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Background The aim of this study was to characterize the variable phenotypes and outcomes associated with the methylmalonic aciduria and homocystinuria type C protein gene ( MMACHC ) c.482G > A mutation in 195 Chinese cases with CblC disease. Methods We carried out a national, retrospective multicenter study of 195 Chinese patients with CblC disease attributable to the MMACHC c.482G > A variant either in a homozygous or compound heterozygous state. The control group consisted of 200 patients diagnosed with CblC disease who did not possess the c.482G > A mutation. Clinical features, including disease onset, symptoms, biochemical metabolites, gene mutation, and follow-up outcomes were reviewed and analyzed in detail. The median follow-up period spanned 3 years and 8 months, with a range of 1 year and 2 months to 12 years and 10 months. Results Among 195 patients carrying the c.482G > A variant, 125 (64.1%) cases were diagnosed by newborn screening (NBS), 60 (30.8%) cases were detected due to disease onset, and 10 (5.1%) cases were identified from sibling diagnoses. One hundred and seventeen (93.6%) individuals who were diagnosed by NBS, and nine patients who came from sibling diagnoses remained asymptomatic in this study. From 69 symptomatic patients of the c.482G > A group, more patients presented with later onset, and the top six common clinical symptoms at disease onset were developmental delay (59.4%), lower limb weakness and poor exercise tolerance (50.7%), cognitive decline (37.7%), gait instability and abnormal posture (36.2%), seizures (26.1%), and psychiatric and behavioral disturbances (24.6%). In the 159 symptomatic patients lacking c.482G > A variants, the most frequently observed clinical manifestations at disease onset included developmental delay (81.8%), lethargy and feeding difficulty (62.9%), lower limb weakness and poor exercise tolerance (54.7%), prolonged neonatal jaundice (51.6%), vomiting (47.2%), and seizures (32.7%). Before treatment, the levels of blood propionylcarnitine, propionylcarnitine/acetylcarnitine ratio, and homocysteine in the c.482G > A group were significantly lower ( P  < 0.05) than those in the non-c.482G > A group, while the concentration of urinary methylmalonic acid was slightly lower ( P  > 0.05). The degree of decline in the above metabolites after treatment in different groups significantly differed in both plasma total homocysteine values and urinary methylmalonic acid levels ( P  < 0.05). In patients carrying the c.482G > A variant compared with the non-c.428G > A group, there were markedly lower rates of mortality (0.5% vs. 2.0%) and developmental delay (20.5% vs. 65.5%). When compared with individuals diagnosed due to disease onset, those identified through NBS in either group exhibited a reduced proportion of disease onset (6.7% vs. 100% in the c.482G > A group, 54.4% vs. 100% in the non-c.482G > A group), lower mortality (0.0% vs. 1.7% in the c.482G > A group, 0.0% vs. 3.6% in the non-c.482G > A group), and had a higher percentage of patients exhibiting normal psychomotor and language development (99.3% vs. 33.3% in the c.482G > A group, 58.9% vs. 10.9% in the non-c.482G > A group). Conclusions The c.482G > A variant in MMACHC is associated with late-onset and milder phenotypes of CblC disease. Patients with this mutation tend to have a relatively better response to hydroxocobalamin, better metabolic control, and more favorable neurological outcomes. NBS and other appropriate pre-symptomatic treatments seem to be helpful in early diagnosis, resulting in favorable clinical outcomes. CNU96JjhPhuCQHh9ViZTVJ Video Abstract (MP4 136794 kb)

Background The aim of this study was to characterize the variable phenotypes and outcomes associated with the meth-ylmalonic aciduria and homocystinuria type C protein gene(MMACHC)c.482G＞A mutation in 195 Chinese cases with CbIC disease. Methods We carried out a national,retrospective multicenter study of 195 Chinese patients with CbIC disease attributable to the MMACHC c.482G＞A variant either in a homozygous or compound heterozygous state.The control group consisted of 200 patients diagnosed with CbIC disease who did not possess the c.482G＞A mutation.Clinical features,including disease onset,symptoms,biochemical metabolites,gene mutation,and follow-up outcomes were reviewed and analyzed in detail.The median follow-up period spanned 3 years and 8 months,with a range of 1 year and 2 months to 12 years and 10 months. Results Among 195 patients carrying the c.482G＞A variant,125(64.1％)cases were diagnosed by newborn screening(NBS),60(30.8％)cases were detected due to disease onset,and 10(5.1％)cases were identified from sibling diagnoses.One hundred and seventeen(93.6％)individuals who were diagnosed by NBS,and nine patients who came from sibling diagnoses remained asymptomatic in this study.From 69 symptomatic patients of the c.482G＞A group,more patients presented with later onset,and the top six common clinical symptoms at disease onset were developmental delay(59.4％),lower limb weakness and poor exercise tolerance(50.7％),cognitive decline(37.7％),gait instability and abnormal posture(36.2％),seizures(26.1％),and psychiatric and behavioral disturbances(24.6％).In the 159 symptomatic patients lacking c.482G＞A variants,the most frequently observed clinical manifestations at disease onset included developmental delay(81.8％),lethargy and feeding difficulty(62.9％),lower limb weakness and poor exercise tolerance(54.7％),prolonged neo-natal jaundice(51.6％),vomiting(47.2％),and seizures(32.7％).Before treatment,the levels of blood propionylcarnitine,propionylcarnitine/acetylcarnitine ratio,and homocysteine in the c.482G＞A group were significantly lower(P＜0.05)than those in the non-c.482G＞A group,while the concentration of urinary methylmalonic acid was slightly lower(P＞0.05).The degree of decline in the above metabolites after treatment in different groups significantly differed in both plasma total homocysteine values and urinary methylmalonic acid levels(P＜0.05).In patients carrying the c.482G＞A variant compared with the non-c.428G＞A group,there were markedly lower rates of mortality(0.5％vs.2.0％)and developmental delay(20.5％vs.65.5％).When compared with individuals diagnosed due to disease onset,those identified through NBS in either group exhibited a reduced proportion of disease onset(6.7％vs.100％in the c.482G＞A group,54.4％vs.100％in the non-c.482G＞A group),lower mortality(0.0％vs.1.7％in the c.482G＞A group,0.0％vs.3.6％in the non-c.482G＞A group),and had a higher percentage of patients exhibiting normal psychomotor and language development(99.3％vs.33.3％in the c.482G＞A group,58.9％vs.10.9％in the non-c.482G＞A group). Conclusions The c.482G＞A variant in MMACHC is associated with late-onset and milder phenotypes of CbIC disease.Patients with this mutation tend to have a relatively better response to hydroxocobalamin,better metabolic control,and more favorable neurological outcomes.NBS and other appropriate pre-symptomatic treatments seem to be helpful in early diagnosis,resulting in favorable clinical outcomes.

Apigenin, a widely distributed flavone, exhibits excellent antioxidant, anti-inflammatory, and antitumor properties. In addition, the methylation of apigenin is generally considered to result in better absorption and greatly increased bioavailability. Here, four putative Class II methyltransferase genes were identified from the transcriptome sequences generated from the liverwort species Plagiochasma appendiculatum. Each was heterologously expressed as a His-fusion protein in Escherichia coli and their methylation activity against apigenin was tested. One of the four Class II OMT enzymes named 4′-O-methyltransferase (Pa4′OMT) was shown to react effectively with apigenin, catalyzing its conversion to acacetin. Besides the favorite substrate apigenin, the recombinant PaF4′OMT was shown to catalyze luteolin, naringenin, kaempferol, quercetin, genistein, scutellarein, and genkwanin to the corresponding 4′-methylation products. In vivo feeding experiments indicated that PaF4′OMT could convert apigenin to acacetin efficiently in E. coli and approximately 88.8 µM (25.2 mg/L) of product was synthesized when 100 µM of apigenin was supplemented. This is the first time that a Class II plant O-methyltransferase has been characterized in liverworts.

Global warming and socio-economic development are together prompting a surge in the use of air-conditioning (AC). Yet the technology that delivers thermal comfort also emits large quantities of greenhouse gases (GHG), exacerbating climate change. We quantify global AC-related GHGs and associated warming impact under five climate scenarios, separating the contributions of global warming and socio-economic development. In a middle-of-the-road scenario (SSP245), cumulative AC-related emissions reach 113.3 GtCO 2 eq between 2010 and 2050, increasing global-mean temperature by 0.05 °C (0.03 °C-0.07 °C), with only about 8.3% to climate-driven cooling demand. Income inequalities exacerbate disparities in AC use, substantially limiting access to cooling in lower-income regions. While rising incomes reduce this inequality, they increase emissions: income-driven AC growth adds 14–146 GtCO 2 eq and a further 0.003–0.05 °C of warming by 2050, even under SSP119. These results highlight the need for a rapid low-carbon cooling transition that balances total warming impacts with equitable cooling access. This study shows that rising incomes and hotter climates are driving a boom in air conditioning use, which adds to global warming. This highlights the need for clean, efficient and equitable cooling solutions.

Background/Objectives: Baichuan Baile (BCBL), a novel functional dietary formula, has been shown to exert antidepressant-like effects through modulation of the 5-HT system in our prior studies. Given the close neurobiological connections between depression and insomnia, along with its pharmacodynamic profile guided by TCM theory and nutritional assessments, BCBL is likely to possess beneficial effects against insomnia. However, this hypothesis and its underlying mechanisms require further validation. Methods: The chemical constituents of BCBL were analyzed by UPLC-Q-TOF-MS, and network pharmacology was applied to predict potential sleep-relevant targets and pathways. Subsequently, BCBL was evaluated for sedative-hypnotic effects using pentobarbital-induced hypnosis, locomotor activity, and polysomnography (EEG/EMG). Its therapeutic efficacy was further assessed in insomnia models induced by environmental stress, serotonin depletion, and rotarod-based sleep deprivation. The rotarod-induced chronic model was selected for mechanistic studies due to its sustained insomnia-like phenotype. Finally, key network-predicted targets were validated in this model through histopathology, Western blotting, and ELISA. Results: Pharmacological evaluation confirmed that BCBL significantly promoted sleep at both behavioral and EEG levels, confirming its sedative-hypnotic properties. BCBL mitigated environmental stress-triggered impairments in NREM sleep continuity and duration, and exerted protective effects against body weight loss and sleep disturbances in a serotonin depletion-induced insomnia model. In the rotarod sleep deprivation model, BCBL treatment increased spontaneous alternation rates and recognition indices, ameliorated hippocampal pathological alterations, and reduced hippocampal levels of HIF-1α, TNF-α, and IL-1β. Furthermore, BCBL elevated the p-GSK3β/GSK3β ratio and enhanced SIRT1 expression in the hypothalamus. It also modulated the activity of key sleep–wake neurotransmitters/neuromodulators (serotonin, dopamine, adenosine, and glutamate) and key circadian rhythm regulators (BMAL1, PER2, and CLOCK) in this region. Conclusions: BCBL exhibits significant therapeutic efficacy against insomnia, indicating its potential as a dietary supplement for managing insomnia. Its mechanisms appear to involve anti-inflammatory effects, rebalancing of neurotransmitters/neuromodulators, and stabilization of circadian rhythm gene expression.

Background/Objectives: Hypericum perforatum L. (H. perforatum), commonly known as St. John’s wort, has been widely used in clinical practice to treat mental disorders. Previous studies and clinical applications have primarily focused on its alcohol-soluble ingredients. Our research was designed to investigate the physicochemical properties, antidepressant-like effects, and anti-post-traumatic stress disorder (PTSD)-like effects of the alcohol-insoluble polysaccharide-rich ingredients from H. perforatum. Meanwhile, the underlying mechanisms were elucidated. Methods: The physicochemical properties of two polysaccharide-rich ingredients, designated as HPP1 and HPP2, were characterized using colorimetric assay, capillary electrophoresis, high-performance gel permeation chromatography, and fourier transform infrared spectroscopy. Behavioral despair tests were conducted to rapidly assess and compare their antidepressant-like effects in mice. Subsequently, behavioral despair mice and foot-shock mice were established to thoroughly explore the impact of HPP2 on depression-like and PTSD-like symptoms. The effects of HPP2 on cerebral pathological changes, neurotrophic factors, and gut microbiota in foot-shock mice were detected through hematoxylin & eosin staining, immunofluorescence staining, and 16S rDNA (V3 + V4 regions) gene sequencing. Results: HPP1 and HPP2 are predominantly composed of arabinose, glucose, galactose, mannose, and galacturonic acid. The molecular weight distribution of HPP1 ranges from 1133 to 67,278 Da, whereas that of HPP2 extends from 1493 to 38,407 Da. Acute pre-treatment with HPP1 or HPP2 (200 mg/kg, i.g.) could reduce mice’s immobility in behavioral despair tests, with HPP2 exhibiting superior efficacy. Additionally, both acute and sub-chronic pre-treatment with HPP2 (50, 200, and 800 mg/kg, i.g.) effectively alleviated depression-like symptoms in behavioral despair mice. Prolonged pre-treatment with HPP2 (200 mg/kg, i.g.) also mitigated the slow increase in body weight and behavioral abnormalities in foot-shock mice. Furthermore, HPP2 (200 mg/kg) successfully restored hippocampal histomorphological abnormalities, neurotrophic disturbance, and dysregulation of the gut microbiota in foot-shock mice. Conclusions: HPP2 exerts noteworthy antidepressant-like and anti-PTSD-like impact in mouse models via multiple targets, indicating a potential therapeutic candidate in depression and PTSD therapy.

Aiming at the problems of high friction coefficient, severe wear, and unsatisfactory service life and operational reliability of brass under complex working conditions such as dry friction, wet friction, and oil-lubricated friction, H62 brass was taken as the research object to improve its friction and wear properties via surface micro-texture technology. This study systematically compares the tribological performance of three typical geometric micro-textures under three coupled working conditions for the first time. Circular, rectangular, and hexagonal micro-dimple textures were fabricated on the brass surface using ultraviolet laser micromachining. The control variable method was adopted to systematically investigate the effects of micro-texture parameters including shape, size, and area density on the friction and wear properties of brass under the three typical working conditions, combined with reciprocating friction and wear tests and ultra-depth-of-field microscope characterization. The results show that the hexagonal micro-dimple texture (200 μm in size, 10% in area density) exhibits the optimal friction-reducing and anti-wear performance. Compared with the smooth surface, the friction coefficient decreases from 0.51 to 0.43, and the wear rate of the GCr15 steel ball is reduced by 2.8% under dry friction; the friction coefficient decreases from 0.43 to 0.12 with an 11.8% reduction in wear rate under wet friction; and the friction coefficient decreases from 0.29 to 0.24 with an 8.3% reduction in wear rate under oil lubrication. Relative to dry friction, the wear rates are further reduced by 16.7% and 8.3% under wet friction and oil lubrication, respectively. Different from most existing studies that only focus on a single texture type or a single friction condition, this paper systematically reveals the coupling regulation mechanism between texture parameters and working conditions, clarifies the optimal micro-texture design strategy for multi-working conditions, verifies that hexagonal micro-textures can significantly improve the wear resistance of brass, and provides technical support for the surface optimization design of brass workpieces under complex working conditions.

Ischemic stroke is a major cause of mortality and disability worldwide. As a part of Traditional Chinese Medicine (TCM), acupuncture has been shown to be effective in promoting recovery after stroke. In this article, we review the clinical and experimental studies that demonstrated the mechanisms of acupuncture treatment for cerebral ischemia. Clinical studies indicated that acupuncture activated relevant brain regions, modulated cerebral blood flow and related molecules in stroke patients. Evidence from laboratory indicated that acupuncture regulates cerebral blood flow and metabolism after the interrupt of blood supply. Acupuncture regulates multiple molecules and signaling pathways that lead to excitoxicity, oxidative stress, inflammation, neurons death and survival. Acupuncture also promotes neurogenesis, angiogenesis as well as neuroplasticity after ischemic damage. The evidence provided from clinical and laboratory suggests that acupuncture induces multi-level regulation via complex mechanisms and a single factor may not be enough to explain the beneficial effects against cerebral ischemia.

IntroductionThe 5th generation (5G) mobile communication and Beidou navigation system (BDS) antennas of offshore small maritime unmanned vehicles (SMUV) are shaken by waves and winds in harsh sea conditions, resulting in poor stability in positioning trajectory tracking and varying degrees of impulse noise in pseudo-range measurements.MethodsTherefore, A Kalman filter algorithm combining approximate message passing (AMP) and variational Bayesian (VB) is proposed under a fusion positioning model of 5G and BDS with a high update rate. The AMP algorithm can predict the instantaneous position movement caused by waves, and the VB algorithm smooths the pulse error of trajectory tracking caused by intermittent shielding.ResultsExperimental results demonstrate that, in 100 positioning epochs, when the impact of waves on SMUV is 20 times, 30 times and 40 times, the root mean square error of the proposed algorithm is 1.19 meter (m), 1.26 m and 1.27 m respectively. Compared with the adaptive variational Bayesian algorithm, the positioning accuracy is improved by 7.75%, 16.4% and 24.4%, which obviously enhances the stability of positioning.DiscussionThe proposed algorithm can achieve high-precision positioning and tracking, and the performance of the algorithm is better than that of the comparison scheme when the amplitude and frequency of the waves are greater.

The function of nuclear receptor corepressor 1 (NCoR1) in cardiomyocytes is unclear, and its physiological and pathological implications are unknown. Here, we found that cardiomyocyte‐specific NCoR1 knockout (CMNKO) mice manifested cardiac hypertrophy at baseline and had more severe cardiac hypertrophy and dysfunction after pressure overload. Knockdown of NCoR1 exacerbated whereas overexpression mitigated phenylephrine‐induced cardiomyocyte hypertrophy. Mechanistic studies revealed that myocyte enhancer factor 2a (MEF2a) and MEF2d mediated the effects of NCoR1 on cardiomyocyte hypertrophy. The receptor interaction domains (RIDs) of NCoR1 interacted with MEF2a to repress its transcriptional activity. Furthermore, NCoR1 formed a complex with MEF2a and class IIa histone deacetylases (HDACs) to suppress hypertrophy‐related genes. Finally, overexpression of RIDs of NCoR1 in the heart attenuated cardiac hypertrophy and dysfunction induced by pressure overload. In conclusion, NCoR1 cooperates with MEF2 and HDACs to repress cardiac hypertrophy. Targeting NCoR1 and the MEF2/HDACs complex may be an attractive therapeutic strategy to tackle pathological cardiac hypertrophy. Synopsis Cardiac hypertrophy constitutes an important risk for heart failure. In this study, NCoR1 was identified as a critical suppressor of cardiac hypertrophy via interaction with MEF2/HDACs. NCoR1 deficiency in cardiomyocytes led to spontaneous cardiac hypertrophy in mice, and exacerbated pressure overload‐induced cardiac hypertrophy and heart failure. NCoR1 was recruited to the promoter region of hypertrophy‐related genes to suppress their expression though interacting with MEF2/Class IIa HDACs. The NCoR1 receptor interaction domain mediated NCoR1/MEF2 interaction and was sufficient to repress cardiomyocyte hypertrophy both in vitro and in vivo . Graphical Abstract Cardiac hypertrophy constitutes an important risk for heart failure. In this study, NCoR1 was identified as a critical suppressor of cardiac hypertrophy via interaction with MEF2/HDACs.