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PurposeInhibition of Notch signaling has been recently demonstrated to promote beige adipocyte biogenesis. However, most γ-secretase inhibitors (GSIs) used to achieve pharmacological inhibition of Notch signaling are at the basic research or preclinical stage, limiting the translation of fundamental findings into clinical practice. This present study aimed to evaluate the potential of several clinical candidates of GSIs as browning agents for the treatment of obesity.MethodsSeven GSIs that are clinical candidates for the treatment of Alzheimer’s disease or cancer were selected and their impacts on Notch inhibition as well as promoting beige biogenesis were compared using in vitro culture of 3T3-L1 preadipocytes.ResultsFour compounds (i.e.RO4929097, PF-03084014, LY3039478, and BMS-906024) that efficiently inhibited the expression of Notch target genes in 3T3-L1 preadipocytes were identified. Moreover, these compounds were optimized for dose-dependent effects at three gradient concentrations (0.5, 1, and 10 μM) to promote beige adipogenesis and mitochondrial biogenesis in 3T3-L1 preadipocytes without causing severe cytotoxicity.ConclusionsOur findings not only highlight the potential of cross-therapeutic application of these GSIs for obesity treatment via inhibition of γ-secretase-mediated processing of Notch signaling, but also provide important experimental evidence to support further design and development of clinically translatable Notch-inhibiting drug delivery systems.

Half-Heuslers emerged as promising candidates for medium- and high-temperature thermoelectric power generation. However, polycrystalline half-Heuslers inevitably suffer from the defect-dominated scattering of electrons that greatly limits the optimization of their electronic properties. Herein, high-quality TiCoSb-based single-crystals with a dimension above 1 cm have been obtained. Benefitting from the improved electron mobility, an average power factor of ~37 μW cm −1 K −2 in the temperature range between 307 and 973 K has been realized in the n-type single-crystalline Ti 1- x Nb x CoSb. In addition, Hf alloying results in the expansion of the weighted scattering phase space and enhances the anharmonic scattering rate, thereby effectively suppressing the lattice thermal conductivity. Eventually, co-doping of Nb/Ta and alloying of Hf effectively elevate the thermoelectric performance of TiCoSb single crystal, and a peak zT above 1.0 has been realized, which outperforms the previously reported polycrystalline (Ti, Zr, Hf)CoSb-based and ZrCoBi-based materials. Importantly, a single leg of TiCoSb-based single crystals exhibits a heat-to-electricity energy conversive efficiency of ~10.2% at a temperature difference of 700 K. Here, our findings reveal the promise of TiCoSb-based single crystals for thermoelectric power generation, and can potentially guide the future explorations of other single-crystalline half-Heuslers. The authors obtain the TiCoSb-based single-crystals with a dimension exceeding 1 cm, leading to an extraordinary enhancement in electron mobility and consequently, an average power factor of 37 W cm −1  K −2 in the Nb-doped TiCoSb single-crystal.

Cold stimulation dynamically remodels mitochondria in brown adipose tissue (BAT) to facilitate non-shivering thermogenesis in mammals, but what regulates mitochondrial plasticity is poorly understood. Comparing mitochondrial proteomes in response to cold revealed FAM210A as a cold-inducible mitochondrial inner membrane protein. An adipocyte-specific constitutive knockout of Fam210a ( Fam210a AKO ) disrupts mitochondrial cristae structure and diminishes the thermogenic activity of BAT, rendering the Fam210a AKO mice vulnerable to lethal hypothermia under acute cold exposure. Induced knockout of Fam210a in adult adipocytes ( Fam210a iAKO ) does not affect steady-state mitochondrial structure under thermoneutrality, but impairs cold-induced mitochondrial remodeling, leading to progressive loss of cristae and reduction of mitochondrial density. Proteomics reveals an association between FAM210A and OPA1, whose cleavage governs cristae dynamics and mitochondrial remodeling. Mechanistically, FAM210A interacts with mitochondrial protease YME1L and modulates its activity toward OMA1 and OPA1 cleavage. These data establish FAM210A as a key regulator of mitochondrial cristae remodeling in BAT and shed light on the mechanism underlying mitochondrial plasticity in response to cold. Mammalians rely on brown adipocytes to generate heat under cold exposure, this thermogenic function requires dynamic remodeling of the mitochondria. Here the authors identify a protein called FAM210A as a key regulator of cold-induced mitochondrial remodeling in brown adipocytes.

Numerous studies have explored interventions to reduce digital addiction outcomes, but inconclusive evidence makes it difficult for decision-makers, managers, and clinicians to become familiar with all available literature and find appropriate interventions. This study aims to summarize and assess the certainty of evidence of interventions proposed to decrease digital addiction from published meta-analyses. An umbrella review of published meta-analyses was performed. We searched PubMed, Cochrane Library, Web of Science, and Embase for meta-analyses published up to February 2024. Eligible studies evaluated interventions using randomized controlled trials, nonrandomized controlled trials, or quasi-experimental studies and were assessed for methodological quality using Assessment of Multiple Systematic Reviews version 2. A random effects model was used to analyze data, considering heterogeneity and publication bias. Grading of Recommendations, Assessment, Development, and Evaluations was applied to assess evidence with certainty. A total of 5 studies assessing 21 associations were included in the umbrella review, of which 4 (80%) were high-quality meta-analyses. Weak evidence was observed in 19 associations, whereas null associations appeared in the remaining 2 associations. These associations pertained to 8 interventions (group counseling, integrated internet addiction [IA] prevention programs, psychosocial interventions, reality therapy, self-control training programs, cognitive behavioral therapy, interventions to reduce screen time in children, and exercise) and 9 outcomes (self-control, self-esteem, internet gaming disorder symptoms, time spent gaming, IA scores, screen use time, interpersonal sensitivity longlines, anxiety, and depression). Cognitive behavioral therapy reduces anxiety (standardized mean difference [SMD] 0.939, 95% CI 0.311 to 1.586), internet gaming disorder symptoms (SMD 1.394, 95% CI 0.664 to 2.214), time spent gaming (SMD 1.259, 95% CI, 0.311 to 2.206), and IA scores (SMD -2.097, 95% CI -2.814 to -1.381). Group counseling had a large effect on improving self-control (SMD 1.296, 95% CI 0.269 to 2.322) and reducing IA levels (SMD -1.417, 95% CI -1.836 to -0.997). Exercise intervention reduced IA scores (SMD -2.322, 95% CI -3.212 to -1.431), depression scores (SMD -1.421, 95% CI -2.046 to -797), and interpersonal sensitivity scores (SMD -1.433, 95% CI -2.239 to -0.627). The evidence indicates that current interventions to reduce digital addiction are weak. Data from more and better-designed studies with larger sample sizes are needed to establish robust evidence. PROSPERO CRD42024528173; crd.york.ac.uk/PROSPERO/display_record.php?RecordID=528173.

Miniaturized thermoelectric coolers, known for their high cooling power density and rapid thermal response, hold promise for localized thermal management. While traditional thermoelectric coolers have primarily relied on Bi 2 Te 3 alloys, the recent development of n-type Mg 3 Bi 2 -based materials presents a compelling alternative, offering enhanced cost-effectiveness and environmental sustainability. In this study, we have designed and fabricated a Mg 3 Bi 2 -based miniscale thermoelectric cooler. At the hot-side temperature of 300 K, the cooler achieves a maximum cooling temperature difference of ~59.0 K, a cooling power density of ~5.7 W cm -2 , and a cooling speed of 65 K s -1 , which surpasses the state-of-the-art Mg 3 Bi 2 -based devices. In addition, the miniaturized Mg 3 Bi 2 -based cooler maintains its cooling performance after cyclic electrical current density between 1 A mm -2 and 3 A mm -2 for approximately 3,000 cycles. Notably, this miniscale cooler has been applied to provide localized cooling for the central processing unit in a microcontroller. Our findings highlight the potential of Mg 3 Bi 2 -based miniscale coolers, offering new possibilities for localized thermal management in electronic devices. The authors develop a miniaturized Mg3Bi2-based thermoelectric cooler, achieving a high cooling power density of 5.7 W cm-2 and a cooling speed of 65 K s-1, demonstrating great promise for localized thermal management in electronics.

Background The health effects of different weight loss strategies vary greatly, and the relationship between weight loss strategies, especially the combination of multiple strategies, and death is still unclear. We aimed to examine the associations of various numbers and combinations of weight loss strategies with all-cause and specific-cause mortality and to further evaluate the associations of different total weight loss volumes with mortality. Methods Using data from NHANES (1999–2018) with 48,430 participants aged 20 and above, we collected fourteen self-reported weight loss strategies and identified five clusters using latent class analysis. Cox proportional hazards models were used to examine the association between the amounts and clusters of weight loss strategies and mortality. Results During a median follow-up of 9.1 years of 48,430 participants, 7,539 deaths were recorded (including 1,941 CVDs and 1,714 cancer). Participants who adopted 2, 3–4, and ≥ 5 weight loss strategies had a lower risk of all-cause mortality, with HRs of 0.88 (95% CI, 0.81 to 0.97), 0.89 (95% CI, 0.81 to 0.96) and 0.71 (95% CI, 0.61 to 0.82). Regardless of weight loss or weight gain categories, there was a significant trend toward reduced mortality as the number of weight loss strategies increased ( P trend < 0.05). Participants who adopted cluster-1 (four strategies), cluster-2 (five strategies) and cluster-3 (three strategies) had a significantly lower risk of all-cause mortality, with HRs of 0.71 (95% CI, 0.60 to 0.84), 0.70 (95% CI, 0.55 to 0.89) and 0.81 (95% CI, 0.70 to 0.94). Among them, cluster-1 and cluster-2 are both characterized by eating less food, exercising, drinking plenty of water, lowering calories and eating less fat. Conversely, cluster-4 (five strategies) and cluster-5 (four strategies) had marginally significant effects, and they both had actual higher total energy intakes. Similar associations were observed for CVDs and cancer mortality. Conclusions Employing two or more weight loss strategies was associated with a lower risk of death, even among those who gained weight. Eating less food, exercising, drinking plenty of water, lowering calories and eating less fat is a better combination of strategies. On this basis, limiting the actual intake of total energy is necessary.

Objective: Unlike mammals, goose fatty liver shows a strong tolerance to fatty acids without obvious injury. Stearyl-coenzyme A desaturase 1 (SCD1) serves crucial role in desaturation of saturated fatty acids (SAFs), but its role in the SAFs tolerance of goose hepatocytes has not been reported. This study was conducted to explore the role of SCD1 in regulating palmitic acid (PA) tolerance of goose primary hepatocytes. Methods: 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide was examined to reflect the effect of PA on hepatocytes viability, and quantitative polymerase chain reaction was used to detect the mRNA levels of several genes related to endoplasmic reticulum (ER) stress, inflammation, and apoptosis, and the role of SCD1 in PA tolerance of goose hepatocytes was explored using RNA interfere. Results: Our results indicated that goose hepatocytes exhibited a higher tolerant capacity to PA than human hepatic cell line (LO2 cells). In goose primary hepatocytes, the mRNA levels of fatty acid desaturation-related genes (SCD1 and fatty acid desaturase 2) and fatty acid elongate enzyme-related gene (elongase of very long chain fatty acids 6) were significantly upregulated with 0.6 mM PA treatment. However, in LO2 cells, expression of ER stressrelated genes (x box-binding protein, binding immunoglobulin protein, and activating transcription factor 6), inflammatory response-related genes (interleukin-6 [IL-6], interleukin- 1β [IL-1β], and interferon-γ) and apoptosis-related genes (bcl-2-associated X protein, b-cell lymphoma 2, Caspase-3, and Caspase-9) was significantly enhanced with 0.6 mM PA treatment. Additionally, small interfering RNA (siRNA) mediated downregulation of SCD1 significantly reduced the PA tolerance of goose primary hepatocytes under the treatment of 0.6 mM PA; meanwhile, the mRNA levels of inflammatory-related genes (IL-6 and IL-1β) and several key genes involved in the phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT), forkhead box O1 (FoxO1), mammalian target of rapamycin and AMPK pathways (AKT1, AKT2, FoxO1, and sirtuin 1), as well as the protein expression of cytochrome C and the apoptosis rate were upregulated. Conclusion: In conclusion, our data suggested that SCD1 was involved in enhancing the PA tolerance of goose primary hepatocytes by regulating inflammation- and apoptosisrelated genes expression.

This study compared the quality and storage characteristics of four pineapple varieties to select those displaying adequate storage resistance and those suitable for freshly cut processing. Four varieties of pineapple, namely Tainong No.16, Tainong No.17, Tainong No.11, and Bali, were used to analyze the quality differences in freshly cut pineapple during storage by measuring the quality, physiological indicators, and total microbial count. The results indicated that the nutritional quality and storability of freshly cut pineapples differed significantly among the varieties. During refrigeration at 4 °C, Tainong No.11 and Bali displayed the shortest storage period of 4 d, while Tainong No.17 and Tainong No.16 presented storage periods of 5 d and 6 d, respectively. A sensory evaluation indicated that the Tainong No.16 variety was superior in terms of consumer preference, while the Bali slices were generally rated lower than the other cultivars. Additionally, the sensory properties, weight loss, firmness, and ascorbic acid (AA) content of Tainong No.16 changed the least during storage, with values of 60.75%, 6.48%, 75.15%, and 20.44%, respectively. Overall, the quality order of the four varieties of freshly cut pineapples during storage was: Tainong No.16 > Tainong No.17 > Tainong No.11 > Bali. Moreover, two-way ANOVA showed that the main effect of variety and storage time on the storage quality of fresh-cut pineapple was significant (p < 0.05). The interaction effect of variety and storage time on other quality characteristics of fresh-cut pineapple was significant (p < 0.05) except for Titratable acid (TA) and AA. In conclusion, Tainong No.16 displayed higher storage potential than the other varieties. The results of this work provide application possibilities to promote the successful processing of pineapple cultivars as freshly cut produce.

Digital addiction, affecting a significant portion of the population, particularly young people, is linked to psychological issues and social problems, making its prevention and management a crucial public health issue. This umbrella review aimed to comprehensively analyze the factors influencing digital addiction by re-evaluating the methodologies and evidence quality of existing meta-analyses. Databases including PubMed, Web of Science, the Cochrane Library, and Embase were systematically searched for reviews and meta-analyses related to factors associated with digital addiction up to September 24, 2024. The methodological quality of the identified studies was assessed using the modified \"A Measurement Tool to Assess Systematic Reviews 2\" (AMSTAR 2) tool, while the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool was used to evaluate the quality of the evidence presented in the literature. A total of 18 articles were included in the review, with AMSTAR 2 assessments revealing 6 moderate-quality, 4 low-quality, and 8 very low-quality studies. In total, 29 significant factors associated with digital addiction were identified. Notably, 4 studies achieved both moderate AMSTAR 2 and GRADE ratings, indicating that positive parent-child relationship (r=-0.15, 95% CI-0.18 to -0.11; P<.05) effectively mitigate the risks of digital addiction. Conversely, urban residence (odds ratio [OR] 2.32, 95% CI 1.19-4.53; P<.001), adverse childhood experiences (r=0.21, 95% CI 0.18-0.24; P<.001), and social anxiety (r=0.34, 95% CI 0.19-0.48; P<.001) were identified as factors that may increase the risk of developing digital addiction. This study found that social factors such as urban residence were associated with an increased risk of digital addiction, whereas social support served as a protective factor against this risk. Nonetheless, the methodologies used in analyzing the factors related to digital addiction require further refinement.

Background Nicotine is known to influence metabolism and body weight, yet existing murine models of nicotine exposure often fail to replicate human smoking behaviors accurately. To address this gap, we designed a cost-effective, self-administered nicotine inhalation system that allows mice to voluntarily inhale nicotine vapor generated from e-liquid. Results Using this system, we investigated the metabolic effects of nicotine exposure in adult and adolescent mice. Adult mice exposed to nicotine vapor for 10 days exhibited significant weight loss, which was rapidly regained upon cessation, paralleling human smoking patterns. In contrast, adolescent mice did not lose weight during nicotine exposure but experienced increased fat mass accumulation after cessation. These results highlight critical age-dependent differences in nicotine’s metabolic effects and challenge the common perception that nicotine aids in weight control among adolescents. Conclusions Our novel e-liquid–based inhalation model provides a valuable tool for studying nicotine’s physiological and behavioral effects, with implications for understanding smoking-related health risks and addiction mechanisms.