian time of onset is an important additional variable for inclusion in epidemiologic natural history studies and in treatment trials of neuroprotective and reperfusion agents for acute ischemic stroke.

The nutrient sensing nuclear receptor peroxisome proliferator-activated receptor-α (PPARα) regulates the host response to short-term fasting by inducing hepatic transcriptional programming of ketogenesis, fatty acid oxidation and transport, and autophagy. This adaptation is ineffective in chronically undernourished individuals, among whom dyslipidemia and hepatic steatosis are common. We recently reported that hepatic PPARα protein is profoundly depleted in male mice undernourished by a low-protein, low-fat diet. Here, we identify PPARα as a deacetylation target of the NAD-dependent deacetylase sirtuin-1 (SIRT1) and link this to the decrease in PPARα protein levels in undernourished liver. Livers from undernourished male mice expressed high levels of SIRT1, with decreased PPARα acetylation and strongly decreased hepatic PPARα protein. In cultured hepatocytes, PPARα protein levels were decreased by transiently transfecting constitutively active SIRT1 or by treating cells with the potent SIRT1 activator resveratrol, while silencing SIRT1 increased PPARα protein levels. SIRT1 expression is correlated with increased PPARα ubiquitination, suggesting that protein loss is due to proteasomal degradation. In accord with these findings, the dramatic loss of hepatic PPARα in undernourished male mice was completely restored by treating mice with the proteasome inhibitor bortezomib. Similarly, treating undernourished mice with the SIRT1 inhibitor selisistat/EX-527 completely restored hepatic PPARα protein. These data suggest that induction of SIRT1 in undernutrition results in hepatic PPARα deacetylation, ubiquitination, and degradation, highlighting a new mechanism that mediates the liver's failed adaptive metabolic responses in chronic undernutrition.

Mitochondrial imaging is crucial for studying disease pathogenesis and diagnosis. However, commercially available mitochondria-specific fluorescent probes are limited due to the difficulty in modifying cationic probes for functional bioimaging of mitochondria. To address this, we prepared a hydroxythiophene-conjugated benzothiazole (BzT-OH) as a platform for the design of functional fluorescent probes. Two probes, BzT-OAc and BzT-OAcryl, were synthesized by substituting the hydroxy group in BzT-OH with acetate and acrylate groups, respectively. BzT-OAc demonstrated blue fluorescence that shifted to green emission after enzymatic cleavage of the acetate group, allowing for monitoring of endogenous esterase activity. BzT-OAcryl showed high selectivity for cysteine at pH > 8.0, owing to its pH-responsive property, and could detect pH perturbations caused by mitochondrial dysfunction. Both probes exhibited high biocompatibility, quantum yield, and large Stokes shifts in mitochondria. BzT-OH can be easily conjugated with other functional groups and substrates of various enzymes for designing fluorescent probes for functional mitochondrial imaging. The photofunctional property of the probe can be changed due to the involvement of the hydroxyl group in the excited state intermolecular proton transfer.